Clinical Focus Of Infection Research Articles

Real-World Outcomes with Intensive Chemotherapy in Acute Myeloid Leukemia Patients Deemed “Unfit” for Remission Induction By Landmark Trials' Criteria

Background: Induction mortality rates in acute myeloid leukemia (AML) ranges from 7.1% to 40% across Indian tertiary care centers (Kayal S, ASH 2022) exceeding those in the western countries, possibly due to treatment delay, multidrug resistant infections, and inadequate social support. Furthermore, patients seen in our clinics are not representative of those in landmark clinical trials, as a majority of them would be considered unfit for intensive induction based on the trial criteria. Consequently, these patients are left with treatment options, such as less intensive hypomethylating agents, BCL2 inhibitors, and newer targeted therapies. However, these drugs often remain unfeasible due to high out-of-pocket costs and regulatory approval delays, so a majority of patients receive intensive induction with antibiotics. In this retrospective study, we evaluate the effectiveness and toxicities associated with the utilization of such a strategy in the Indian context. Method: This retrospective study was conducted at a single tertiary care cancer center in India. It included patients aged ≥15 years, with acute myeloid leukemia, who received intensive induction chemotherapy as decided by the multidisciplinary joint clinic between January 01, 2017, and December 31, 2019. Patient data were extracted from the Indian acute leukemia research database [INwARD], which is a prospective registry of multiple centers, maintained and audited by the Clinical Data Management Center [CDMC], Vellore for the Hematology cancer consortium and is compliant with ICH-GCP regulations. Ethical approval was obtained from the institutional ethics committee, and the study was registered in the Clinical Trial Registry - India (CTRI/2020/02/023455). Patients were categorized based on the established criteria for “unfit for intensive chemotherapy” derived from landmark trials (VIALE-A, NCT02203773, VIALE-C), and subsequent analyses were performed. Outcomes assessed included 30-day induction mortality, documented infection at diagnosis (defined as fever with radiological, microbiological, or clinical focus of infection) and fungal infections according to EORTC and MSG classifications. Post-induction bone marrow response was defined as complete response/complete response with incomplete marrow recovery (CR/CRi) with ≤5% BM blasts, platelet count <100 × 10 9/L, and absolute neutrophil count <1.0 × 10 9/L. Kaplan-Meier analyses were conducted to assess event-free survival and overall survival. Results: Among 1326 eligible patients, 385 received intensive chemotherapy during the study period (49 received less intensive therapy, 442 referred outside, 210 on palliative care, 212 lost to follow up and 28 died). Demographic and baseline characteristics are detailed in Table 1. Cytarabine and daunorubicin (98.9%) were the most common first-line treatments. Of the 385 patients receiving intensive chemotherapy, 188 were categorized as unfit according to the study criteria (Refer Table 1). The unfit cohort exhibited higher 30-day induction mortality compared to the fit cohort (20.5% vs. 6%, P<0.0001) with a trend for higher incidence of proven and probable fungal infections (18.4% vs. 11.2%, P=0.054). Complete remission rates (CR+CRi) were lower in the unfit cohort (52.4% vs. 68%, P<0.001), while no difference in documented bloodstream infections was observed (P=0.754). Univariate analysis revealed that induction mortality was most influenced by age>50 (P=0.019), ECOG ≥2 (P=0.002) and infection at diagnosis (P<0.0001). However, upon conducting multivariate analyses, infection at diagnosis emerged as the strongest predictor of induction mortality (OR:2.91, 95%CI, 1.51 to 5.59, P=0.001). The median follow up was 15.7 months (range, 0.2-73.8). The 2-year estimated event-free survival (EFS) and overall survival (OS) of the entire cohort was 42.9% and 69.2% respectively. For the unfit and fit cohort, the 2-year EFS was 42.2% vs 43.9% (P=0.065), and the 2-year OS was 62.5% vs 75.1% (P=0.001) respectively. Conclusion: Unfit patients who received intensive chemotherapy had higher induction mortality and lower overall survival. Furthermore, it underscores the importance of improving accessibility to novel therapies, to provide a safe and viable alternative for nearly half of our AML patient population.

Coinfections and antimicrobial treatment in a cohort of falciparum malaria in a non-endemic country: a 10-year experience

IntroductionFalciparum malaria remains one of the deadliest infectious diseases worldwide. In Germany, it is mainly an imported infection among travellers. Rates of coinfection are often unknown, and a clinical rationale for the beneficial use of calculated antibiotic therapy in patients with malaria and suspected coinfection is lacking.MethodsWe conducted an analysis of all in-patients treated with falciparum malaria at a German infectious diseases centre in vicinity to one of Europe’s major airports for 2010–2019. Logistic regression and time-to-event analysis were used to evaluate predictors for bacterial coinfection, the use of antibacterial substances, as well as their influence on clinical course.ResultsIn total, 264 patients were included. Of those, 64% received an additional antibacterial therapy (n = 169). Twenty-nine patients (11.0%) were found to have suffered from a relevant bacterial coinfection, while only a small fraction had relevant bacteremia (n = 3, 1.4%). However, patients with severe malaria did not suffer from coinfections more frequently (p = 0.283). CRP levels were not a reliable predictor for a bacterial coinfection (OR 0.99, 95% CI 0.94–1.06, p = 0.850), while another clinical focus of infection was positively associated (OR 3.86, 95% CI 1.45–11.55, p = 0.010).ConclusionAlthough bacterial coinfections were rare in patients with malaria at our centre, the risk does not seem negligible. These data point rather towards individual risk assessment in respective patients than to general empiric antibiotic use.

Do we overtreat patients with presumed neutropenic sepsis?

PurposeMany aspects of the management of neutropenic sepsis remain controversial. These include the choice of empiric antibiotic, the duration of antibiotic therapy and the possibility that very low-risk cases may...

Risk factors for the appearance of secondary foci of infection in children with community-acquired Staphylococcus aureus bacteraemia. Cohort study 2010–2016

IntroductionCommunity-acquired Staphylococcus aureus (SA) bacteraemia is a common cause of hospitalisation in children. The occurrence of secondary foci (SF) of SA infection is associated with higher morbidity and mortality. ObjectivesTo identify risk factors for SF of infection in children with community-acquired SA bacteraemia. Material and methodsProspective cohort. All children aged from 30 days to 16 years admitted to a paediatric referral hospital between January 2010 and December 2016 for community-acquired infections, with SA isolated in blood cultures, were included. Microbiological, demographic and clinical characteristics were compared, with or without SF infection after 72h of hospitalisation. ResultsA total of 283 patients were included, 65% male (n=184), with a median age of 60 months (IQR: 30–132). Seventeen per cent (n=48) had at least one underlying disease and 97% (n=275) had some clinical focus of infection, the most common being: osteoarticular 55% (n=156) and soft tissue abscesses 27% (n=79). A total of 65% (n=185) were resistant to methicillin. A SF of infection was found in 16% of patients (n=44). The SF identified were pneumonia 73% (n=32), osteoarticular 11% (n=5), soft tissue 11% (n=5) and central nervous system 5% (n=2). In the multivariate analysis, the persistence of positive blood cultures after the fifth day (OR: 2.40, 95%CI: 1.07–5.37, p<0.001) and sepsis (OR: 17.23, 95%CI 5.21–56.9, p<0.001) were predictors of SF. There was no association with methicillin sensitivity. ConclusionsIn this cohort, methicillin-resistant SA infections predominated. The occurrence of SF of infection was associated with the persistence of bacteraemia after the fifth day and sepsis on admission.

Factores de riesgo de focos secundarios de infección en niños con bacteriemia por Staphylococcus aureus adquirida en la comunidad. Estudio de cohorte 2010-2016

IntroductionCommunity-acquired Staphylococcus aureus (SA) bacteraemia is a common cause of hospitalisation in children. The occurrence of secondary foci (SF) of SA infection is associated with higher morbidity and mortality. ObjectivesTo identify risk factors for SF of infection in children with community-acquired SA bacteraemia. Material and methodsProspective cohort. All children aged from 30 days to 16 years admitted to a paediatric referral hospital between January 2010 and December 2016 for community-acquired infections, with SA isolated in blood cultures, were included. Microbiological, demographic and clinical characteristics were compared, with or without SF infection after 72hours of hospitalisation. ResultsA total of 283 patients were included, 65% male (n=184), with a median age of 60 months (IQR: 30-132). Seventeen per cent (n=48) had at least one underlying disease and 97% (n=275) had some clinical focus of infection, the most common being: osteoarticular 55% (n=156) and soft tissue abscesses 27% (n=79). A total of 65% (n=185) were resistant to methicillin. A SF of infection was found in 16% of patients (n=44). The SF identified were pneumonia 73% (n=32), osteoarticular 11% (n=5), soft tissue 11% (n=5) and central nervous system 5% (n=2). In the multivariate analysis, the persistence of positive blood cultures after the fifth day (OR: 2.40, 95%CI: 1.07–5.37, P<0.001) and sepsis (OR: 17.23, 95%CI 5.21-56.9, P<0.001) were predictors of SF. There was no association with methicillin sensitivity. ConclusionsIn this cohort, methicillin-resistant SA infections predominated. The occurrence of SF of infection was associated with the persistence of bacteraemia after the fifth day and sepsis on admission.

Can complications in febrile neutropenia be predicted? Report from a developing country.

Febrile neutropenia (FN) is an important cause of morbidity and mortality in children with acute lymphoblastic leukemia (ALL). We aimed to look at complications in febrile neutropenia and to derive a risk model for developing complications from the variables predicting complications. Children on treatment for ALL, presenting with FN, were prospectively enrolled over a period of 1year. Their clinical presentation, course during hospital stay, and outcomes were recorded. Complications recorded included septic shock, pneumonia requiring invasive or non-invasive ventilation, renal failure, neutropenic enterocolitis, encephalopathy, congestive heart failure, and bleeding manifestations. There were 320 episodes of FN among 176 patients. Complications occurred during 73 (22.8%) episodes. Time since last chemotherapy ≤7days [OR 2.2 (1-4.5)], clinical focus of infection [OR 2.7 (1.3-5.5)], undernutrition [OR 2.5 (1.1-5.5)], absolute neutrophil count (ANC)≤100/μL [OR 2.8 (1.3-5.9)], and C-reactive protein (CRP)>60mg/L at admission [OR 13.3 (5.2-33.8)] were independent predictors of complications. A risk model (total score=13) was developed based on these predictors. Children with score of ≥7 had 17.2 (7.7-38.6) odds of developing complications as compared to those with score <7. Score of <7 predicted children at lower risk of complications [sensitivity 88% (78.2-93.8%), specificity 72.5% (65.7-78.4%), PPV 53.6% (44.3-62.6%), NPV 94.4% (89.3-97.1%)]. Complications during febrile neutropenia are high in a developing country setup. A risk score model based on identified risk factors can possibly help in recognizing low-risk febrile neutropenic children at admission.

BISON (Bloodstream Infections and Sepsis Outcomes measurement Network) initiative: an ESGBIS proposal

Motivation Outcome of a bloodstream infection/sepsis (BSI/S) is defined in different ways in different research projects [1]. In this, BSI/S share the characteristics of other fields of medicine; specific issues are related to diversity of causative agents, the clinical focus of infection, severity of comorbid conditions, presence of indwelling devices, multiplicity of affected patient populations, and others [2]. A preliminary list of putative core outcome set (COS) might be:

Predicting complications of chemotherapy-induced febrile neutropenia: A single-center experience.

e20678 Background: Identifying the parameters associated with increased complications would help to formulate a cost-effective and rational therapy in patients with chemotherapy induced febrile neutropenia. Methods: We prospectively collected data from January 2007-December 2011 of consecutive episodes of neutropenic fever at our centre. Clinical features, laboratory characteristics and MASCC score were analysed to identify patients at higher risk for developing complications. Complications were defined as either of the following event: failure of first line antibiotics, organ failure, delay in next cycle of chemotherapy, inpatient admission and death. Results: Three hundred and eighty-eight febrile neutropenia (FN) episodes in 373 patients were included, 256 episodes of FN in hematolymphoid malignancies and 132 episodes of FN in solid tumours. The median age was 31 years (11-76 years). Two hundred and forty-four (65.4%) patients were male. One hundred forty-nine patients (39.94%) had FN during previous cycles, while primary GCSF prophylaxis was used for 205 (52.84%) cases. The median haemoglobin, nadir neutrophil count &amp; median number of days with severe neutropenia (&lt; 1X109/L) were 7.9 gm/dl, 0.04X109/L and 4 days respectively. A clinical focus of infection was present in 174 (44.8%) episodes, with gastrointestinal being the commonest in 70episodes (40.23%). High risk MASCC score (&lt;21) was present in 156 episodes (40%). Complications were seen in 133(34%) instances. On Univariate analysis, age, type of malignancy, prophylactic growth factor use, clinical focus of infection, day of FN, MASCC score, nadir Hb and platelet count were significantly associated with complications. All predictive factors except age and nadir Hb could independently predict complication on multivariate analysis. Conclusions: Clinical and laboratory parameters in addition to MASCC score could help in identifying patients with FN who require hospitalisation and more intensive management strategies.

Infectious Events Prior to Chemotherapy Initiation in Children with Acute Myeloid Leukemia

BackgroundThe primary objective was to describe infectious complications in children with acute myeloid leukemia from presentation to the healthcare system to initiation of chemotherapy and to describe how these infections differ depending on neutropenia.MethodsWe conducted a retrospective, population-based cohort study that included children and adolescents with acute myeloid leukemia diagnosed and treated at 15 Canadian centers. We evaluated infections that occurred between presentation to the healthcare system (for symptoms that led to the diagnosis of acute myeloid leukemia) until initiation of chemotherapy.ResultsAmong 328 children, 92 (28.0%) were neutropenic at presentation. Eleven (3.4%) had sterile-site microbiologically documented infection and four had bacteremia (only one Gram negative). Infection rate was not influenced by neutropenia. No child died from an infectious cause prior to chemotherapy initiation.ConclusionIt may be reasonable to withhold empiric antibiotics in febrile non-neutropenic children with newly diagnosed acute myeloid leukemia until initiation of chemotherapy as long as they appear well without a clinical focus of infection. Future work could examine biomarkers or a clinical score to identify children presenting with leukemia and fever who are more likely to have an invasive infection.

A Proposed Score for Predicting Severe Infection Complications in Children With Chemotherapy-induced Febrile Neutropenia

Febrile neutropenia (FN) is one of most common complications in patients with cancer during chemotherapy. Identifying factors associated with severe infectious complications (SICs) at time of admission for fever and neutropenia is necessary for better treatment. We revised all medical charts of patients under 18 years old who developed a first episode of FN present from January 2000 to December 2003. Criteria for a SIC were defined. These included the presence of bacteremia or fungemia, sepsis, septic shock, and/or death from infection. To identify risk factors SIC was associated with the first FN episode. Factors identified in univariate analysis were female sex, age less than 5 years old, acute myeloid leukemia, baseline disease activity, use of central venous catheter, hemoglobin level < 7 g/dL, leukocytes count < 500 cells/mm(3), granulocytes count < 500 cells/mm(3), monocytes count < 100 cells/mm(3), platelets < 20,000, and body temperature > 38.5 degrees C, a chemotherapy interval < 7 days, presence of mucositis, pneumonia, absence of upper respiratory tract infection, or the presence of any clinical focus on first physical examination. In multivariate analysis the variables that remained as independent predictive risk factors for SIC were age less than 5 years, use of central venous catheter, body temperature > 38.5 degrees C, hemoglobin level < 7 g/dL, any clinical focus of infection on first examination and absence of upper respiratory tract infection. The FN population was than divided among 3 different risk groups as follows: group 1 (low risk), group 2 (intermediate risk), with a 13 (4.4 to 38.3)-fold risk for SIC; and group 3 (high risk) with a 50 (16.4 to 149.2)-fold risk for SIC. This study suggests that patients with FN can be stratified for risk of SIC using clinical parameters at hospital admission.

Circulating inflammatory mediators in patients with fever: predicting bloodstream infection.

The systemic host response to microbial infection involves clinical signs and symptoms of infection, including fever and elevated white blood cell (WBC) counts. In addition, inflammatory mediators are released, including activated complement product C3a, interleukin 6 (IL-6), and the acute-phase reactant secretory phospholipase A(2) (sPLA(2)). To compare the value of the latter with the former in predicting (the degree of) microbial infection at the bedside, we determined clinical variables and took blood samples daily for 3 consecutive days in 300 patients with a new fever (>38.0 degrees C rectally or >38.3 degrees C axillary). Microbiological culture results for 7 days after inclusion were collected. Patients were divided into clinical and microbial categories: those without and with a clinical focus of infection and those with negative cultures, with positive local cultures or specific stains for fungal (n = 13) or tuberculous infections (n = 1), and with positive blood cultures, including one patient with malaria parasitemia. The area under the curve (AUC) of the receiver operating characteristic (ROC) for prediction of positive cultures was 0.60 (P < 0.005) for peak temperature and 0.59 (P < 0.01) for peak WBC count, 0.60 (P < 0.005) for peak C3a, 0.63 (P < 0.001) for peak IL-6, and 0.61 (P < 0.001) for peak sPLA(2). The AUC under the ROC curve for prediction of positive blood cultures was 0.68 (P < 0.001) for peak temperature and 0.56 for peak WBC count (P < 0.05). The AUC for peak C3a was 0.69, that for peak IL-6 was 0.70, and that for sPLA(2) was 0.67 (for all, P < 0.001). The degree of microbial invasion is thus a major determinant of the clinical and inflammatory host response in patients with fever. Moreover, circulating inflammatory mediators such as C3a and IL-6 may help to predict positive blood cultures, together with clinical signs and symptoms of the host response to microbial infection, even before culture results are available. This may help in the designing of entry criteria for therapeutic intervention studies.

Adult Patient Care Plan: Management of the Febrile Neutropenic Cancer Patient on an Outpatient Basis

Invasive infection may complicate the course of neutropenic cancer patients receiving intensive chemotherapy. The rate of complications is related to prognostic factors including the underlying malignant diagnosis, the state of responsiveness of the underlying disease to treatment, the dose‐intensity of the cytotoxic therapy, the duration of neutropenia, the performance status of the patient and comorbid conditions. The pathogens involved are usually the patients’ endogenous microflora, and the sites of infection are those anatomic sites colonized with the endogenous microflora. The approach to the febrile neutropenic episode requires a sequence of steps including the recognition of the febrile state (oral temperature higher than 38°C), the depth and duration of the neutropenia (absolute neutrophil count less than 0.5×109/L), the identification of a clinical focus of infection and a potential pathogen, the administration of empirical antibacterial therapy, and finally, an assessment of the outcome. Management decisions about whether to treat with oral or parenteral antibacterial agents, with a combination or single agent therapy, or as an inpatient or an outpatient can be based on an assessments of risks of the severity of the patient’s comorbid conditions and the patient’s risk of developing medical complications that would require inpatient management. The duration of antimicrobial treatment depends on the recovery from the state of neutropenia and the origin of the infectious process.

Coccidioidomycosis during Human Immunodeficiency Virus Infection

Through a retrospective review, we identified 77 previously unreported cases of coccidioidomycosis during HIV infection. Patients were classified into 1 of 6 categories based on their primary clinical presentation: 20 had focal pulmonary disease (Group 1), 31 had diffuse pulmonary disease (Group 2), 4 had cutaneous coccidioidomycosis (Group 3), 9 had meningitis (Group 4), 7 had extrathoracic lymph node or liver involvement (Group 5), and 6 has positive coccidioidal serology without a clinical focus of infection (Group 6). Coccidioidal serologies were positive on initial testing in 83% of the patients in whom such serologic testing was performed. Sera from 39% of patients were positive for TP antibodies while 74% had CF antibodies. Eleven of 12 seronegative patients had pulmonary disease (Group 1 or 2). Serologic results of other patients sent to a single reference laboratory were similar, with 26% positive for immunodiffusion TP antibodies and 79% positive for immunodiffusion CF antibodies. For the 77 patients in this study, the CD4-lymphocyte count was below 0.250 X 10(9) cells/L in 46 of the 55 patients who had this test performed, and a low CD4 count was significantly associated with mortality (p less than 0.01). At the time of follow-up, 32 of the 77 patients (42%) had died. There were significantly more deaths in those with diffuse pulmonary disease (Group 2) than in other groups (p less than 0.001). Amphotericin B, ketoconazole, fluconazole, and itraconazole were all used as antifungal therapies. Outcome could not be related to the therapy used. Of note, 3 patients developed coccidioidomycosis while receiving ketoconazole for other conditions.(ABSTRACT TRUNCATED AT 250 WORDS)

Scintigraphic Findings of Uncommon Focal Manifestations of Haemophilus Influenzae Septicemia

Haemophilus influenzae septicemia is usually associated with a clinical focus of infection. The investigators describe early scintigraphic findings in some uncommon manifestations of H. influenzae septicemia.