Transitions of blood immune endotypes and improved outcome by anakinra in COVID-19 pneumonia: an analysis of the SAVE-MORE randomized controlled trial.

BACKGROUND: Endotype classification may guide immunomodulatory management of patients with bacterial and viral sepsis. We aimed to identify immune endotypes and transitions associated with response to anakinra (human interleukin 1 receptor antagonist) in participants in the SAVE-MORE trial. METHODS: Adult patients hospitalized with radiological findings of PCR-confirmed severe pneumonia caused by SARS-CoV-2 and plasma-soluble urokinase plasminogen activator receptor levels of ≥ 6 ng/ml in the SAVE-MORE trial (NCT04680949) were characterized at baseline and days 4 and 7 of treatment using a previously defined 33-messenger RNA classifier to assign an immunological endotype in blood. Endpoints were changes in endotypes and progression to severe respiratory failure (SRF) associated with anakinra treatment. RESULTS: At baseline, 23.2% of 393 patients were designated as inflammopathic, 41.1% as adaptive, and 35.7% as coagulopathic. Only 23.9% were designated as the same endotype at days 4 and 7 compared to baseline, while all other patients transitioned between endotypes. Anakinra-treated patients were more likely to remain in the adaptive endotype during 7-day treatment (24.4% vs. 9.9%; p < 0.001). Anakinra also protected patients with coagulopathic endotype at day 7 against SRF compared to placebo (27.8% vs. 55.9%; p = 0.013). CONCLUSION: We identify an association between endotypes defined using blood transcriptome and anakinra therapy for COVID-19 pneumonia, with anakinra-treated patients shifting toward endotypes associated with a better outcome, mainly the adaptive endotype. Trial registration ClinicalTrials.gov, NCT04680949, December 23, 2020.

Endemic Systemic Mycoses in Italy: A Systematic Review of Literature and a Practical Update.

Endemic systemic mycoses such as blastomycosis, coccidioidomycosis, histoplasmosis, talaromycosis, paracoccidioidomycosis are emerging as an important cause of morbidity and mortality worldwide. We conducted a systematic review on endemic systemic mycoses reported in Italy from 1914 to nowadays. We found out: 105 cases of histoplasmosis, 15 of paracoccidioidomycosis, 10 of coccidioidomycosis, 10 of blastomycosis and 3 of talaromycosis. Most cases have been reported in returning travelers and expatriates or immigrants. Thirtytwo patients did not have a story of traveling to an endemic area. Fortysix subjects had HIV/AIDS. Immunosuppression was the major risk factor for getting these infections and for severe outcomes. We provided an overview on microbiological characteristics and clinical management principles of systemic endemic mycoses with a focus on the cases reported in Italy.

Critical analysis of Chagas disease treatment in different countries.

As a result of globalization and constant migratory flows, Chagas disease is now present in almost all continents. The management and treatment of the disease is often influenced by the economic and social context of the societies that host patients. In this manuscript, we aim to provide a comparative review of approaches to patients with Chagas disease in the Americas and Europe.

The challenge of infectious diseases consultations in the emergency department: an Italian nationwide survey.

Diagnosis and management of infectious diseases (ID) at the emergency department (ED) are challenging due to the peculiar setting and the available diagnostic tools. The involvement of an ID consultant has been described to improve clinical outcomes and antimicrobial stewardship (AMS) programs. An online survey was sent to 100 Italian Departments of Infectious Diseases affiliated with the Italian Society of Infectious Diseases and Tropical Medicine (SIMIT). The primary objective of our study was to describe the characteristics of ID services in Italian EDs to identify possible challenges and shortcomings and provide tips to improve the management of patients. Secondary objectives included the evaluation of diagnostic capability and the management of patients with suspected or confirmed ID. Seventy-six out of the 100 SIMIT centers, 32 (42.1%) of which were teaching hospitals, answered the survey. In 62 (82.7%) centers, consultations were performed by the IDs specialist on call. In 29 (38.2%) centers, there was a formal AMS program, and 32 (42.7%) had protocols for antibiotic use in the ED. Microbiological tests to be performed before starting antibiotic treatment in the ED were clearly defined in 44 (57.9%) hospitals. This survey highlighted several challenges in the current organization of ID consultations in Italian EDs.

Longitudinal study based on a safety registry for malaria patients treated with artenimol-piperaquine in six European countries.

BACKGROUND: European travellers to endemic countries are at risk of malaria and may be affected by a different range of co-morbidities than natives of endemic regions. The safety profile, especially cardiac issues, of artenimol (previously dihydroartemisinin)-piperaquine (APQ) Eurartesim® during treatment of uncomplicated imported falciparum malaria is not adequately described due to the lack of longitudinal studies in this population. The present study was conducted to partially fill this gap. METHODS: Participants were recruited through Health Care Provider's safety registry in 15 centres across 6 European countries in the period 2013-2016. Adverse events (AE) were collected, with a special focus on cardiovascular safety by including electrocardiogram QT intervals evaluated after correction with either Bazett's (QTcB) or Fridericia's (QTcF) methods, at baseline and after treatment. QTcB and/or QTcF prolongation were defined by a value > 450 ms for males and children and > 470 ms for females. RESULTS: Among 294 participants, 30.3% were women, 13.7% of Caucasian origin, 13.5% were current smoker, 13.6% current alcohol consumer and 42.2% declared at least one illness history. The mean (SD) age and body mass index were 39.8 years old (13.2) and 25.9 kg/m2 (4.7). Among them, 75 reported a total of 129 AE (27 serious), 46 being suspected to be related to APQ (11 serious) and mostly labelled as due to haematological, gastrointestinal, or infection. Women and Non-African participants had significantly (p < 0.05) more AEs. Among AEs, 21 were due to cardiotoxicity (7.1%), mostly QT prolongation, while 6 were due to neurotoxicity (2.0%), mostly dizziness. Using QTcF correction, QT prolongation was observed in 17/143 participants (11.9%), only 2 of them reporting QTcF > 500 ms (milliseconds) but no clinical symptoms. Using QTcB correction increases of > 60 ms were present in 9 participants (6.3%). A trend towards increased prolongation was observed in those over 65 years of age but only a few subjects were in this group. No new safety signal was reported. The overall efficacy rate was 255/257 (99.2%). CONCLUSIONS: APQ appears as an effective and well-tolerated drug for treatment of malaria in patients recruited in European countries. AEs and QT prolongation were in the range of those obtained in larger cohorts from endemic countries. Trial registration This study has been registered in EU Post-Authorization Studies Register as EUPAS6942.

Efficacy of High-Dose Albendazole with Ivermectin for Treating Imported Loiasis, Italy.

We describe the outcomes of 16 cases of imported loiasis in Italy. Patients had microfilaremia <20,000/mL and were treated with high-dose albendazole for 28 days and a single dose of ivermectin. This combination might be an effective treatment option in nonendemic areas, when diethylcarbamazine, the drug of choice, is not available.

Benign acute viral myositis in African migrants: A clinical, serological, and pathological study.

BACKGROUND: Several viruses have been described as causes of acquired inflammatory myopathies; however, the mechanisms by which they cause muscle disease are still unclear. The aim of this study was to describe the laboratory features of benign acute myositis in a small case series. METHODS: A detailed pathological and serological analysis was performed in five African migrants who developed an acute viral myositis complicated by rhabdomyolysis. RESULTS: Muscle biopsies clearly documented an inflammatory myopathy with histological features similar to polymyositis including CD8+ T cells surrounding and invading nonnecrotic muscle fibers, CD68+ macrophages and major histocompatibility complex class I antigen upregulation. In addition, positivity for myositis-specific antibodies (MSA), in particular anti-aminoacyl tRNA synthetases, was found in the serum of two patients. CONCLUSIONS: Our study demonstrated that T-cell mediated injury occurs in muscle of patients with acute viral myositis, and that MSA may be present in the serum of these patients.

Neglected tropical diseases in Europe: rare diseases and orphan drugs?

Neglected tropical diseases are becoming more and more frequent in Europe due to the increasing immigration from endemic areas. Nonetheless specific treatments are scarcely available in many European countries, since they are neither officially licensed nor marketed. Only a few referral health centres can afford to access drugs for NTDs due to complex bureaucracy and high cost, importing or providing them via the WHO. Health professionals and institutions in this domain should solicit other stakeholders (such as NGOs, the civil society, scientific societies) to sensitize health authorities to improve access to treatment for such debilitating diseases.

A systematic review of transfusion-transmitted malaria in non-endemic areas.

BACKGROUND: Transfusion-transmitted malaria (TTM) is an accidental Plasmodium infection caused by whole blood or a blood component transfusion from a malaria infected donor to a recipient. Infected blood transfusions directly release malaria parasites in the recipient's bloodstream triggering the development of high risk complications, and potentially leading to a fatal outcome especially in individuals with no previous exposure to malaria or in immuno-compromised patients. A systematic review was conducted on TTM case reports in non-endemic areas to describe the epidemiological characteristics of blood donors and recipients. METHODS: Relevant articles were retrieved from Pubmed, EMBASE, Scopus, and LILACS. From each selected study the following data were extracted: study area, gender and age of blood donor and recipient, blood component associated with TTM, Plasmodium species, malaria diagnostic method employed, blood donor screening method, incubation period between the infected transfusion and the onset of clinical symptoms in the recipient, time elapsed between the clinical symptoms and the diagnosis of malaria, infection outcome, country of origin of the blood donor and time of the last potential malaria exposure. RESULTS: Plasmodium species were detected in 100 TTM case reports with a different frequency: 45% Plasmodium falciparum, 30% Plasmodium malariae, 16% Plasmodium vivax, 4% Plasmodium ovale, 2% Plasmodium knowlesi, 1% mixed infection P. falciparum/P. malariae. The majority of fatal outcomes (11/45) was caused by P. falciparum whilst the other fatalities occurred in individuals infected by P. malariae (2/30) and P. ovale (1/4). However, non P. falciparum fatalities were not attributed directly to malaria. The incubation time for all Plasmodium species TTM case reports was longer than what expected in natural infections. This difference was statistically significant for P. malariae (p = 0.006). A longer incubation time in the recipient together with a chronic infection at low parasite density of the donor makes P. malariae a subtle but not negligible risk for blood safety aside from P. falciparum. CONCLUSIONS: TTM risk needs to be taken into account in order to enhance the safety of the blood supply chain from donors to recipients by means of appropriate diagnostic tools.

Prospective comparative multi-centre study on imported Plasmodium ovale wallikeri and Plasmodium ovale curtisi infections.

BACKGROUND: Few previous retrospective studies suggest that Plasmodium ovale wallikeri seems to have a longer latency period and produces deeper thrombocytopaenia than Plasmodium ovale curtisi. Prospective studies were warranted to better assess interspecies differences. METHODS: Patients with imported P. ovale spp. infection diagnosed by thick or thin film, rapid diagnostic test (RDT) or polymerase chain reaction (PCR) were recruited between March 2014 and May 2017. All were confirmed by DNA isolation and classified as P. o. curtisi or P. o. wallikeri using partial sequencing of the ssrRNA gene. Epidemiological, analytical and clinical differences were analysed by statistical methods. RESULTS: A total of 79 samples (35 P. o. curtisi and 44 P. o. wallikeri) were correctly genotyped. Males predominate in wallikeri group (72.7%), whereas were 48.6% in curtisi group. Conversely, 74.3% of curtisi group were from patients of African ethnicity, whilst 52.3% of Caucasians were infected by P. o. wallikeri. After performing a multivariate analysis, more thrombocytopaenic patients (p = 0.022), a lower number of platelets (p = 0.015), a higher INR value (p = 0.041), and shorter latency in Caucasians (p = 0.034) were significantly seen in P. o. wallikeri. RDT sensitivity was 26.1% in P. o. curtisi and 42.4% in P. o. wallikeri. Nearly 20% of both species were diagnosed only by PCR. Total bilirubin over 3 mg/dL was found in three wallikeri cases. Two patients with curtisi infection had haemoglobin under 7 g/dL, one of them also with icterus. A wallikeri patient suffered from haemophagocytosis. Chemoprophylaxis failed in 14.8% and 35% of curtisi and wallikeri patients, respectively. All treated patients with various anti-malarials which included artesunate recovered. Diabetes mellitus was described in 5 patients (6.32%), 4 patients of wallikeri group and 1 curtisi. CONCLUSIONS: Imported P. o. wallikeri infection may be more frequent in males and Caucasians. Malaria caused by P. o. wallikeri produces more thrombocytopaenia, a higher INR and shorter latency in Caucasians and suggests a more pathogenic species. Severe cases can be seen in both species. Chemoprophylaxis seems less effective in P. ovale spp. infection than in P. falciparum, but any anti-malarial drug is effective as initial treatment. Diabetes mellitus could be a risk factor for P. ovale spp. infection.

Acute histoplasmosis in immunocompetent travelers: a systematic review of literature.

BACKGROUND: Histoplasmosis is a fungal infection highly endemic in the American continent. The disease can be severe in immunocompromised subjects. In immunocompetent subjects the clinical manifestations are variable. Aim of this work was to review the cases of acute histoplasmosis in immunocompetent travelers reported in literature. METHODS: A systematic review of literature was conducted. Electronic search was performed in Pubmed and LILACS. Two reviewers independently extracted data on demographic, clinical and radiological features, and treatment. Cases were classified according to Wheat's definitions. RESULTS: Seventy-one studies were included in the analysis, comprising a total of 814 patients. Twenty-one patients diagnosed at the Centre of Tropical Diseases, Negrar (VR), Italy were also included. The most common travel destination was Central America (168 people, 29.8%); the most common way of exposure to histoplasma was the exploration of caves and/or contact with bat guano (349 people, 60.9%). The multivariate logistic regression model showed association between the development of disseminated histoplasmosis (DH) and activities that involved the exploration of caves and/or the contact with bats' guano (adjusted OR: 34.20 95% CI: 5.29 to 220.93) or other outdoor activities (adjusted OR: 4.61 95% CI: 1.09 to 19.56). No significant difference in the attack rate between countries of destination was observed (p-value: 0.8906, Kruskal-Wallis test). CONCLUSIONS: Histoplasmosis often causes no or mild symptoms in immunocompetent individuals, although a severe syndrome may occur. The infection can mimic other diseases, and the epidemiological risk of exposure is an important clue to raise the index of suspicion.

Screening for neurocysticercosis in internationally adopted children: yield, cost and performance of serological tests, Italy, 2001 to 2016.

IntroductionNeurocysticercosis (NCC) is one of the leading causes of epilepsy worldwide. The majority of cases in Europe are diagnosed in immigrants. Currently in Italy, routine serological screening for cysticercosis is recommended for internationally adopted children (IAC) coming from endemic countries. Methods: We retrospectively analyse the results of the serological screening for cysticercosis in IAC 16 years old or younger, attending two Italian third level paediatric clinics in 2001-16. Results: Of 2,973 children included in the study, 2,437 (82.0%) were screened by enzyme-linked immune electro transfer blot (EITB), 1,534 (51.6%) by ELISA, and 998 (33.6%) by both tests. The seroprevalence of cysticercosis ranged between 1.7% and 8.9% according to EITB and ELISA, respectively. Overall, 13 children were diagnosed with NCC accounting for a NCC frequency of 0.4% (95% confidence interval (CI): 0.2-0.6%). Among the 168 seropositive children, only seven (4.2%) were diagnosed with NCC. Of these children, three were asymptomatic and four presented epilepsy. Among seronegative children (n = 2,805), seven presented with neurological symptoms that lead to the diagnosis of NCC in six cases. The sensitivity, specificity, positive and negative predictive value for the diagnosis of NCC were 54.5%, 98.6%, 14.6%, 99.8% for EITB and 22.2%, 91.1%, 1.4%, 99.5% for ELISA. The yield of the screening programme was 437 NCC cases per 100,000. The number needed to screen to detect one NCC case was 228. The cost per NCC case detected was EUR 10,372. Conclusion: On the base of our findings we suggest the ongoing serological screening for cysticercosis to be discontinued, at least in Italy, until further evidence in support will be available.

Imported Infections with Mansonella perstans Nematodes, Italy.

We report 74 patients in Italy infected with Mansonella perstans nematodes, a poorly described filarial parasite. M. perstans nematodes should be included in the differential diagnosis for patients with eosinophilia from disease-endemic countries. Serologic analysis is useful for screening, and testing for microfilaremia in peripheral blood should be performed for parasite-positive patients.

Four clusters of Trichostrongylus infection diagnosed in a single center, in Italy.

Trichostrongylus spp. are parasites that are seldom recognized as a cause of eosinophilia and gastroenteric symptoms in industrialized countries. The index of suspicion raises when several members of a same household present eosinophilia. We report four clusters of Trichostrongylus infection diagnosed in a single center, in northern Italy. Patients came from four different provinces of three Italian Regions. Some patients presented symptoms (abdominal pain and diarrhea were the most frequent ones, reported by 67 and 42% of our patients, respectively), while other were asymptomatic. All of them presented eosinophilia, that was severe (>5000 eosinophils/mmc) in 58% cases. Obtaining an accurate history from patients, investigating possible ingestion of vegetables contaminated by organic manure or sheep dejections, is particularly important to achieve diagnosis, also in light of the low sensitivity of parasitological tests.

The hidden epidemic of schistosomiasis in recent African immigrants and asylum seekers to Italy.

The prevalence of schistosomiasis among recent refugees from sub-Saharan Africa in Italy is unknown. This is a retrospective review of African immigrants screened at Centre for Tropical Diseases of Negrar from March 2014 to February 2016. Of the 373 immigrants tested, 34% were positive at least at one schistosomiasis test. The proportion of positive ELISA serology was 103/373 (27.6%). At microscopy, infected subjects were 65/373 (17.4%), (51% Schistosoma haematobium, 38% Schistosoma mansoni, 11% both). CCA antigen for S. mansoni was positive in 47/373 individuals (12.6%). We found a particularly high positivity rate in subjects from Mali (72.1%) and Ivory Coast (48%). This "hidden epidemic" of schistosomiasis cannot be longer neglected, considering the risk of severe complications, and the effective and inexpensive treatment available.

Sentinel surveillance of imported dengue via travellers to Europe 2012 to 2014: TropNet data from the DengueTools Research Initiative.

We describe the epidemiological pattern and genetic characteristics of 242 acute dengue infections imported to Europe by returning travellers from 2012 to 2014. The overall geographical pattern of imported dengue (South-east Asia > Americas > western Pacific region > Africa) remained stable compared with 1999 to 2010. We isolated the majority of dengue virus genotypes and epidemic lineages causing outbreaks and epidemics in Asia, America and Africa during the study period. Travellers acted as sentinels for four unusual dengue outbreaks (Madeira, 2012-13; Luanda, 2013; Dar es Salaam, 2014; Tokyo, 2014). We were able to characterise dengue viruses imported from regions where currently no virological surveillance data are available. Up to 36% of travellers infected with dengue while travelling returned during the acute phase of the infection (up to 7 days after symptom onset) or became symptomatic after returning to Europe, and 58% of the patients with acute dengue infection were viraemic when seeking medical care. Epidemiological and virological data from dengue-infected international travellers can add an important layer to global surveillance efforts. A considerable number of dengue-infected travellers are viraemic after arrival back home, which poses a risk for dengue introduction and autochthonous transmission in European regions where suitable mosquito vectors are prevalent.

Control and management of congenital Chagas disease in Europe and other non-endemic countries: current policies and practices.

OBJECTIVES: Identifying pregnant women infected with Trypanosoma cruzi is one of the major challenges for preventing and controlling Chagas disease (CD) in non-endemic countries. The aim of this paper was to perform a policy evaluation of the current practices of congenital Chagas disease (CCD) control in non-endemic countries and to propose specific targets for enhanced interventions to tackle this emerging health problem outside the endemic areas of Latin America. METHODS: We conducted a mixed method review of CCD policy strategies by searching the literature in the PubMed, Google Scholar and the World Health Organization (WHO) databases using the key terms 'CCD', 'paediatric Chagas disease' and 'non-endemic countries'; as free text and combined as one phrase to increase the search sensitivity. Reviews, recommendations, guidelines and control/surveillance programme reports were included. RESULTS: Of 427 CCD papers identified in non-endemic countries, 44 matched the inclusion. Although local programmes were launched in different countries with large numbers of Latin American immigrants, there were considerable disparities in terms of the programmes' distribution, delivery, integration and appropriated CCD control strategies. Moreover, Catalonia, Spain is the only region/country with an established systematic monitoring of CCD in pregnant women from Latin American countries. CONCLUSIONS: Given the worldwide dissemination of CD, the nature of its vertical transmission, and the gaps of the current strategies in non-endemic countries, there is an urgent need to standardise, expand and reinforce the control measures against CCD transmission.

Failure of dihydroartemisinin-piperaquine treatment of uncomplicated Plasmodium falciparum malaria in a traveller coming from Ethiopia.

BACKGROUND: Artemisinin combination therapy (ACT) is used worldwide as the first-line treatment against uncomplicated Plasmodium falciparum malaria. Despite the success of ACT in reducing the global burden of malaria, the emerging of resistance to artemisinin threatens its use. CASE REPORT: This report describes the first case of failure of dihydroartemisinin-piperaquine (DHA-PPQ) for the treatment of P. falciparum malaria diagnosed in Europe. It occurred in an Italian tourist returned from Ethiopia. She completely recovered after the DHA-PPQ treatment but 32 days after the end of therapy she had a recrudescence. The retrospective analysis indicated a correct DHA-PPQ absorption and genotyping demonstrated that the same P. falciparum strain was responsible for the both episodes. CONCLUSION: In consideration of the growing number of cases of resistance to ACT, it is important to consider a possible recrudescence, that can manifest also several weeks after treatment.

Chronic malaria and hyper-reactive malarial splenomegaly: a retrospective study on the largest series observed in a non-endemic country.

BACKGROUND: Chronic malaria is usually defined as a long-term malarial infection in semi-immune subjects, usually without fever or other acute symptoms. The untreated infection may evolve to hyper-reactive malarial splenomegaly (HMS), a life-threatening complication. This paper describes the largest series of HMS ever observed outside endemic countries, and the clinical outcome after a single anti-malarial treatment. Contrarily to most authors, still reporting the traditional, long-term treatment, regardless possible further exposure, the patients in this series did not receive any further prophylaxis if they were not re-exposed to malaria infection. METHODS: A retrospective, longitudinal study, describing all patients with HMS diagnosed at the Centre for Tropical Diseases of Negrar, Verona, took place over a 25-year period. HMS was defined by a longitudinal spleen diameter ≥16 cm, IgM ≥ 2.5 g/L, anti-malarial antibody titre ≥160, exclusion of other causes of splenomegaly. The short-term (≤6 months) clinical outcome after a single anti-malarial treatment was analysed and so was the long-term outcome of subjects re-exposed to malaria and submitted or not to anti-malarial prophylaxis or intermittent treatment. The association of the outcome with the main independent variables was first assessed with univariate analysis. Logistic regression was also performed. RESULTS: Forty-four subjects with HMS were retrieved. Of those with a short-term follow-up visit (<6 months, median 43 days) available before returning to endemic areas, 20/22 resulted improved/cured, two were unchanged. Of 22 expatriates seen at long-term follow-up after re-exposure, 18 were improved/cured, including eight out of nine who had followed an anti-malarial prophylaxis and 10/13 who had opted for the alternative of an intermittent treatment. CONCLUSION: HMS is the most severe form of chronic malaria. A single anti-malarial treatment is probably adequate to treat HMS in the absence of re-exposure, while an adequate prophylaxis is necessary for patients exposed again to malaria transmission. Intermittent treatment would probably be the only viable approach in endemic countries.