key: cord-0006571-r724j9if authors: Engervall, Per; Björkholm, Magnus title: Infections in neutropenic patients I: Aetiology date: 1995 journal: Med Oncol DOI: 10.1007/bf02990570 sha: cfb8026dc2ca36d7de811f78fb59cc225a2eb333 doc_id: 6571 cord_uid: r724j9if Improvement in supportive care including the introduction of new antibiotics, antiviral and antifungal agents and haematopoietic growth factors have all contributed to a decreased chemotherapy-related mortality and morbidity in cancer patients. However, infections/septic shock during neutropenia still constitutes a major threat to these patients. Most patients develop fever during neutropenia and in 20–40% a manifest bacteremia is documented. In patients with prolonged neutropenia, the risk for fungal infections is increased. The spectrum of bacterial, fungal and viral infections in the neutropenic patient is reviewed. With the introduction of modern chemo-and radio-therapy, an increasing fraction of patients with previously lethal malignant diseases can be cured. Myelosuppression is often the dose limiting toxicity and the resulting neutropenia constitutes a major threat to the patient. The risk for serious infections increases with the depth and duration of the neutropenia [1] . During profound neutropenia most patients develop fever and in 20-40% a manifest bacteremia is documented [2] . Although broad-spectrum antibiotics are promptly instituted, some patients with potentially curable diseases will die from septic shock. The early mortality rate (within 72 hours) due to bacteremia in patients with neutropenia ranges from 0 to 12% in different studies [3] [4] [5] [6] . The spectrum of infections seen in immunocompromised patients varies depending on the underlying disease and its treatment. In general, infections caused by bacteria and fungi are predominant in neutropenic patients while intracellular organisms (e.g. mycobacteria, viruses and parasites) are more frequent in patients with impaired cell-mediated immunity. "To whom correspondence should be addressed. The spectrum of causative agents in bacteremia in neutropenic patients has fluctuated: during the 1950s and 1960s Gram-positive bacteria were most commonly encountered [7] , during the 1970s Gram-negative isolates dominated [8] and since the 1980s Gram-positive bacteria have reemerged as prevailing pathogens [2, 5, 9, 10] . These changes are illustrated by the changing proportion between Gram-positive and Gram-negative singleorganism bacteremias documented in EORTC trials from 1973 to 1991 (Table 1) . The-most common Gram-negative isolates are Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa which together account for more than 90% of the Gram-negative bacteremias in most series (Table 1) [11, 12] . There is clear evidence that these bacteria mainly arise from the gastrointestinal tract and translocation of bacteria from the gut to blood by the dominant fecal strains of Enterobacteriaceae or P. aeruginosa was observed in 45 of 55 neutropenic patients with Gram-negative bacteremia [13] . In patients with concomitant gut colonization of Enterobacteriaceae and P. aeruginosa, the latter organism was most likely to be isolated from blood whether or not the Pseudomonas had the highest bacterial counts [13] . The invasive properties of Pseudomonas were also documented in a study by Schimpff et al. [14] . Thus, patients with leukemia who were colonized with Pseudomonas in the gut subsequently became bacteremic with the same strain. This was not true for E. coli and K. pneumoniae colonization which only occasionally led to bacteremia. More than 50% of bacteremias in that study were acquired during hospitalization [14] . There is a substantial mortality among neutropenic patients with Gramnegative bacteremia and the prognosis of both E. coli and P. aeruginosa bacteremia is worsened by a decreasing neutrophil count, delay in appropriate antibiotic therapy and concomitant pneumonia [15, 16] . Coagulase negative staphylococci (CNS), Staphylococcus aureus and alpha streptococci are the most common Gram-positive bacteria found in blood cultures from neutropenic patients (Table 1 ) [11, 12, 17] . Although S. aureus tends to be more virulent and capable of inducing septic shock [18] , CNS infections may carry both a high morbidity and mortality [19] . Furthermore, the rate of CNS infections increases in neutropenic patients (Table 1 ) [20] . The frequency of methicillin-resistant CNS isolates has increased, though most strains are still susceptible to vancomycin [21] . There is a fear that vancomycin-resistant strains of enterococci will transfer the responsible gene to CNS and thereby cause a difficult therapeutic dilemma. The incidence of alpha streptococcal bacteremia has increased (Table 1) which is associated with a substantial mortality (6-30%) and morbidity such as septic shock (7-18%) and adult respiratory distress syndrome (ARDS; 3-33%) [22] . Predisposing factors for severe streptococcal infection were prophylactic antibiotics, profound neutropenia and the use of acid-reducing drugs for treatment of gastritis'as reported by Elting et al. [23] . Anaerobic bacteria account for approximately 5% of bacteremias in the neutropenic patient [24] . Bacteroides fragilis and Clostridium spp. are the most frequently encountered. It is important to be aware of the possibility of mixed anaerobic and aerobic infections in the oral and perianal regions [25] . Another feared complication of chemotherapy-induced neutropenia is neutropenic enterocolitis. This condition is characterized by fever and abdominal pain often accompanied by vomiting and/or diarrhoea and is mainly caused by anaerobic bacterias [26, 27] . A conservative attitude with bowel rest, decompression, nutritional support, and broad spectrum antibiotics is to be preferred before surgery [27] . Granulocyte count restitution is essentially why haematopoetic growth factors should be tried and the use of granulocyte transfusions may be considered. One specific, although not systemic, nosocomial anaerobic infection is caused by the toxin producing Clostridium difficile, inducing a spectrum of gastrointestinal symptoms from diarrhoea to fulminant colitis [28] . Antibiotic treatment predisposes to this infection but patients may be colonized also without prior exposure to antibiotics [29] . Furthermore, it is well known that other more diffuse symptoms besides diarrhoea, such as abdominal pain, distention and even constipation, may be due to C. difficile infection in neutropenic patients [30] . Mycobacterial infections do not constitute a major problem in patients with neutropenia but both mycobacterium tuberculosis and atypical mycobacteria must be kept in mind when evaluating neutr0penic patients with fever not responding to MEDICAL ONCOLOGY (1995) 12 (4) antibiotics or antifungal drugs [31] . The patient's age, geographical origin and social living conditions are of importance when considering start of empirical anti-tuberculous treatment. Furthermore, a finding of bone marrow granulomas strongly motivates empirical treatment before results of cultures are available [32] . Patients with prolonged neutropenia are predisposed to become infected with candida or aspergillus [33] and fungal infections constitute a majority of fatal infections in patients with acute leukemia [34, 35] . Furthermore, the isolation of candida in blood cultures has become more common in neutropenic patients [36] . The dominating candida species is Candida albicans although increasing incidences of Candida (Torulopsis) glabrata, Candida tropicalis and Candida krusei have been reported in patients receiving prophylactic ketokonazole or fluconazole treatment [37, 38] . Patients receiving intensive chemotherapy often become colonized with candida in urine and feces [39] and they also have a high risk (unless prophylactic fluconazole therapy is given) to develop oropharyngeal candidiasis [40] . The risk of disseminated disease increases with the number of sites colonized and the duration of neutropenia [8, 41] . Most candida infections disseminate from the gastrointestinal tract but candida may also be an aetiologic agent in pneumonia, as demonstrated in 103 neutropenic patients with clinically and microbiologically documented lung infiltrates from which candida were isolated in 24% [42] . This issue is, however, controversial since there are no strict criteria to differentiate between colonization of candida in the respiratory tract and a true infection caused by candida. Despite extensive serological studies [43] and occasional reports of a highly predictive test (candida antigen) [44] , no established method for early diagnosis of disseminated candidiasis with both a high specihcity and sensitivity has emerged [45] . Another important clinical entity in the spectrum of candida related disorders in neutropenic patients is chronic disseminated candidiasis (previously named hepatosplenic candidiasis) which is a disorder characterized by persistence of fever after granulocyte recovery, elevated serum alkaline phosphatase and abdominal pain [46, 47] . Aspergillosis is the second most common fungal infection in neutropenic patients. Aspergillus fumigatus and Aspergillus flavus are the dominating pathogens and the lung is the primary site of infection. This was illustrated in one study where invasive pulmonary aspergiUus infection was the cause of nosocomial pneumonia in 20 of 55 pa-tients undergoing bone marrow transplantation [48] . The mortality rate among these 20 patients was 95% but lower mortality rates have been reported by others [49] . Aspergillus spreads predominately by local invasion/tissue infection and in pulmonary infection subsequent necrosis often extends to the pleura causing a pleuritic chest pain in a majority of patients. In addition, aspergillus infection frequently involves sinuses and in one third of patients with pulmonary involvement a concomitant sinus infection was diagnosed [50] . An early diagnosis and treatment is mandatory and repeated computerized tomography (CT) scans may be of great diagnostic value [51] . Pneumocystis carinii, formerly classified as a parasite, is a rather rare fungal pathogen in the neutropenic patient. However, dusters of infections in patients with leukemia and lymphoma have been described [52] and this agent must be kept in mind also in neutropenic patients with bilateral diffuse alveolar pulmonary infiltrates, particularly in patients undergoing bone marrow transplantation [42, 53] . Mainly viruses from the herpes group (i.e. Herpes simplex virus (HSV), Varicella-zoster virus (VZV) and cytomegalovirus (CMV)) infect patients receiving combination chemotherapy. Recurrent HSV infections may manifest as painful lesions in the oral and perioral areas. HSV oesophagitis is clinically indistinguishable from that of candida origin [54] . Reactivation of HSV is commonly seen in neutropenic patients with haematological malignancies. Twenty-four of 43. patients (72 fever episodes) developed mucocutaneous HSV infection during at least one fever episode [55] . Furthermore, the incidence of fever not responding to antibiotics was higher in patients in whom HSV was isolated. The risk for VZV infection increases with the intensity of treatment and, following bone marrow transplantation, patients have an increased risk for up to I year [56] . CMV infections are mainly seen in patients following allogeneic bone marrow transplantation 'and CMV pneumo* nitis is a major threat carrying a high mortality rate. Acyclovir is the key drug in both prophylaxis and treatment of the herpes virus infections and some studies in bone marrow recipients have shown a reduction of herpetic gingivostomatitis and CMV pneumonitis by the use of prophylactic acyclovir [57, 58] . Acyclovir has also been shown to reduce the incidence of bacterial infections in acute leukemia patients probably by reducing oral herpetic lesions otherwise used as bacterial entry [59] . Earlier attempts to treat manifest CMV pneumo-nitis with various antiviral agents, such as acyclovir, ganciclovir and foscarnet, have not significantly reduced mortality [60] . However, the combination of ganciclovir and intravenous immunoglobulin has shown some improvement of survival and is the recommended treatment for CMV pneumonitis in bone marrow transplant recipients [60] . Another category of viral disorders is the nosocomial hepatitis among which hepatitis C appears to have an increased chronicity rate and late seroconversion in patients with haematological disorders [61] . Frequent patient-to-patient transmission of hepatitis C virus in a haematology ward has been described [62] . Influenza A and B are other viral infections that may be severe but in most neutropenic patients are mild and self-limiting [63, 64] . Gram-positive bacteremias (i.e., CNS and alpha streptococci) dominate in febrile neutropenic patients and some streptococcal species may, as Gram-negative bacteremias, induce septic shock. During prolonged neutropenia fungal infections mainly caused by candida and aspergillus are commonly encountered. Quantitative relationships between circulating leukocytes and infection in patients with acute leukemia Guidelines for the use of antimicrobial agents in neutropenic patients with unexplained fever A randomized trial comparing ceftazidime alone with combination antibiotic therapy in cancer patients with fever and neutropenia Ceftazidime monotherapy is as effective as ceftazidime combined with gentamicin in the treatment of febrile neutropenic patients Vancomycin added to empirical combination antibiotic therapy for fever in granulocy-INFECTIONS DURING NEUTROPENIA topenic cancer patients Ceftazidime compared with piperacillin and tobramycin for empiric treatment of fever in neutropenic patients with cancer Bacteremia at Boston City Hospital: occurrence and mortality during 12 selected years (1935-1972), with special reference to hospital acquired cases Multivariate analysis of factors associated with invasive fungal disease during remission induction therapy for acute myelogenous leukemia Fever and neutropenia during intensive chemotherapy Management of fever in patients with cancer and treatment induced neutropenia A 10-year survey of clinically significant blood culture isolates and antibiotic susceptibilities from adult patients with hematological diseases at a major Swedish hospital. Scand Incidence and clinical significance of positive blood cultures in febrile episodes of patients with haematological malignancies. Scand Bacterial translocation and gram-negative bacteremia in patients with hematological malignancies Origin of infection in acute nonlymphocytic leukemia. Significance of hospital acquisition of potential pathogens Pseudomonas bacteremia: Retrospective analysis of 410 episodes Escherichia coli bacteremia in cancer patients Septicemia in patients with hematological disorders and neutropenia. A retrospective study of causative agents and their resistance profile. Scand Toxic shock syndrome-associated staphylococcal and streptococcal pyrogenic toxins are potent inducers of tumor necrosis factor production Coagulase-negative staphylococcal bacteremia. Mortality and hospital stay Staphylococcus epidermidis/an increasing cause of infection in patients with granulocytopenia Clinically significant coagulase-negative staphylococci: identification and resistance patterns Bacteremia due to viridans streptococci in neutropenic patients: a review Septicemia and shock syndrome due to viridans streptococci: a casecontrol study of predisposing factors Anaerobic bacteremia in patients with acute leukemia Anorectal infections in patients with malignant diseases Acute abdominal pain in the granulocytopenic patient -a clinical dilemma. (Swedish) Neutropenic enterocolitis Clostridium difficile colitis Clostridium difficile colitis in leukemia patients Clostridium difficile in haematological malignancy Disseminated mycobacterium malmoense infection in a patient with chronic granulocytic leukemia Significance of granulomas in the bone marrow Prolonged granulocytopenia: the major risk factor for invasive pulmonary aspergillosis in patients with acute leukemia Nosocomial fungal infections. Old problems and new challenges Candida and Aspergillus infections in immunocompromised patients Overview of management of fungal infections: Part 1 Comparative trial of ketoconazole and nystatin for the prevention of fungal infection in neutropenic patients treated within protected environment Increase in Candida krusei infection among patients with bone marrow transplantation and neutropenia treated prophylactically with fluconazole Fungal infections in neutropenic patients. Necessary with adequate prophylaxis A controlled trial of fluconazole to prevent infections in patients undergoing bone marrow transplantation Invasive fungal disease in pediatric acute leukemia patients with fever and neutropenia during induction chemotherapy: A multivariate analysis of risk factors Pulmonary infiltrations in febrile patients with Invasive fungal infections. Incidence, diagnosis, risk-factors and treatment in bone marrow and liver transplant recipients. Thesis Detection of circulating candida enolase by immunoassay in patients with cancer and invasive candidiasis Severe Candidal infections in neutropenic patients Hepatic candidiasis: an increasing problem in immunocompromised patients Successful treatment of hepatosplenic candidiasis with a liposomal amphotericin B preparation. A case report Nosocomial pneumonia in adult patients undergoing bone marrow transplantation Invasive pulmonary Aspergillosis in early diagnosis and treatment Invasive pulmonary Aspergillosis in adult acute leukemia: clinical clues to its diagnosis Invasive pulmonary Aspergillosis in acute leukemia. The contribution of CT to early diagnosis and aggressive management Pneumocystis carinii pneumonia: a duster of eleven cases Pneumocystis carinii pneumonitis Herpes simplex infections in hematological malignancies Antibiotic resistant fever associated with herpes simplex virus infection in neutropenic patients with haematological malignancy Herpes group viruses infections in the compromised host Acyclovir prophylaxis of herpes-simplex-virus infections: a randomized, double-blind, controlled trial in bone-marrow-transplant recipients Acyclovir for prevention of cytomegalovirus infection and disease after allogeneic marrow transplantation Oral acyclovir prophylaxis for bacterial infections during induction therapy for acute leukemia in adults Treatment and prevention of cytomegalovirus pneumonia after bone marrow transplantation: where do we stand? Late seroconversion and high chronicity rate of hepatitis C virus infection in patients with hematological disorders Frequent patient-to-patient transmission of hepatitis C virus in a Haematology ward Influenza B in transplant patients Influenza A in immunocompromised patients Febrile neutropenia. Focus on antibacterial therapy This work was supported by the Swedish Cancer Society and Karolinska Institute foundations.