by Petr Sedlacek, Charles University, Prague, Czech Rep.

BACKGROUND

Chemotherapy and irradiation, used during the conditioning regimen prior to transplantation, have a devastating effect on the immune system, reducing the defense against pathogens, particularly bacteria, as a common cause of life-threatening sepsis. Careful monitoring of the child, mostly during the aplastic phase prior to engraftment, is therefore necessary so that infection is recognized early and treatment initiated rapidly. Evidence-based guidelines reflecting local epidemiology for the prevention and management of febrile neutropenia (FN) should be followed. FN is usually caused by bacterial infection. Neutropenic fever requires immediate empiric antibiotic therapy following baseline diagnostics. If there is no improvement after 48-72 hours (h), therapy should be modified and further tests initiated. In these cases, fungal or viral infection should be considered. A new febrile episode is defined as a relapse. Early infectious complications are mostly seen early post-transplant during the neutropenic phase. However, since immune reconstitution requires at least six months following allogeneic hematopoietic stem cell transplantation (HSCT), late infectious complications are also frequently seen, mainly in patients already discharged from the transplant unit.

Epidemiology of early post-transplant infections

In the last two decades, the epidemiology of bacteremia in neutropenic patients has changed: the constant prevalence of Gram-positive microorganisms has replaced the re-emergence of Gram-negative bacilli, often with a multi-drug resistance phenotype. The prevalence of Gram-positive bacteria is linked to the continued use of central venous catheter (CVC), the oral and gastrointestinal mucositis from chemotherapy and, at least in part, to the prophylactic use of fluoroquinolones. Coagulase-negative staphylococci (CNS) and Viridans group streptococci are the pathogens most often responsible, while the isolation of Staphylococcus aureus including methicillin resistance (MRSA) is less frequent. The spread of strains with natural or acquired reduced susceptibility to glycopeptides is increasing. In local contexts, enterococci resistant to vancomycin (VRE) may be relevant as well. The continuous increase in resistance among strains of Escherichia coli and Pseudomonas aeruginosa makes these and other Gram-negative bacteria potentially responsible for bacteremia in neutropenic patients. Because of their high early lethality, partly due to their ability to cause septic shock syndrome, the Gram-negative bacteria are the main target of the empirical antibiotic therapy that should be adopted immediately in neutropenic patients who develop fever, while every effort should be made to define the site of infection and the responsible pathogen(s).

Diagnostic approach

The anamnestic investigation should evaluate the overall “score” of impairment of defenses in relation to the underlying disease and its treatment and define the febrile episode as primary or secondary (the first episode of fever during recent-onset neutropenia is caused mostly by bacteria, especially if the patient has not previously received antibiotic therapy, while subsequent episodes are mainly fungal or viral in nature). As neutropenia markedly changes the host inflammatory response, it might be difficult to detect infections. Patients with pneumonia may lack the clinical signs of consolidation, typical radiological signs or purulent sputum production; patients with urinary infections show leukocyturia in only a small percentage of cases; and patients with meningitis may lack detectable signs of meningeal irritation, and cerebrospinal fluid (CSF) pleocytosis may be absent. The physical examination of the patient with FN should be accurate and should always precede any therapeutic action, except for the emergency of septic shock. The examination should have particular regard for neurological signs and symptoms (mental status, cranial nerves, fundus oculi), skin lesions (including perirectal area, site of catheter insertion, the site of previous diagnostic maneuvers such as bone biopsy, etc.), oropharynx (teeth, gums), chest (heart, lungs), abdomen (liver, spleen), lymph nodes, and the pelvic region. In case of suggestive symptoms, special examinations should be done, i.e., lumbar puncture for neurological signs or altered mental status. Other microbiological investigations include urine culture and swabs or needle aspiration from the infected sites. Biomarkers have a potential diagnostic role in invasive fungal infections (search for Aspergillus galactomannan antigen with Pastorex® Aspergillus; beta-d-glucan detection with Fungitell®). Their positivity may suggest a fungal etiology, and in the case of galactomannan, indicate the specific cause. Chest computed tomography (CT) plays an important role and may be repeated to gather evidence suggestive of an infection by filamentous fungi: the so-called “halo sign” that appears early in the course of neutropenia and the “air crescent sign” that appears later (more often only after engraftment) are characteristic diagnostic elements suggestive (though certainly not diagnostic) of pulmonary aspergillosis. Special investigations, sometimes adopted in patients with FN, include bronchoalveolar lavage (BAL) in patients with suspected pneumonia (BAL is also useful in the search for galactomannan), biopsy of any skin lesions, abdominal ultrasound or CT (neutropenic enterocolitis, hepatosplenic candidiasis, signs of lymphoproliferation, etc.), brain CT scan (stroke), and paranasal sinus CT (sinusitis).

Empirical antibiotic therapy

The mean goal of empirical antibiotic therapy is to protect patients from premature death that may occur due to infectious complications (septicemia by Gram-negative bacilli, septic shock) during the first 48–72 h, when the results of microbiological examinations are not yet known. Especially for patients undergoing HSCT, the treatment options are usually represented by beta-lactam antibiotics with antipseudomonal activity (carbapenems, third- or fourth-generation cephalosporins, piperacillin/tazobactam). The choice between these options should take into account the local epidemiology of resistance and the need to maintain low levels of antibiotic selective pressure. The possible options for combination are represented by early administration of aminoglycosides and later vancomycin or teicoplanin. Both glycopeptides, used in combination with other antibiotics, have shown similar efficacy in neutropenic patients with Gram-positive infections. Any initial empirical antibiotic therapy regimen requires reassessment after 48–72 h, when the febrile episode may be classified on the basis of investigations. During neutropenia, especially if severe and prolonged, the patient may suffer from multiple infectious episodes caused by bacterial pathogens and other microbes (fungi, viruses, protozoa). These are manifested with recurrence or persistence of fever, with or without signs of localization, and may be represented by secondary infections (different site, different microorganism), superinfections (same site, different microorganism), and rarely, by relapse (same site, same microorganism). Therefore, appropriate integrations of initial antibiotic therapy are required. In the case of microbiologically documented infection, the choice of maintaining the original regimen or switching to a targeted therapy remains under debate. In the case of a clear location of infection (mucositis, cellulitis, pneumonia, etc.), therapeutic changes will take into account the presumed etiology. When fever and neutropenia persist after 3–5 days of empirical antibiotic therapy (with possible variations between institutions), and it has not been possible to document the site or the pathogen responsible for infection (fever of unknown origin, FUO), an empirical antifungal therapy is usually recommended. The patient with persistent fever and neutropenia has a high risk of developing a fungal infection, especially if multi-colonized by Candida spp. (presence of fungus in swabs taken from two non-contiguous sites) or with nasal colonization by Aspergillus spp. Microbiological documentation of a fungal infection is quite uncommon and may require invasive procedures. The early administration of intravenous antifungal medication may improve the prognosis of invasive fungal infections in neutropenic patients, and the use of this treatment modality is established in clinical practice. Today, lipid preparations of amphotericin B (liposomal amphotericin B [Ambisome®] and amphotericin B complexed with lipids [Abelcet®] have replaced deoxycholate. These preparations share a high cost but, to varying extent, less nephrotoxicity and better tolerability. More recently, a new group of antifungals that act by inhibiting the synthesis of beta-d-glucan, a specific component of some fungi, has been introduced. Echinocandins have a predominantly fungicidal effect and spectrum of activity that includes Candida albicans and non-albicans (including strains resistant to azole) and also Aspergillus spp. Among the echinocandins (caspofungin, micafungin and anidulafungin), caspofungin has been validated for empirical therapy in neutropenic patients. In transplant recipients, prophylaxis with oral azoles is used frequently (fluconazole, itraconazole, voriconazole, or posaconazole). Voriconazole is particularly effective against Aspergillus spp., and is the preferred agent for treatment of documented aspergillosis, but it lacks efficacy against zygomycosis.

Late post-transplant infections

Late infections are related to the level of immune reconstitution after HSCT. Immune reconstitution is delayed in patients treated with prolonged combinations of immunosuppressive drugs (including steroids and/or biologicals) for acute/chronic graft-versus-host disease (GvHD) and in those transplanted with T-cell-depleted grafts (haploidentical donors, other mismatched donors), as well as following cord blood transplantation. There are specific situations in patients suffering from serious infections prior to transplant where re-activation of these pathogens could be observed after HSCT, including fungal infections (yeasts or molds), toxoplasmosis, mycobacterial infections (tuberculosis [TB], bacillus Calmette-Guérin [BCG]), and hepatitis B and C, etc. Thus, it is necessary to evaluate carefully the medical history of the patient for such risk factors in order to tailor the diagnostics more specifically. Many patients may suffer from viral reactivations and/or primary viral infections presenting a wide spectrum of different symptoms of the skin (varicella zoster virus [VZV], herpes simplex virus [HSV], human herpesvirus [HHV]6), the liver or intestinal tract (adenoviruses [AdV], cytomegalovirus [CMV], Epstein-Barr virus [EBV]), the urinary tract (BK virus, AdV, CMV), the respiratory tract (respiratory syncytial virus [RSV], CMV, AdV, influenza, parainfluenza, meta-pneumovirus, and others), and the bone marrow (CMV, HHV6, etc.). Diagnostic procedures, therefore, include polymerase chain reaction (PCR) techniques to search for relevant pathogens in relevant tissue samples (blood, stool, urine, CSF, skin, gut, lungs, effusions, and others). While the acyclovir prophylaxis became a highly effective measure to prevent HSV and VZV reactivations, the molecular detection of other viruses usually requires a so-called preemptive antiviral treatment (ganciclovir, foscavir, ribavirin, cidofovir, or combinations) before they cause life-threatening complications, but in part with significant side effects. Therefore, adoptive treatment with virus-specific T-cells might be the treatment of choice in the future..

Conclusions

Infections in patients following HSCT are serious and very frequent complications, and if not properly diagnosed and treated, may result in a fatal outcome. Several pathogens causing repeated infections in a single patient are frequently encountered in HSCT practice. Infections are not limited to the neutropenic phase! Some pathogens are resistant to drugs used in frontline therapy. The infectious risk is prolonged if reconstitution of immunity is delayed.

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• Internal revision by Prof. Dr. Duygu Uçkan, Hacettepe University, Ankara, Turkey; Dr. Jaime Sanz Caballer, La Fe University, Valencia, Spain
  


• External revision by Prof. Dr. Wolfram Ebell, Charite University, Berlin, Germany
  


• Edited by Corinne Can