Resolution of Disseminated Intravascular Coagulation in a Patient with COVID-19 and Associated Sepsis-Induced Neutropenia.

COVID-19 has been associated with a hypercoagulable state and thrombotic events. Venous thromboembolism has been the most commonly reported type of thrombosis but also arterial thrombosis and disseminated intravascular coagulation in inpatients have been described frequently in several clinical experiences. Patients with COVID-19, because of its tendency to induce leucopenia and overlapping of bacterial infection, may experience sudden disseminated intravascular coagulation (DIC), as in the case that we report here. However, early diagnosis and treatment may be associated with positive resolution of these severe complications.

Impact of respiratory viral panel testing on length of stay in pediatric cancer patients admitted with fever and neutropenia.

BACKGROUND: Polymerase chain reaction (PCR) respiratory viral panel (RVP) testing is often used in evaluation of pediatric cancer patients with febrile neutropenia (FN), but correlation with adverse outcomes has not been well characterized. PROCEDURE: A retrospective cohort of all children ages 0-21 years with cancer admitted to Children's Healthcare of Atlanta for FN from January 2013 to June 2016 was identified. Patient demographic and clinical variables such as age, RVP results, length of stay (LOS), and deaths were abstracted. Relationship between RVP testing and positivity and LOS, highest temperature (Tmax), hypotension and intensive care unit (ICU) admission were compared using Wilcoxon rank sums, chi-square, or Fisher's exact tests adjusting for age, sex, bacteremia, and diagnosis. RESULTS: The 404 patients identified had 787 total FN admissions. RVPs were sent in 38% of admissions and were positive in 59%. Patients with RVPs sent were younger (median 5.5 vs 8.0 years, P < .0001) with higher Tmax (39.2° vs 39.1°, P = .016). The most common virus identified was rhinovirus/Enterovirus (61%). There were no significant differences in highest temperature or lowest blood pressure based on RVP positivity. Patients admitted to the ICU were more likely to have RVPs sent (odds ratio [OR] = 3.19, P < .002); however, neither having RVP testing nor RVP positivity were significantly associated with increased LOS or death. Coinfection with bacteremia and a respiratory virus was identified in 9.1% of patients. CONCLUSIONS: These data raise the question of the utility of sending potentially costly RVP testing as RVP positivity during febrile neutropenia does not impact LOS, degree of hypotension, or ICU admission.

COVID-19 in Neonates and Infants: Progression and Recovery.

Between March 10, 2020 and April 17, 2020, of 8/70 (11.4%) SARS-CoV-2 positive infants that presented, 5/8 (63%) developed fever, 4/8 (50%) had lower respiratory tract involvement, 2/8 (25%) had neutropenia and thrombocytosis, and 4/8 infants (50%) were treated for suspected sepsis with broad-spectrum antibiotics. Only 1/8 (13%) required pediatric intensive care. All patients were eventually discharged home well.

A case report of catheter-related bloodstream infection due to Trichosporon coremiiforme in a patient with secondary neutropenia to HIV.

Here, we describe an invasive infection due to Trichosporon coremiiforme in an HIV positive patient with neutropenia. The strain was first erroneously identified as Trichosporon asahii by conventional methods, but correctly identified by mass spectrometry using matrix-assisted laser desorption/ionization time-of-flight technology (MALDI-TOF MS) and ribosomal DNA sequencing. The infection was successfully resolved after antifungal treatment with amphotericin B and fluconazole. This case report is a contribution to the study of T. coremiiforme infections and reinforces its relevance as a species capable of causing invasive human infection in immunocompromised patients and also contributes to the study of its susceptibility profile against antifungal drugs.

Ibrutinib-associated invasive fungal diseases in patients with chronic lymphocytic leukaemia and non-Hodgkin lymphoma: An observational study.

BACKGROUND: Invasive fungal diseases (IFD) are life-threatening infections most commonly diagnosed in acute leukaemia patients with prolonged neutropenia and are uncommonly diagnosed in patients with lymphoproliferative diseases. OBJECTIVES: Following the initial report of aspergillosis diagnosed shortly after beginning ibrutinib for chronic lymphocytic leukaemia, a survey was developed to seek additional cases of IFD during ibrutinib treatment. METHODS: Local and international physicians and groups were approached for relevant cases. Patients were included if they met the following criteria: diagnosis of chronic lymphocytic leukaemia/non-Hodgkin lymphoma; proven or probable IFD; and ibrutinib treatment on the date IFD were diagnosed. Clinical and laboratory data were captured using REDCap software. RESULT: Thirty-five patients with IFD were reported from 22 centres in eight countries: 26 (74%) had chronic lymphocytic leukaemia. The median duration of ibrutinib treatment before the onset of IFD was 45 days (range 1-540). Aspergillus species were identified in 22 (63%) of the patients and Cryptococcus species in 9 (26%). Pulmonary involvement occurred in 69% of patients, cranial in 60% and disseminated disease in 60%. A definite diagnosis was made in 21 patients (69%), and the mortality rate was 69%. Data from Israel regarding ibrutinib treated patients were used to evaluate a prevalence of 2.4% IFD. CONCLUSIONS: The prevalence of IFD among chronic lymphocytic leukaemia/non-Hodgkin lymphoma patients treated with ibrutinib appears to be higher than expected. These patients often present with unusual clinical features. Mortality from IFD in this study was high, indicating that additional studies are urgently needed to identify patients at risk for ibrutinib-associated IFD.

Risk factors for mortality after respiratory syncytial virus lower respiratory tract infection in adults with hematologic malignancies.

BACKGROUND: Respiratory syncytial virus (RSV) lower respiratory tract infection (LRTI) is associated with high mortality in patients with hematologic malignancies (HM). We sought to determine whether allogeneic hematopoietic cell transplant (allo-HCT) recipients would be at higher risk for 60-day mortality. METHODS: We examined a retrospective cohort of adults with HM with or without HCT treated for RSV LRTI (n = 154) at our institution from 1996-2013. We defined possible RSV LRTI as RSV detected only in the upper respiratory tract with new radiologic infiltrates and proven RSV LRTI as RSV detected in BAL fluid with new radiologic infiltrates. Immunodeficiency Scoring Index (ISI) and Severe Immunodeficiency (SID) criteria were calculated for HCT recipients. Multivariable logistic regression analyses were performed to identify independent risk factors associated with 60-day all-cause mortality. RESULTS: Mortality was high in HM patients (25%), but there was no difference between those without HCT, autologous or allo-HCT recipients in logistic regression models. Separate multivariate models showed that at RSV diagnosis, neutropenia (OR 8.3, 95% CI 2.8-24.2, P = 0.005) and lymphopenia (OR 3.7, 95% CI 1.7-8.2, P = 0.001) were associated with 60-day mortality. Proven LRTI was associated with higher 60-day mortality (neutropenia model: OR 4.7, 95%CI 1.7-13.5; lymphopenia model: OR 3.3, 95% CI 1.2-8.8), and higher ICU admission. In HCT recipients, high ISI and very severe immunodeficiency by SID criteria were associated with higher 60-day all-cause mortality. CONCLUSIONS: Mortality is similarly high among HM patients without HCT and HCT recipients. High-grade immunodeficiency and detection of RSV from BAL fluid are associated with higher 60-day mortality.

Chemoradiotherapy completion and neutropenia risk in HIV patients with cervical cancer.

Cervical cancer (CC) is one of the acquired immunodeficiency syndrome (AIDS) defining diseases and the human immunodeficiency virus (HIV) infection is thought to relate with increased acute toxicity of chemoradiotherapy (CRT).We investigated the effect of HIV status in the incidence of neutropenia associated with cisplatin-based CRT for CC and its impact in treatment completion.This is a single-center retrospective cohort study. Data collection was performed for all the consecutive stage Ib-IV CC women treated with cisplatin-based CRT from 2012 to 2016, and with known HIV status.Sixty-one patients were included, 6 were HIV+. HIV+ patients had a higher risk of neutropenia at any cycle during cisplatin CRT [adjusted odds ratio (OR) 7.3, 95% confidence interval (95% CI) 1.02-52.3; P = .05]. Despite the absolute differences, mean neutrophil count was nonsignificantly lower in HIV+ women, both at baseline [4455/µL (interquartile range, IQR: 1830-6689) vs 6340 (IQR: 1720-18,970) for HIV-, P = .98] and at the end of treatment [1752/µL (IQR: 1100-2930) vs 3147/µL (IQR: 920-18,390) in HIV-; P = .06]. Moreover, when considering the effect of time, CRT seems to induce a consistent drop of neutrophils in both groups (P = .229). No febrile neutropenia events occurred.In HIV+ women, there were more CT cycle delays (P = .013), patients were more prone to use granulocyte colony-stimulating factor (G-CSF; HIV+ 40.0% vs HIV- 4.0%; P = .04) and less likely to complete at least 5 cycles of cisplatin (P = .02). All patients received adequate dose of pelvic RT, regardless of HIV status.HIV+ patients have a significantly increased risk of neutropenia during CRT treatment for CC and are less likely to complete chemotherapy with cisplatin.

Severe neutropenia revealing a rare presentation of dengue fever: a case report.

BACKGROUND: Arboviruses are a common cause of fever in the returned traveler often associated with leucopenia, especially lymphopenia and thrombocytopenia. Transient neutropenia has been described in a few cases of arboviruses. However, prolonged and severe neutropenia (<500/mm3) has rarely been reported in dengue fever, especially in the returned traveler in Europe. CASE PRESENTATION: A 26-year-old healthy female without any medical past history, flying back from Thailand, presented a transient fever with severe neutropenia (<500/mm3). Laboratory tests showed a mild hepatic cytolysis and thrombocytopenia, mimicking malaria or viral hepatitis. While she underwent protective isolation, NS1 antigen returned positive in favor of a dengue fever. Outcome was favorable without any antimicrobial therapy. CONCLUSION: Physicians should be wary of possible unusual presentation of dengue fever with prolonged neutropenia. Although such biological sign is more often associated with malaria or severe bacterial infection, it may be a sign of arbovirus.

[Cytopenias and their correction during antiviral therapy of chronic hepatitis C in patients with genotype 1].

The main reason for the ineffectiveness of antiviral therapy in patients with chronic hepatitis C that impedes full and adequate treatment of IFN-α and ribavirin is the development of neutropenia and thrombocytopenia. The present study included 63 patients (59% men and 41% women) with chronic hepatitis C that did not previously receive antiviral therapy. All patients had HCV genotype-1 (15 patients with genotype 1a; 42 people, with genotype 1b; 6 patients, with genotypes (1a + 1b)). The patients' age was 33.8 ± 0.7 years, with term of infection 6,1 ± 0,8 years. It was shown that in the case of treatment with Peg-IFN-alpha in combination with ribavirin, a significant decrease in the number of white blood cells, neutrophils and platelets prevailed in patients with HCV-monoinfected genotype 1b in the F0-F2 stages (2,8-8,6 kPa) at METAVIR. With the development of moderate "early" (less than 12 weeks of antiviral therapy) and for the prevention of "late" (more than 12 weeks of treatment) neutropenia, appointment of immune medicine likopid (glucosaminylmuramyldipeptide) at a dosage of 1 mg, 2 times a day for 20 days, in patients with chronic hepatitis C (genotype 1b ) with

Limited Generalizability of Registration Trials in Hepatitis C: A Nationwide Cohort Study.

BACKGROUND: Approval of drugs in chronic hepatitis C is supported by registration trials. These trials might have limited generalizability through use of strict eligibility criteria. We compared effectiveness and safety of real world hepatitis C patients eligible and ineligible for registration trials. METHODS: We performed a nationwide, multicenter, retrospective cohort study of chronic hepatitis C patients treated in the real world. We applied a combined set of inclusion and exclusion criteria of registration trials to our cohort to determine eligibility. We compared effectiveness and safety in eligible vs. ineligible patients, and performed sensitivity analyses with strict criteria. Further, we used log binomial regression to assess relative risks of criteria on outcomes. RESULTS: In this cohort (n = 467) 47% of patients would have been ineligible for registration trials. Main exclusion criteria were related to hepatic decompensation and co-morbidity (cardiac disease, anemia, malignancy and neutropenia), and were associated with an increased risk for serious adverse events (RR 1.45-2.31). Ineligible patients developed significantly more serious adverse events than eligible patients (27% vs. 11%, p< 0.001). Effectiveness was decreased if strict criteria were used. CONCLUSIONS: Nearly half of real world hepatitis C patients would have been excluded from registration trials, and these patients are at increased risk to develop serious adverse events. Hepatic decompensation and co-morbidity were important exclusion criteria, and were related to toxicity. Therefore, new drugs should also be studied in these patients, to genuinely assess benefits and risk of therapy in the real world population.

The burden of mucormycosis in HIV-infected patients: A systematic review.

OBJECTIVES: Mucormycosis is an invasive fungal infection afflicting immunocompromised patients, causing a significant degree of morbidity and mortality. The purpose of the study was to provide a comprehensive analysis describing the epidemiology and outcome of mucormycosis in the scenario of HIV infection. METHODS: We systematically searched PubMed for reports about mucormycosis associated with HIV. Eligible studies describe the predisposing factor, clinical form, treatment, and survival outcome. RESULTS: We included 61 articles from 212 reviewed abstracts, corresponding to 67 cases. Patients were mostly men (68.2%) with a median CD4(+) count of 47 [IQR 17-100] cells/mm(3). Intravenous drug use (50%), neutropenia (29.7%) and corticosteroid use (25%) were the predominant associated factors. The main clinical forms were disseminated (20.9%), renal (19.4%), and rhino-cerebral (17.9%). Rhizopus (45.5%) and Lichtheimia spp (30.3%) were the main fungal isolates. Treatment consisted of antifungal therapy and surgery in 38.8%. Overall mortality rate was 52.2%, and varied with the site of infection: 92.9% for disseminated disease, 62.5% for cerebral disease, 60% for pulmonary infection, and 36.4% for cutaneous infection. Survival was worse for those who did not initiate antifungals (p = .04), who were antiretroviral naïve (p = .01), who were admitted to ICU (p = .003) or had disseminated disease (p = .007). CONCLUSIONS: Mucormycosis is a life-threatening infection in HIV patients and clinician should be aware of this co-infection in the differential diagnosis of HIV opportunistic infections.

Metagenomic analysis of bloodstream infections in patients with acute leukemia and therapy-induced neutropenia.

Leukemic patients are often immunocompromised due to underlying conditions, comorbidities and the effects of chemotherapy, and thus at risk for developing systemic infections. Bloodstream infection (BSI) is a severe complication in neutropenic patients, and is associated with increased mortality. BSI is routinely diagnosed with blood culture, which only detects culturable pathogens. We analyzed 27 blood samples from 9 patients with acute leukemia and suspected BSI at different time points of their antimicrobial treatment using shotgun metagenomics sequencing in order to detect unculturable and non-bacterial pathogens. Our findings confirm the presence of bacterial, fungal and viral pathogens alongside antimicrobial resistance genes. Decreased white blood cell (WBC) counts were associated with the presence of microbial DNA, and was inversely proportional to the number of sequencing reads. This study could indicate the use of high-throughput sequencing for personalized antimicrobial treatments in BSIs.

Telaprevir-based therapy for treatment of HIV-1 and hepatitis C virus co-infected patients: An early access programme.

OBJECTIVES: HPC3005 is a multicentre, open-label, telaprevir trial in HCV/HIV coinfected patients with severe fibrosis or compensated cirrhosis. METHODS: Patients were treated with telaprevir 750 mg every 8 h (1125 mg if on efavirenz) plus pegylated interferon-alpha (PEG-IFN, 180 µg once-weekly) and ribavirin (RBV, 800 mg/day) for 12 weeks, followed by 36 weeks of PEG-IFN/RBV. RESULTS: Mean age was 44 years, 97/118 patients were male and all were Caucasian, 68 had severe fibrosis and 50 had cirrhosis. Seventy-eight had HCV RNA levels ≥800 000 IU/mL, 72 had HCV genotype 1a, baseline HIV RNA was <50 copies/mL in 112 patients. Overall, 114/118 patients continued antiretroviral treatment, 4 were untreated. Seventy-five patients received tenofovir and 74 emtricitabine; in addition 53 received atazanavir/ritonavir, 43 raltegravir, and 24 efavirenz. By intention-to-treat, 78 (66%) patients achieved SVR24. Nineteen discontinued telaprevir, 8 for virological endpoint, 5 for adverse events (2 anaemia, 2 rash, 1 asthenia), 5 for non-compliance and 1 withdrew consent. The most common adverse events were anaemia (36 patients), thrombocytopaenia (33), rash (26), bilirubin increase (17), and neutropenia (16). CONCLUSIONS: In this early access programme in coinfected patients with severe fibrosis or cirrhosis, 66% of patients achieved SVR. The most common adverse events were haematological. CLINICAL TRIAL NUMBER: NCT01500616.

Characteristics and outcomes of human parechovirus infection in infants (2008-2012).

UNLABELLED: Human parechoviruses (HPeVs) cause a spectrum of disease ranging from self-limiting illness to severe disease and, sometimes, death. We describe the clinical characteristics and outcomes of HPeV infection in infants. The study describes the clinical and laboratory characteristics and outcomes of infants with HPeV infection during 2008-2012, from three paediatric hospitals in London each with a paediatric intensive care unit. The infants were retrospectively identified through laboratory and patient discharge databases and diagnosed through HPeV PCR. Fifty infants were identified. Half required admission to PICU. Infants less than 3 months were more likely to require PICU (16/25: p < 0.01). Clinical signs at presentation were often indistinguishable from those of bacterial sepsis and meningitis, but inflammatory markers were nearly always (95 % of cases) within normal ranges. Brain MRI showed white matter changes in 10/12 infants. Three of 19 infants with follow-up data (16 %) had significant neurological sequelae. CONCLUSION: HPeV may cause severe disease and long-term neurological sequelae in young infants. HPeV should be considered in infants with clinical features of sepsis/meningitis with normal CSF microscopy. Prospective observational studies are warranted to better define the epidemiology of infection and thus inform future treatment trials.

Pathogenesis of fulminant monkeypox with bacterial sepsis after experimental infection with West African monkeypox virus in a cynomolgus monkey.

The pathogenesis of severe human monkeypox, which causes systemic and fulminant infections, is not clear. This study presents a case repot of fulminant monkeypox with bacterial sepsis after experimental infection with monkeypox virus in a cynomolgus monkey (Macaca fascicularis). In our previous study (Saijo et al., 2009, J Gen Virol), two cynomolgus monkeys became moribund after experimental infection with monkeypox virus Liberia strain, West African strain. One exhibited typical monkeypox-related papulovesicular lesions. The other monkey presented fulminant clinical symptoms with a characteristic flat red rash similar to that found in smallpox, which is associated with extremely high fatality rates. In this study, we found that the monkey with flat red rash had high levels of viremia and neutropenia, as well as high plasma levels of pro-inflammatory cytokines and chemokines compared with the other monkey. Monkeypox virus replicates in epithelial cells and macrophages in various organs. Sepsis due to Gram-positive cocci was confirmed histopathologically in the monkey with flat red rash. The lack of inflammatory response in the lesion suggested that the monkey with sepsis experienced strong immune suppression during the viral infection. The neutropenia and excessive inflammatory cytokine responses indicate that neutrophils play key roles in the pathogenesis of systemic and fulminant human monkeypox virus infections with sepsis.

Exacerbation of invasive Candida albicans infection by commensal bacteria or a glycolipid through IFN-γ produced in part by iNKT cells.

BACKGROUND: The commensal yeast Candida albicans is a major cause of invasive fungal infections. Despite treatment with antifungal agents, the mortality rate attributed to these types of infection is high. Although numerous cases have been reported regarding a poor outcome for patients with bacterial and C. albicans coinfection, the mechanisms by which the coinfecting bacteria exacerbate the C. albicans infection remain elusive. METHODS AND RESULTS: We evaluated how glycolipid-mediated activation of invariant natural killer T (iNKT) cells affects the clearance of C. albicans. Surprisingly, C. albicans-infected, glycolipid-treated mice exhibited significantly lower survival rates, increased fungal burden, and higher interleukin (IL)-6 production in the kidneys compared with control mice. Glycolipid-induced exacerbation of C. albicans infection was not observed in interferon-gamma knockout (IFN-γKO) mice. In the C. albicans-infected, glycolipid-treated mice, the number of neutrophils in the blood and bone marrow dramatically decreased in an IFN-γ-dependent manner. Furthermore, mice that were coinfected with C. albicans and nonfermentative gram-negative commensal bacteria exhibited increased fungal burden and inflammatory cytokine production in the kidneys that were dependent on IFN-γ and iNKT cells. CONCLUSIONS: Our results indicate that coinfecting commensal bacteria exacerbate C. albicans infection through IFN-γ produced, in part, by iNKT cells.