An open label trial of anakinra to prevent respiratory failure in COVID-19.

Background: It was studied if early suPAR-guided anakinra treatment can prevent severe respiratory failure (SRF) of COVID-19. Methods: A total of 130 patients with suPAR ≥6 ng/ml were assigned to subcutaneous anakinra 100 mg once daily for 10 days. Primary outcome was SRF incidence by day 14 defined as any respiratory ratio below 150 mmHg necessitating mechanical or non-invasive ventilation. Main secondary outcomes were 30-day mortality and inflammatory mediators; 28-day WHO-CPS was explored. Propensity-matched standard-of care comparators were studied. Results: 22.3% with anakinra treatment and 59.2% comparators (hazard ratio, 0.30; 95% CI, 0.20-0.46) progressed into SRF; 30-day mortality was 11.5% and 22.3% respectively (hazard ratio 0.49; 95% CI 0.25-0.97). Anakinra was associated with decrease in circulating interleukin (IL)-6, sCD163 and sIL2-R; IL-10/IL-6 ratio on day 7 was inversely associated with SOFA score; patients were allocated to less severe WHO-CPS strata. Conclusions: Early suPAR-guided anakinra decreased SRF and restored the pro-/anti-inflammatory balance. Funding: This study was funded by the Hellenic Institute for the Study of Sepsis, Technomar Shipping Inc, Swedish Orphan Biovitrum, and the Horizon 2020 Framework Programme. Clinical trial number: NCT04357366.

People infected with the SARS-CoV-2 virus, which causes COVID-19, can develop severe respiratory failure and require a ventilator to keep breathing, but this does not happen to every infected individual. Measuring a blood protein called suPAR (soluble urokinase plasminogen activator receptor) may help identify patients at the greatest risk of developing severe respiratory failure and requiring a ventilator. Previous investigations have suggested that measuring suPAR can identify pneumonia patients at highest risk for developing respiratory failure. The protein can be measured by taking a blood sample, and its levels provide a snapshot of how the body's immune system is reacting to infection, and of how it may respond to treatment. Anakinra is a drug that forms part of a class of medications called interleukin antagonists. It is commonly prescribed alone or in combination with other medications to reduce pain and swelling associated with rheumatoid arthritis. Kyriazopoulou et al. investigated whether treating COVID-19 patients who had developed pneumonia with anakinra could prevent the use of a ventilator and lower the risk of death. The findings show that treating COVID-19 patients with an injection of 100 milligrams of anakinra for ten days may be an effective approach because the drug combats inflammation. Kyriazopoulou et al. examined various markers of the immune response and discovered that anakinra was able to improve immune function, protecting a significant number of patients from going on a ventilator. The drug was also found to be safe and cause no significant adverse side effects. Administering anakinra decreased of the risk of progression into severe respiratory failure by 70%, and reduced death rates significantly. These results suggest that it may be beneficial to use suPAR as an early biomarker for identifying those individuals at highest risk for severe respiratory failure, and then treat them with anakinra. While the findings are promising, they must be validated in larger studies.

Efficient management of secondary haemophagocytic lymphohistiocytosis with intravenous steroids and γ-immunoglobulin infusions.

BACKGROUND: Secondary haemophagocytic lymphohistiocytosis (sHLH) is a rare life-threatening condition mainly associated with underlying infections, malignancies, and autoimmune or immune-mediated diseases. AIM: To analyse all sHLH cases that were diagnosed and managed under real-world circumstances in our department focusing on the treatment schedule and the outcome. METHODS: Prospectively collected data from all adult patients fulfilling the criteria of sHLH who diagnosed and managed from January 1, 2010 to June 1, 2018, in our department of the tertiary care university hospital of Larissa, Greece, were analysed retrospectively (n = 80; 52% male; median age: 55 years). The electronic records and/or written charts of the patients were reviewed for the demographic characteristics, clinical manifestations, underlying causes of sHLH, laboratory parameters, treatment schedule and 30-d-mortality rate. Most of patients had received after consent intravenous γ-immunoglobulin (IVIG) for 5 d (total dose 2 g/kg) in combination with intravenous steroid pulses followed by gradual tapering of prednisolone. RESULTS: Seventy-five patients (94%) reported fever > 38.5 °C, 47 (59%) had liver or spleen enlargement and 76 (95%) had ferritin > 500 ng/mL including 20 (25%) having considerably high levels (> 10000 ng/mL). Anaemia and thrombocytopenia occurred in 72% and leucopoenia in 47% of them. Underlying infections were diagnosed in 59 patients (74%) as follows: leishmaniasis alone in 15/80 (18.9%), leishmaniasis concurrently with Coxiella Burnetti or non-Hodgkin lymphoma in 2/80 (2.5%), bacterial infections in 14/80 (17.5%) including one case with concurrent non-Hodgkin lymphoma, viral infections in 13/80 (16.3%), fungal infections in 2/80 (2.5%), infections by mycobacteria in 1/80 (1.3%) and unidentified pathogens in 12/80 (15%). Seventy-two patients (90%) had received combination treatment with IVIG and intravenous steroids. Overall, sHLH resolved in 76% of patients, 15% died within the first month but 82.5% of patients were still alive 6 mo after diagnosis. Univariate analysis showed older age, anaemia, thrombocytopenia, low fibrinogen, disseminated intravascular coagulation (DIC), and delay of diagnosis as factors that negatively affected remission. However, multivariate analysis showed low platelets and DIC as the only independent predictors of adverse outcome. CONCLUSION: sHLH still carries a remarkable morbidity and mortality. Underlying infections were the major cause and therefore, they should be thoroughly investigated in patients with sHLH. Early recognition and combination treatment with IVIG and corticosteroids seem an efficient treatment option with successful outcome in this life-threatening condition.

Current clinical, laboratory, and treatment outcome characteristics of visceral leishmaniasis: results from a seven-year retrospective study in Greece.

OBJECTIVES: Visceral leishmaniasis (VL) is re-emerging in endemic areas. The epidemiological, clinical, laboratory, and treatment outcome characteristics in a large cohort of VL patients is described herein. METHODS: The cases of 67 VL patients (57% male, mean age 56 years) treated in two Greek hospitals over the last 7 years were identified and evaluated retrospectively. RESULTS: Forty-six percent of patients reported contact with animals. Seventeen patients (25%) were immunocompromised, and 22% were co-infected with another pathogen. Sixty-four percent of patients had fever, 57% had weakness, 37% had sweats, 21% had weight loss, and 13% had a dry cough, while 6% developed haemophagocytic syndrome. The median duration of symptoms was 28 days. Fifty-eight percent of patients had splenomegaly, 49% had hepatomegaly, and 36% had lymphadenopathy. The diagnosis was established by positive PCR in peripheral blood (73%) and/or bone marrow specimens (34%). Sixty-one patients (91%) received liposomal amphotericin (L-AMB). Six patients (10%) did not respond or relapsed but were eventually cured after a second cycle of L-AMB. During a 6-month follow-up, the overall mortality was 9%, although none of these deaths was attributed to VL. CONCLUSIONS: VL is still a common disease in endemic areas, affecting immunocompetent and immunocompromised patients. Its diagnosis is challenging, and molecular techniques are valuable and helpful tools to achieve this. Treatment with L-AMB is safe and very effective.

Risk factors for early mortality in haematological malignancy patients with pulmonary mucormycosis.

Pulmonary mucormycosis (PM) is a life-threatening opportunistic mycosis with a variable clinical evolution and few prognostic markers for outcome assessment. Several clinical risk factors for poor outcome present at the diagnosis of PM were analyzed in 75 consecutive hematology patients from 2000-2012. Significant variables (P < 0.1) were entered into a multivariate Cox-proportional hazard regression model adjusting for baseline APACHE II to identify independent risk factors for mortality within 28 days. Twenty-eight of 75 patients died within 4-week follow up. A lymphocyte count < 100/mm³ at the time of diagnosis (adjusted hazard ratio 4.0, 1.7-9.4, P = 0.01) and high level of lactate dehydrogenase (AHR 3.7, 1.3-10.2, P = 0.015) were independent predictors along with APACHE II score for 28-day mortality. A weighted risk score based on these 3 baseline variables accurately identified non-surviving patients at 28 days (area under the receiver-operator curve of 0.87, 0.77-0.93, P < 0.001). A risk score > 22 was associated with 8-fold high rates of mortality (P < 0.0001) within 28 days of diagnosis and median survival of 7 days versus ≥28 days in patients with risk scores ≤22. We found that APACHE II score, severe lymphocytopenia and high LDH levels at the time of PM diagnosis were independent markers for rapid disease progression and death.

Impaired bactericidal but not fungicidal activity of polymorphonuclear neutrophils in patients with chronic lymphocytic leukemia.

We examined the qualitative polymorphonuclear neutrophil (PMN)-associated immune impairment in patients with chronic lymphocytic leukemia (CLL) by characterizing phagocytic killing of key non-opsonized bacterial (Staphylococcus aureus and Pseudomonas aeruginosa) and fungal (Candida albicans and Aspergillus fumigatus) pathogens. Neutrophils were collected from 47 non-neutropenic patients with CLL (PMN count > 1000/mm(3)) and age-matched and young healthy controls (five each). A subset of patients (13%) had prior or subsequent infections. We found that the patients with CLL had diminished PMN microbicidal response against bacteria but not against fungi compared with the controls. Compared to patients with effective PMN responses, we did not identify differences of basal PMN pathogen-associated molecular pattern receptor gene expression, soluble pathogen-associated molecular pattern gene expression or inflammatory cytokine signatures in patients with impaired PMN responses when PMNs were analyzed in multiplex real-time polymerase chain reaction assays. However, differences in PMN microbicidal response against A. fumigatus in patients with CLL were associated with the degree of hypogammaglobulinemia.

Candiduria in haematologic malignancy patients without a urinary catheter: nothing more than a frailty marker?

There is scarcity of data regarding significance of candiduria in patients with haematologic malignancies and its association with invasive candidiasis. To that end, we retrospectively evaluated all hospitalised, non-intensive care unit patients with haematologic malignancies and candiduria during a 10-year period (2001-2011). To decrease the possibility of bladder colonisation and sample contamination, we excluded all patients with candiduria who had urinary catheters and those with concomitant bacteriuria. Twenty-four such patients (21 females) were identified, with median age at diagnosis 62 years (range, 20-82 years). Acute leukaemia was the most common underlying disease (54%); 62% of these cases were not in remission. Twenty-nine percent of the patients had diabetes mellitus and 25% were neutropenic. The most common isolated Candida species was Candida glabrata (37%), followed by C. albicans (29%). Only 8% of them had urinary tract infection symptoms. However, 88% received systemic antifungals. Candidemia and crude mortality rates at 4 weeks were low (4% and 12% respectively). Isolated candiduria in patients with haematologic malignancies has risk factors similar to those in other hospitalised patients, and it does not seem to be a strong predictor of subsequent invasive candidiasis.

Concurrent lung infections in patients with hematological malignancies and invasive pulmonary aspergillosis: how firm is the Aspergillus diagnosis?

BACKGROUND: Immunocompromised patients with hematological malignancies and/or recipients of hematopoietic stem cell transplants are constantly exposed to several fungal, bacterial, and viral respiratory pathogens. METHODS: We retrospectively evaluated all patients with invasive pulmonary aspergillosis (IPA) and underlying hematological malignancies for the presence of concurrent, microbiologically documented pulmonary infections during a 5-year period (2005-2010). RESULTS: We found 126 such patients that frequently had coinfections (49%) with respiratory pathogens other than Aspergillus species, with a higher rate in patients with probable IPA (53%) than in those with proven IPA (29%; P=0.038). CONCLUSIONS: As the majority of patients with IPA in daily practice have probable IPA, often according to only the combination of positivity for serological biomarkers and radiological findings, our data may raise skepticism about both the certainty of IPA diagnosis and the evaluation of response to antifungals in a subset of these patients.

Invasive Mold Infections in Pediatric Cancer Patients Reflect Heterogeneity in Etiology, Presentation, and Outcome: A 10-Year, Single-Institution, Retrospective Study.

BACKGROUND: There is scarcity of data regarding invasive mold infections (IMIs) in children with cancer. METHODS: We retrospectively identified patients (18 years old or younger) with malignant disease who developed proven or probable IMIs (European Organization for Research on the Treatment of Cancer/Mycoses Study Group criteria) during a 10-year period (1998-2008). We reviewed their risk factors and clinical characteristics and assessed their crude mortality rates and treatment outcomes 12 weeks after IMI diagnosis. RESULTS: Forty-eight patients (30 males) were identified, 30 (63%) of whom had a proven IMI. The most prevalent mold were Aspergillus species (40%), followed by Mucorales (20%) and Fusarium species (11%). Acute leukemia was the most common underlying malignancy (39 patients, [81%]). Twenty-three (59%) of them had refractory leukemia. Neutropenia was present at the day of IMI diagnosis in 67% of the patients. Sixty-two percent of the patients received prior corticosteroids. The dominant site of infection was the lungs (79%), followed by skin (29%) and sinuses (10%). Seventy-one percent of patients had radiological findings suggestive of fungal pneumonia (either nodules or masses). The mainstay of antifungal therapy was a lipid formulation of amphotericin B. Antifungal therapy resulted in 54% response rate (33% complete) at 12 weeks. The crude 12-week mortality rate was 31%. Logistic regression analysis demonstrated that monocytopenia (P = .013), malnutrition (P = .012), and intensive care admission in the month prior to IMI diagnosis (P = .027) were risk factors for death within 12 weeks. CONCLUSIONS: Although Aspergillus spp. was the most common mold in our pediatric cancer population, the epidemiology of the IMIs was diverse. Adults and children share similar risk factors for and epidemiology of IMIs.

The diagnostic value of halo and reversed halo signs for invasive mold infections in compromised hosts.

The halo sign is a CT finding of ground-glass opacity surrounding a pulmonary nodule or mass. The reversed halo sign is a focal rounded area of ground-glass opacity surrounded by a crescent or complete ring of consolidation. In severely immunocompromised patients, these signs are highly suggestive of early infection by an angioinvasive fungus. The halo sign and reversed halo sign are most commonly associated with invasive pulmonary aspergillosis and pulmonary mucormycosis, respectively. Many other infections and noninfectious conditions, such as neoplastic and inflammatory processes, may also manifest with pulmonary nodules associated with either sign. Although nonspecific, both signs can be useful for preemptive initiation of antifungal therapy in the appropriate clinical setting. This review aims to evaluate the diagnostic value of the halo sign and reversed halo sign in immunocompromised hosts and describes the wide spectrum of diseases associated with them.

Reversion of severe hepatopulmonary syndrome in a non cirrhotic patient after corticosteroid treatment for granulomatous hepatitis: a case report and review of the literature.

Hepatopulmonary syndrome (HPS) is defined as a clinical triad including liver disease, abnormal pulmonary gas exchange and evidence of intrapulmonary vascular dilatations. We report a 61-year-old male presented with fatigue, long-lasting fever, loss of weight, signs of portal hypertension, hepatosplenomegaly, cholestasis and progressive dyspnoea over the last year. Clinical, laboratory and histological findings confirmed the diagnosis of granulomatous hepatitis. HPS due to hepatic granuloma-induced portal hypertension was proved to be the cause of severe hypoxemia of the patient as confirmed by contrast-enhanced echocardiography. Reversion of HPS after corticosteroid therapy was confirmed by a new contrast-enhanced echocardiography along with the normalization of cholestatic enzymes and improvement of the patient's conditions. This is the first case of complete reversion of HPS in a non-cirrhotic patient with hepatic granuloma, indicating that intrapulmonary shunt in liver diseases is a functional phenomenon and HPS can be developed even in miscellaneous liver involvement as in this case.