Intravenous methylprednisolone pulses in hospitalised patients with severe COVID-19 pneumonia: a double-blind, randomised, placebo-controlled trial.

RATIONALE: Pulse glucocorticoid therapy is used in hyperinflammation related to coronavirus disease 2019 (COVID-19). We evaluated the efficacy and safety of pulse intravenous methylprednisolone in addition to standard treatment in COVID-19 pneumonia. METHODS: In this multicentre, randomised, double-blind, placebo-controlled trial, 304 hospitalised patients with COVID-19 pneumonia were randomised to receive 1 g of methylprednisolone intravenously for three consecutive days or placebo in addition to standard dexamethasone. The primary outcome was the duration of patient hospitalisation, calculated as the time interval between randomisation and hospital discharge without the need for supplementary oxygen. The key secondary outcomes were survival free from invasive ventilation with orotracheal intubation and overall survival. RESULTS: Overall, 112 (75.4%) out of 151 patients in the pulse methylprednisolone arm and 111 (75.2%) of 150 in the placebo arm were discharged from hospital without oxygen within 30 days from randomisation. Median time to discharge was similar in both groups (15 days, 95% CI 13.0-17.0 days and 16 days, 95% CI 13.8-18.2 days, respectively; hazard ratio (HR) 0.92, 95% CI 0.71-1.20; p=0.528). No significant differences between pulse methylprednisolone and placebo arms were observed in terms of admission to intensive care unit with orotracheal intubation or death (20.0% versus 16.1%; HR 1.26, 95% CI 0.74-2.16; p=0.176) or overall mortality (10.0% versus 12.2%; HR 0.83, 95% CI 0.42-1.64; p=0.584). Serious adverse events occurred with similar frequency in the two groups. CONCLUSIONS: Methylprenisolone pulse therapy added to dexamethasone was not of benefit in patients with COVID-19 pneumonia.

Effect of Tocilizumab vs Standard Care on Clinical Worsening in Patients Hospitalized With COVID-19 Pneumonia: A Randomized Clinical Trial.

Importance: The coronavirus disease 2019 (COVID-19) pandemic is threatening billions of people worldwide. Tocilizumab has shown promising results in retrospective studies in patients with COVID-19 pneumonia with a good safety profile. Objective: To evaluate the effect of early tocilizumab administration vs standard therapy in preventing clinical worsening in patients hospitalized with COVID-19 pneumonia. Design, Setting, and Participants: Prospective, open-label, randomized clinical trial that randomized patients hospitalized between March 31 and June 11, 2020, with COVID-19 pneumonia to receive tocilizumab or standard of care in 24 hospitals in Italy. Cases of COVID-19 were confirmed by polymerase chain reaction method with nasopharyngeal swab. Eligibility criteria included COVID-19 pneumonia documented by radiologic imaging, partial pressure of arterial oxygen to fraction of inspired oxygen (Pao2/Fio2) ratio between 200 and 300 mm Hg, and an inflammatory phenotype defined by fever and elevated C-reactive protein. Interventions: Patients in the experimental arm received intravenous tocilizumab within 8 hours from randomization (8 mg/kg up to a maximum of 800 mg), followed by a second dose after 12 hours. Patients in the control arm received supportive care following the protocols of each clinical center until clinical worsening and then could receive tocilizumab as a rescue therapy. Main Outcome and Measures: The primary composite outcome was defined as entry into the intensive care unit with invasive mechanical ventilation, death from all causes, or clinical aggravation documented by the finding of a Pao2/Fio2 ratio less than 150 mm Hg, whichever came first. Results: A total of 126 patients were randomized (60 to the tocilizumab group; 66 to the control group). The median (interquartile range) age was 60.0 (53.0-72.0) years, and the majority of patients were male (77 of 126, 61.1%). Three patients withdrew from the study, leaving 123 patients available for the intention-to-treat analyses. Seventeen patients of 60 (28.3%) in the tocilizumab arm and 17 of 63 (27.0%) in the standard care group showed clinical worsening within 14 days since randomization (rate ratio, 1.05; 95% CI, 0.59-1.86). Two patients in the experimental group and 1 in the control group died before 30 days from randomization, and 6 and 5 patients were intubated in the 2 groups, respectively. The trial was prematurely interrupted after an interim analysis for futility. Conclusions and Relevance: In this randomized clinical trial of hospitalized adult patients with COVID-19 pneumonia and Pao2/Fio2 ratio between 200 and 300 mm Hg who received tocilizumab, no benefit on disease progression was observed compared with standard care. Further blinded, placebo-controlled randomized clinical trials are needed to confirm the results and to evaluate possible applications of tocilizumab in different stages of the disease. Trial Registration: ClinicalTrials.gov Identifier: NCT04346355; EudraCT Identifier: 2020-001386-37.

Multiple origins and regional dispersal of resistant dhps in African Plasmodium falciparum malaria.

BACKGROUND: Although the molecular basis of resistance to a number of common antimalarial drugs is well known, a geographic description of the emergence and dispersal of resistance mutations across Africa has not been attempted. To that end we have characterised the evolutionary origins of antifolate resistance mutations in the dihydropteroate synthase (dhps) gene and mapped their contemporary distribution. METHODS AND FINDINGS: We used microsatellite polymorphism flanking the dhps gene to determine which resistance alleles shared common ancestry and found five major lineages each of which had a unique geographical distribution. The extent to which allelic lineages were shared among 20 African Plasmodium falciparum populations revealed five major geographical groupings. Resistance lineages were common to all sites within these regions. The most marked differentiation was between east and west African P. falciparum, in which resistance alleles were not only of different ancestry but also carried different resistance mutations. CONCLUSIONS: Resistant dhps has emerged independently in multiple sites in Africa during the past 10-20 years. Our data show the molecular basis of resistance differs between east and west Africa, which is likely to translate into differing antifolate sensitivity. We have also demonstrated that the dispersal patterns of resistance lineages give unique insights into recent parasite migration patterns.

Monitoring for multidrug-resistant Plasmodium falciparum isolates and analysis of pyrimethamine resistance evolution in Uige province, Angola.

OBJECTIVES: To assess the extent of drug resistance in Uige through molecular genetic analysis and to test whether the dhfr triple mutant alleles present in Angola are of southeast Asian origin. METHODS: Seventy-one samples of blood from children admitted to the Pediatric Emergency Unit of Uige Provincial Hospital in 2004 were screened for resistance mutations at pfcrt, pfmdr1, pfdhfr, pfdhps and pfATPase6. RESULTS: Mutations in pfcrt (codon76), pfmdr1 (codon86), pfdhfr (codons 51, 59, 108) and pfdhps (codons 436, 437) were common. Among the 66 isolates for which we were able to determine complete genetic information 13.7% carried all seven of these mutations. Flanking microsatellite analysis revealed the triple mutant pfdhfr was derived from the southeast Asian lineage, while the N51I+S108N double mutant pfdhfr alleles are a local origin. pfATPase6 mutations were rare and S769N was not found. CONCLUSION: The parasite population of Uige Angola has high frequency mutations in pfcrt, dhfr and dhps associated with resistance to chloroquine and sulphadoxine pyrimethamine, reflecting past reliance on these two drugs which were the mainstay of treatment until recently. Our findings show that drug resistance in Uige has occurred through a combination of local drug pressure and the regional and international dispersal of resistance mutant alleles.

Desimplification to multi-tablet antiretroviral regimens in human immunodeficiency virus-type 1 infected adults: A cohort study.

BACKGROUND: Highly active antiretroviral therapy (HAART) is provided free of charge to all human immunodeficiency virus (HIV) positive residents in Italy. As fixed dose coformulations (FDCs) are often more expensive in comparison to the same drugs administered separately in a multi-tablet regimen (MTR), we considered a cost-effective strategy involving patients in the switch from their FDCs to corresponding MTRs including generic antiretrovirals. AIM: To verify if this would affect the virological and immunological response in comparison to maintaining the FDC regimens. METHODS: From January 2012 to December 2013, we assessed the eligibility of all the HIV-1 positive adults on stable HAART being treated at our hospital-based outpatient clinic in Treviso, Italy. Participants who accepted to switch from their FDC regimen to the corresponding MTR joined the MTR group, while those who maintained a FDC regimen joined the FDC group. Clinical data, including changes in HAART regimens, respective reasons why and adverse effects, were recorded at baseline and at follow-up visits occurring at weeks 24, 48 and 96. All participants were assessed for virological and immunological responses at baseline and at weeks 24, 48 and 96. RESULTS: Two hundred and forty-three eligible HIV-1 adults on HAART were enrolled: 163 (67%) accepted to switch to a MTR, joining the MTR group, while 80 (33%) maintained their FDCs, joining the FDC group. In a parallel analysis, there were no significant differences in linear trend of distribution of HIV-RNA levels between the two groups and there were no significant odds in favour of a higher level of HIV-RNA in either group at any follow-up and on the overall three strata analysis. In a before-after analysis, both FDC and MTR groups presented no significant differences in distribution of HIV-RNA levels at either weeks 48 vs 24 and weeks 96 vs 24 cross tabulations. A steady increase of mean CD4 count was observed in the MTR group only, while in the FDC group we observed a slight decrease (-23 cells per mmc) between weeks 24 and 48. CONCLUSION: Involving patients in the switch from their FDC regimens to the corresponding MTRs for economic reasons did not affect the effectiveness of antiretroviral therapy in terms of virological response and immunological recovery.

Mycobacterium chimaera infections following cardiac surgery in Treviso Hospital, Italy, from 2016 to 2019: Cases report.

BACKGROUND: An epidemic of Mycobacterium chimaera (M. chimaera) infections following cardiac surgery is ongoing worldwide. The outbreak was first discovered in 2011, and it has been traced to a point source contamination of the LivaNova 3T heater-cooler unit, which is used also in Italy. International data are advocated to clarify the spectrum of clinical features of the disease as well as treatment options and outcome. We report a series of M. chimaera infections diagnosed in Treviso Hospital, including the first cases notified in Italy in 2016. CASE SUMMARY: Since June 2016, we diagnosed a M. chimaera infection in nine patient who had undergone cardiac valve surgery between February 2011 and November 2016. The time between cardiac surgery and developing symptoms ranged from 6 to 97 mo. Unexplained fever, psychophysical decay, weight loss, and neurological symptoms were common complaints. The median duration of symptoms was 32 wk, and the longest was almost two years. A new cardiac murmur, splenomegaly, choroidoretinitis, anaemia or lymphopenia, abnormal liver function tests and hyponatremia were common findings. All the patients presented a prosthetic valve endocarditis, frequently associated to an ascending aortic pseudoneurysm or spondylodiscitis. M. chimaera was cultured from blood, bioprosthetic tissue, pericardial abscess, vertebral tissue, and bone marrow. Mortality is high in our series, reflecting the poor outcome observed in other reports. Three patients have undergone repeat cardiac surgery. Five patients are being treated with a targeted multidrug antimycobacterial regimen. CONCLUSION: Patients who have undergone cardiac surgery in Italy and presenting with signs and symptoms of endocarditis must be tested for M. chimaera.

[Tuberculous peritonitis: experience in Treviso from 2000 to 2010]. / Peritonite tubercolare: esperienza di Treviso nel decennio 2000-2010.

Peritonitis is an uncommon localization of tuberculosis in Italy; diagnosis and treatment are often difficult and delayed. Fifteen cases, followed by Infectious Diseases Department in Treviso from 2000 to 2010, are described. Mortality and long term complications were absent, in contrast with medical literature. The usefulness of steroid therapy is still uncertain. Other sites of infection were present in 60 percent of patients (pulmonary TB in 47%), urging the clinician to examine the case promptly to determine infectiousness status.

Progressive disseminated histoplasmosis among human immunodeficiency virus-infected patients from West-Africa: report of four imported cases in Italy.

We report four imported cases of progressive disseminated histoplasmosis (PDH) due to Histoplasma capsulatum variety capsulatum in Human Immunodeficiency Virus-infected patients from West Africa. This report highlights the need to consider diagnosis of PDH among patients with acquired immunodeficiency syndrome who originate from West Africa and present with a prolonged febrile illness and very low CD4 count.

Diagnosing human African trypanosomiasis in Angola using a card agglutination test: observational study of active and passive case finding strategies.

OBJECTIVE: To assess the operational feasibility of detecting human African trypanosomiasis by active and passive case finding using the card agglutination test with serial dilution of serum to guide treatment. SETTING: Trypanosomiasis control programme in the Negage focus, northern Angola, during a period of civil war. DESIGN: Observational study. PARTICIPANTS: 359 patients presenting themselves to health centres with symptoms (passive case finding) and 14,446 people actively screened in villages. MAIN OUTCOME MEASURES: Whole blood and serological tests at different dilutions using the card agglutination test, and detection of parasites by microscopy. RESULTS: Active case finding identified 251 people with a positive card agglutination test result, 10 of whom had confirmed parasites. In those presenting for investigation 34 of 51 with a positive card agglutination test result at the dilution of 1:8 or more used to guide treatment had parasites in blood, lymph node fluid, or cerebrospinal fluid, compared with 10 of 76 in those detected by active case finding: positive predictive values of 67% for passive case detection and 13% for active case detection. Only at a cut-off dilution more than 1:32 was the positive predictive value in active case detection reasonable (46%) and at this dilution 40% of microscopically proved cases were missed. CONCLUSIONS: The card agglutination test is useful for initial screening in active detection of cases with human African trypanosomiasis but, given the toxicity of the drugs, serology using the card agglutination test should be not used alone to guide treatment after active case finding. A second confirmatory test is needed.