Non-neutropenic Patient Research Articles

Candidemia: Evolution of Drug Resistance and Novel Therapeutic Approaches.

Candidemia and invasive candidiasis are the most common healthcare-associated invasive fungal infections, with a crude mortality rate of 25–50%. Candida albicans remains the most frequent etiology, followed by C. glabrata, C. parapsilosis and C. tropicalis. With the exception of a limited number of species (ie: C. krusei, C. glabrata and rare Candida species), resistance to fluconazole and other triazoles are quite uncommon. However, recently fluconazole-resistant C. parapsilosis, echinocandin-resistant C. glabrata and the multidrug resistant C. auris have emerged. Resistance to amphotericin B is even more rare due to the reduced fitness of resistant isolates. The mechanisms of antifungal resistance in Candida (altered drug-target interactions, reduced cellular drug concentrations, and physical barriers associated with biofilms) are analyzed. The choice of the antifungal therapy for candidemia must take into account several factors such as type of patient, presence of devices, severity of illness, recent exposure to antifungals, local epidemiology, organs involvement, and Candida species. The first-line therapy in non-neutropenic critical patient is an echinocandin switching to fluconazole in clinically stable patients with negative blood cultures and azole susceptible isolate. Similarly, an echinocandin is the drug of choice also in neutropenic patients. The treatment duration is 14 days after the first negative blood culture or longer in cases of organ involvement. An early removal of vascular catheter improves the outcome. The promising results of new antifungal molecules, such as the terpenoid derivative ibrexafungerp, the novel echinocandin with an enhanced half-life rezafungin, oteseconazole and fosmanogepix, representative of new classes of antifungals, are discussed.

Rapid Absolute Neutrophil Count Testing Guides Targeted Antimicrobial Therapy in Febrile Pediatric Oncology Patients.

It is well established that early antibiotic administration leads to improved outcomes in febrile neutropenic patients. To achieve this, many institutions administer empiric antibiotics to all febrile oncology patients in the emergency setting, before knowing their neutropenic status. This study evaluates the role of rapid absolute neutrophil count (ANC) testing in the targeted antimicrobial management of nonneutropenic febrile oncology patients. We conducted a retrospective review of patients 19 years or younger presenting to the pediatric emergency service with an oncologic process and fever or history of fever. We examined the administration of antibiotics and outcomes in nonneutropenic patients. We included 101 patient encounters, representing 62 distinct patients. The rapid ANC test influenced antibiotic management in 94% (95/101) of patient encounters and resulted in no antibiotics or targeted antibiotic therapy in 88% (60/68) of nonneutropenic patients. Use of the rapid ANC test to guide treatment would have spared antibiotic administration in 68% (46/68) of well-appearing nonneutropenic patients with no alternate indication. No well-appearing, nonneutropenic patient had a positive blood culture, and only 1 required hospital admission on a repeat visit. The rapid ANC is a useful tool to balance the goal of early antibiotic administration in febrile neutropenic oncology patients while promoting antibiotic stewardship in this vulnerable population.

Association between Periprocedural Neutropenia and Early Infection-related Chest Port Removal.

Background Patients who require long-term central venous access can present for port placement with depressed immune function as a result of their treatment or disease process. At present, there is no consensus regarding whether neutropenia at the time of port placement confers a higher risk for early infection-related port removal. Purpose To compare the incidence of early infection-related chest port removal in adults when placed in neutropenic versus nonneutropenic patient groups. Materials and Methods This retrospective cohort study examined 2580 port placements in 1081 men (41.9%) and 1499 women (58.1%) at a single tertiary medical center between June 2007 and July 2017. Mean patient age ± standard deviation was 56 years ± 14 (range, 18-91 years). The electronic medical record was used to identify neutropenia (absolute neutrophil count <1500 cells/mm3) at the time of port placement and incidence of infection-related port removal. Electronic medical record follow-up was conducted for 30 days following port placement. End points were infection-related port removal or death related to port infection within 30 days. Statistical analysis compared the neutropenic (n = 159) and nonneutropenic (n = 2421) patient groups by using a χ2 test for categorical data and a Student t test for continuous variables, with a Fisher exact test to compare incidence of port removal and death related to port infection. Results Ports placed in patients with neutropenia had an infection-related removal rate of 3.8% (six of 159) versus 0.91% (22 of 2421) in patients without neutropenia (P = .003). Patients with neutropenia had a port infection-related death rate of 0.63% (one of 159) versus 0.12% (three of 2421) for patients without neutropenia (P = .22). Conclusion Neutropenia in adults at the time of implantable subcutaneous chest port placement was associated with a higher risk for early infection-related port removal. There was no difference in the incidence of death related to port infection in neutropenic or nonneutropenic populations. © RSNA, 2019 See also the editorial by Johnson in this issue.

Treatment of Aspergillosis.

Infections caused by Aspergillus spp. remain associated with high morbidity and mortality. While mold-active antifungal prophylaxis has led to a decrease of occurrence of invasive aspergillosis (IA) in those patients most at risk for infection, breakthrough IA does occur and remains difficult to diagnose due to low sensitivities of mycological tests for IA. IA is also increasingly observed in other non-neutropenic patient groups, where clinical presentation is atypical and diagnosis remains challenging. Early and targeted systemic antifungal treatment remains the most important predictive factor for a successful outcome in immunocompromised individuals. Recent guidelines recommend voriconazole and/or isavuconazole for the primary treatment of IA, with liposomal amphotericin B being the first alternative, and posaconazole, as well as echinocandins, primarily recommended for salvage treatment. Few studies have evaluated treatment options for chronic pulmonary aspergillosis (CPA), where long-term oral itraconazole or voriconazole remain the treatment of choice.

Evaluation of role of granulocyte macrophage colony stimulating factor (GM-CSF) in treatment of patients with perforation peritonitis: a prospective study

Background: GM-CSF has been demonstrated to be effective in reducing the incidence of infection in patients who receive myelosuppressive anticancer chemotherapy or patients who are neutropenic and agranulocytic. We study the role of GM-CSF in non-neutropenic patients with Systemic Inflammatory Response Syndrome (SIRS), infections and sepsis with impaired neutrophil function to access the current rationale for administering GM-CSF in addition to standard antibiotic therapy to critically ill patientsMethods: All patients undergoing surgery for peritonitis due to gastrointestinal perforations were included in this study and were divided into two groups alternatively to avoid any bias i.e. Group A 1, 3, 5 etc. and Group B 2, 4, 6 etc. Group A - all patients received GM-CSF along with standard antibiotics. Group B patients received antibiotics only. Course of patient in immediate postoperative period, time to improvement, duration of hospital stay, antibiotic therapy, rate of complications were compared.Results: Patients in group A had a lower duration of antibiotic therapy and hospital stay. Patients in group A took less time to show clinical improvement compared to patients in Group B. Group A also had a much lower rate of infectious and systemic complications compared to group B. Conclusions: Results of the present study show that GM-CSF is an important molecule when used as adjunct to antibiotics in cases of abdominal sepsis. Use of this growth factor is associated with less incidence of septic complications and morbidity, a shorter duration of antibiotic therapy and hospital stay without significantly compromising the cost. The results of present study help in identifying its role in non-neutropenic patient groups who are most likely to benefit from its administration.

Noncandidal Fungal Infections

Fungal infections remain an important cause of morbidity and mortality in surgical settings, with critically ill patients, transplant recipients, and sick neonates all especially vulnerable. Over the past few decades, technological and scientific advancements have improved physicians’ ability to sustain life in critically ill patients; developments in chemotherapeutics and immune-based therapies have yielded increased survival for many cancer patients; organ transplantation has evolved dramatically; and the use of invasive therapies (eg, ventricular assist devices) has increased markedly. With these changes has come an increase in the incidence of serious fungal infections, including the less common but potentially fatal noncandidal infections caused by Aspergillus and the Zygomycetes Mucor and Rhizopus. This review outlines an approach to the workup and management of the nonneutropenic surgical patient with a suspected noncandidal infection (aspergillosis and zygomycosis). Figures show biopsy samples from an elderly man with chronic progressive disseminated histoplasmosis and thick-walled, broad-based budding yeasts typical for Blastomyces dermatitidis on biopsy material. This review contains 2 figures and 47 references Key words: aspergillosis, aspergillosis prophylaxis, blastomycosis, Cryptococcus, histoplasmosis, noncandidal fungal infections

Noncandidal Fungal Infections

Fungal infections remain an important cause of morbidity and mortality in surgical settings, with critically ill patients, transplant recipients, and sick neonates all especially vulnerable. Over the past few decades, technological and scientific advancements have improved physicians’ ability to sustain life in critically ill patients; developments in chemotherapeutics and immune-based therapies have yielded increased survival for many cancer patients; organ transplantation has evolved dramatically; and the use of invasive therapies (eg, ventricular assist devices) has increased markedly. With these changes has come an increase in the incidence of serious fungal infections, including the less common but potentially fatal noncandidal infections caused by Aspergillus and the Zygomycetes Mucor and Rhizopus. This review outlines an approach to the workup and management of the nonneutropenic surgical patient with a suspected noncandidal infection (aspergillosis and zygomycosis). Figures show biopsy samples from an elderly man with chronic progressive disseminated histoplasmosis and thick-walled, broad-based budding yeasts typical for Blastomyces dermatitidis on biopsy material. This review contains 2 figures and 47 references Key words: aspergillosis, aspergillosis prophylaxis, blastomycosis, Cryptococcus, histoplasmosis, noncandidal fungal infections

Microbiological and immunological characteristics of a lethal pulmonary Aspergillus niger infection in a non-neutropenic patient

Invasive pulmonary aspergillosis is increasingly described in non-neutropenic patients, such as patients with COPD receiving corticosteroids and the critically ill. Here, we present a case of a lethal pulmonary Aspergillus niger infection in a COPD patient. Immunological tests showed an impaired innate and adaptive immune response to Aspergillus. A history of COPD, unresponsiveness to antibiotics and especially a suggestive CT-scan should trigger the clinician to consider diseases caused by Aspergillus.

Successful Use of Extracorporeal Life Support in a Hematopoietic Stem Cell Transplant Patient with Neuroblastoma

Respiratory failure associated with hematopoietic stem cell transplantation (HSCT) has been considered a contraindication for use of extracorporeal membrane oxygenation (ECMO) at many centers. We describe a child with neuroblastoma and hypoxemic respiratory failure following HSCT who was successfully managed with veno-venous (VV) ECMO. The patient was an 18-month-old female with high-risk neuroblastoma status post tumor resection, chemotherapy, autologous HSCT, and primary site radiation. On day 113 posttransplant while receiving maintenance immunotherapy, she had an acute respiratory decompensation because of rhinovirus, aspiration pneumonia, and capillary leak syndrome. The patient was intubated and transitioned to a high frequency oscillatory ventilation and inhaled nitric oxide. Because of refractory hypoxemia, she was cannulated for VV ECMO. She was weaned and decannulated after 7.5 days on ECMO, then subsequently transferred for inpatient rehabilitation. The most recent Extracorporeal Life Support Organization registry analysis showed low survival (3/29) in patients requiring ECMO after HSCT, and 2 of 3 survivors had nononcological diagnoses. However, our patient’s outcome suggests that HSCT status should not be an absolute contraindication. The presence of a reversible single organ failure and the absence of significant bleeding risk in an engrafted, neurologically intact, and non-neutropenic HSCT patient with a favorable prognosis can support the potential benefit of ECMO.

An Unusual Case of Nosocomial Trichosporon asahii Fungemia in a Patient with Tuberculous meningitis

Introduction: Invasive Trichosporon species have been documented mostly in neutropenic patients with underlying hematological malignancies with high mortality, and in critically ill patients exposed to multiple invasive medical procedures. This fungus has been recognized as the second or third most common agent of yeast fungemia. Case Presentation: This study reports on invasive infection with Trichosporon asahii in a non-neutropenic patient with Tuberculous meningitis, who was a known case of diabetes mellitus type II. Conclusions: Although fungemia due to Trichosporon species is an opportunistic pathogen in granulocytopenic patients, there is a steady increase in the number of such cases in non-neutropenic and non-hematological malignant patients. Thus, clinicians as well as microbiologists should be aware of such infections in critically ill patients as early diagnosis and timely management with appropriate antifungal drugs could decrease morbidity and mortality rate.

Sustained Clostridium tertium Bacteremia in a Nonneutropenic Patient

Abstract We report a case of sustained Clostridium tertium bacteremia mimicking an endovascular infection in a nonneutropenic patient with metastatic pancreatic neuroendocrine cancer. Clostridium tertium infection has been increasingly recognized in immunocompromised patients. The significance of this organism in nonneutropenic host, however, is unclear. The diagnosis and treatment can be challenging owing to morphology and antibiotic resistance patterns. Newer rapid identification testing with mass spectrometry enables for early diagnosis and treatment. We discuss the clinical significance of C. tertium as an emerging pathogen with review of the literature.

Postoperative Clostridium tertium septicemia in a non-neutropenic pediatric patient

Clostridium tertium (C. tertium) septicemia is rare, and most cases are observed in neutropenic patients. Our case was a non-neutropenic 7-month-old male who underwent anorectal surgery. On postoperative day 2, his body temperature increased to 40.0°C and gram-positive bacilli were isolated from the aerobic blood culture. We started empiric antibiotic therapy with meropenem. Because the strain was initially identified as Listeria grayi, we switched to ampicillin following susceptibility testing. However, the sequence analysis of the 16S-rRNA gene showed 99% similarity to C. tertium. Here we review the characteristics and management of C. tertium septicemia in non-neutropenic patients.

A phase II study to evaluate lenalidomide in combination with metronomic-dose cyclophosphamide in patients with heavily pretreated classical Hodgkin lymphoma

Background. Relapsed or refractory (R/R) classical Hodgkin lymphoma (cHL) after autologous stem cell transplantation (ASCT) remains a challenge. For these patients treatments with different mechanisms of action rather than classical chemotherapy are needed.Patients and methods. Patients with R/R cHL after ASCT were recruited in a phase II trial (EUDRA CT: 2009-016588-12). Lenalidomide was administered at 20 mg/day for 21 days and cyclophosphamide at 50 mg/day for 28 days (cycles every 28 days). Dose escalation for lenalidomide was permitted. In 2009 we considered that this treatment would be promising if response rate were over 60% and a Simon two-stage binomial design was used to calculate the sample size. A total of 46 patients were planned but the trial would be stopped if less than seven responses after four cycles were obtained in the first 16 patients.Results. The trial was closed early because only five responses were observed after four cycles in the first 16 patients included. Median age was 34 years (18–77). The median number of previous lines was five (2–6). At inclusion, 10 patients were primary refractory and 11 refractory to the last therapy. A total of 110 cycles were administered, with grade ≥ 3 toxicity in 43 cycles (39%). One non-neutropenic patient developed septic shock resulting in death. An ORR of 38% (1 CR and 5 PR) was observed and a total of 10 patients (62%) achieved clinical benefit. Median progression free survival and overall survival were seven and 19 months, respectively. With a median follow-up of 19 months (3–38+), three-year progression-free and overall survival were 6% and 31%, respectively.Conclusion. The optimistic assumptions of this trial led to an early closure. However, the promising clinical benefit observed with the oral combination of lenalidomide and metronomic cyclophosphamide may justify its use for outpatient palliative treatment.

Fungal pneumonia in intensive care unit: When to suspect and decision to treatment: A critical review

Fungal pneumonia is classically found in neutropenic patients. There is increase in concern about this entity in nonneutropenic critically ill patients. Aspergillus is the main offending organism. Although Candida is frequently found in respiratory sample in intensive care unit (ICU) it is always colonization rather than pneumonia. Other than neutropenia, chronic obstructive pulmonary disease and long-term steroid use are the main risk factors for invasive pulmonary aspergillosis in an ICU setting. Treatment in a nonneutropenic patient is only considered if the culture of Aspergillus comes positive in respiratory sample in the background of risk factors.

Sepsis and neutropenia in hematological malignancies

The pre-existing inflammatory state influences the behavior of infection, a first peak of inflammation may be the risk factor during infection and predispose to a severe form of the disease [1,2]. This hypothesis is frequently accepted but has never been tested. Patients with hematological malignancies treated by chemotherapy in case of autologous stem cell transplantation (ASCT) are exposed to a neutropenic state: an abnormal low number of neutrophils. In the neutropenic patient, sepsis is more frequent than in the non-neutropenic patient. The severity of infection depends on many factors, particularly the pre-existing inflammatory state, the genetic factors, and the duration and the depth of neutropenia. In the literature, the factors involved in inflammation and infection are often confused. On the other hand, no predictive transcriptomic signature of sepsis was found. Our objective is to identify predictive genes that influence the outcomes of the infection in neutropenic patients.

Recurrent Lung Abscesses during Chemotherapy in Non-neutropenic Patient with Limited Stage Small Cell Lung Cancer: A Case Report and Review

Background: Small cell lung cancer (SCLC) represents 14% of all lung cancer cases. The current standard of care for limited stage SCLC is the chemotherapy combination of EP (etoposide, cisplatin) with concomitant radiotherapy. Treatment protocol is tolerated well and is associated with few side effects.Case Description: 58 y.o. lady diagnosed to have limited stage SCLC in our institute in November 2013. She was planned for concomitant chemoradiotherapy (CCRT). She started initially on chemotherapy protocol EP. On day 12 of cycle 2, the patient complained of Fever, excessive cough. CT thorax showed newly developed peripherally situated pulmonary abscess. She was kept in with IV antibiotics, and her condition was improved thereafter. Then she was started on CCRT, with cycle 3 EP. On day 6 of her cycle 3, she developed fatigue, poor general condition, high fever, cough and neutropenia. She was admitted as neutropenic sepsis, with improvement of neutropenia after only 1 shot of short acting GCSF. Sputum culture showed Klebsiella pneumonia. CT Thorax showed new lung abscess in the Left ligula. She was treated by IV antibiotic for 10 days. Her condition was improving thereafter and she was returned back to radiotherapy, as well as Cycle 4 EP. Currently, she finished her treatment since 1 month with no complication related to treatment protocol. Discussion: Although few, studies attributed the reason for lung abscess development to leuconeutropenia in some patients, and to relatively large primary tumour size in other patients. Conclusion: Many reasons may explain the development of lung abscess in non-neutropenic patient including chemotherapy side effect, underlying chest condition, and relatively large primary tumour size.

Case report: Enteral nutritional supplement as a likely cause of false-positive galactomannan testing

The detection of galactomannan (GM) in the serum of in immunocompromised patients is widely used for the early diagnosis of invasive aspergillosis. We report a case of a false-positive GM test presumably caused by the enteral nutritional supplement given to a non-neutropenic patient with intestinal graft-versus-host disease after a hematopoietic stem cell transplant. Clinicians should be alert to the possibility of false-positive GM results in patients on nutritional supplements.

Assessment of the significance of respiratory culture of Aspergillus in the non-neutropenic patient. A critique of published diagnostic criteria

Assessment of the significance of isolation of Aspergillus sp. from respiratory culture in patients who are not neutropenic is a continuing problem in respiratory medicine. In recent years a number of criteria for defining patients with invasive or chronic pulmonary aspergillosis in this group have been proposed. This study sought to assess the value of three sets of these criteria in distinguishing between colonisation and aspergillosis requiring therapy when applied retrospectively to 121 patients with positive sputum or BAL culture for Aspergillus sp. Two patients (1.6%) were identified as having proven or probable aspergillosis by the EORTC criteria, two different patients fulfilled the criteria for invasive aspergillosis in the 62 patients with chronic obstructive pulmonary disease (3.2%), and yet another two different patients met the criteria for chronic pulmonary aspergillosis (1.6%). It is suggested that difficulties in the application of some of these criteria may prevent the accurate diagnosis of aspergillosis in the non-neutropenic patient setting.

Pulmonary Zygomycosis in a Non-neutropenic Patient With Myelodysplastic Syndrome on Lenalidomide

Pulmonary zygomycosis is an uncommon infection that occurs mostly in immunocompromised patients. We report the case of a 75-year-old man with myelodysplastic syndrome, treated with lenalidomide for 3 months, who developed respiratory failure and a rapidly progressive left upper lobe consolidation. An extensive workup was unrevealing of the etiology, and the patient expired. A full autopsy was declined, but an in situ post-mortem transbronchial lung biopsy revealed pulmonary zygomycosis. This unique case illustrates the potential risks of lenalidomide therapy in patients with myelodysplastic syndrome and the difficulties in diagnosing pulmonary zygomycosis. To our knowledge this is the first report of a diagnostic in situ post-mortem transbronchial lung biopsy.

Treated Follicular Lymphoma, Recurrent Invasive Pneumococcal Disease, Nonresponsiveness to Vaccination, and a Unique Pneumococcus

A nonneutropenic patient with treated low-grade non-Hodgkin's (Follicular) lymphoma and secondary hypogammaglobulinemia recovered from pneumococcal pneumonia and septicemia (serotype 7F; ST191) subsequent to influenza A H1N1 (2009). Both infections were potentially vaccine preventable. The patient then developed pneumococcal meningitis due to a serotype 35F pneumococcus with a unique Multilocus Sequence Type (ST7004) which was not vaccine preventable. Patient management was influenced by host predisposition to pneumococcal infection, antibiotic intolerance, and poor response to polysaccharide pneumococcal vaccine. Indirect immunofluorescence with anti-human immunoglobulin confirmed a poor or intermediate response to Pneumovax II. Prophylactic erythromycin was initiated, and immunoglobulin transfusions were also commenced as a preventive strategy. ST7004 is a single locus variant of ST1635 which has been associated with the serotype 35F capsule in England. The spi gene in ST7004, which differentiates it from ST1635, is the same as the spi gene present in ST191 which could have arisen from the first disease episode suggesting that horizontal gene transfer may have occurred between different populations of pneumococci present within the patient in an attempt to evade vaccination selection pressure.