Neutropenia

Although the first scientist who showed, in pivotal studies, the direct relationship between infection and neutropenia was Gerald Bodey, from Houston in 1966, the first report in which the risk was reported in terms of infection rate was probably published in 1993 by Carlisle and colleagues,²⁷ who showed that the rate of infections in neutropenic cancer patients was 46.3 episodes per 1000 days of neutropenia (DN), with rates of 12.9 for bacteremia and 2.9 for invasive mycoses. More recent data from a prospective study in children and adults with neutropenia showed a median incidence of infectious complications of 43% and a rate of 22.8 episodes per 1000 DN; bacteremia was diagnosed in 21% of the episodes and mold infections in 5%, with rates of 10.2 and 2.4 for 1000 DN, respectively.⁷ As shown in Table 310-2, the rate of infections is higher after high-intensity chemotherapies and lower after maintenance treatment. Although the epidemiology of infections has been studied more extensively in children, in general, data from adults report higher rates of infectious complications compared with pediatric populations. The majority of primary febrile episodes usually occur soon (a few days) after the onset of neutropenia.

Mucositis

As already mentioned, in addition to neutropenia, the severity of mucosal barrier injury may have an impact on infection rates. Indeed, it has been demonstrated that in patients receiving HSCT, the fever is strictly related to the severity of mucosal barrier injury, independently of the severity and duration of myelosuppression. Mucositis is one of the most important factors predisposing to bloodstream infections, both caused by bacteria and by Candida. The damage of mucosal barrier allows colonizing pathogens to enter the bloodstream, where, in the absence of granulocytes, severe infection can rapidly develop, even in case of a low bacterial load. Mucositis, with or without neutropenia, might also be responsible for severe oral and intestinal infections. The pathogenesis and the role of mucositis after chemotherapy is described in detail elsewhere (see Chapter 309).

Central Venous Catheters

The presence of a central venous catheter (CVC) is another well-known factor facilitating infection in cancer patients and influencing the etiology of bacteremia. Table 310-4 reports the incidence of CVC-related complications in cancer patients.^{20,28–35,36–38} Bacteremia represents the most frequent condition, whereas exit site, tunnel, and other types of CVC-related infections are less frequently reported. These complications are more frequent in partially implanted than in totally implanted catheters and also in double-lumen compared with single-lumen devices. It is noteworthy that in patients with totally implanted CVCs, infectious complications are more frequent in younger patients with hematologic malignancies than in other categories.³⁷ The number of CVC manipulations, which is mainly related with the intensity of antineoplastic chemotherapy and the severity of clinical conditions, represents the most important risk factor for the development of these infections.

A detailed description of complex problem of CVC-related infections is beyond the scope of this chapter and can be found elsewhere (see Chapter 302). The incidence of CVC-related infections should be kept at the minimum by several educational and organizational measures, such as repeated teaching sessions for patients, parents, and staff, or establishing teams dedicated to the insertion and maintenance of intravascular devices. Technical measures that have been suggested include the use of chlorhexidine-impregnated dressings or sponges and the antiseptic/antimicrobial coating of intravascular catheters, for example, with chlorhexidine and silver sulfadiazine. The benefit of their routine use depends on their cost, the observed rate and outcome of CVC infections, and, in case of antibiotic-impregnated devices, on the risk of inducing antimicrobial resistance.

Genetic Factors

The existence of genetic factors that are able to increase or decrease the susceptibility to infection in immunocompromised patients underlines an apparently trivial but important aspect, that is, all cancer patients are not the same, and every single patient might deserve an individualized approach. For example, in nonleukemic patients receiving less intensive chemotherapy, decreased levels of mannose-binding protein were associated with an increased risk of infection (49.9 vs. 29.6/1000 days at risk, P = .01). This effect, less evident in the context of prolonged neutropenia, was not confirmed in all the studies. However, in a recent study of 269 children with cancer, mannose-binding lectin deficiency influenced both the incidence and the severity of febrile neutropenia.³⁹ Polymorphisms of Toll-like receptors and other components of innate immunity have been associated with an increased risk of invasive aspergillosis, both in cancer patients (including recipients of HSCT) and in other immunocompromised patients.⁴⁰ The future will tell us whether genetic polymorphisms, alone or in combination, have an actual impact and might dictate prophylactic or therapeutic approaches.

Biologic Agents and Other New Drugs

As already mentioned, in recent years, monoclonal antibodies and other pharmaceutical compounds, specifically engineered for targeting cells or cytokines involved in the pathogenesis of specific diseases, have been introduced in the armamentarium of antineoplastic chemotherapy. These include biologic response modifiers and protein kinase inhibitors. Alemtuzumab is a monoclonal antibody against the CD52 receptor that is used in the treatment of acute or chronic lymphocytic leukemia or non-Hodgkin’s lymphoma. This monoclonal antibody has a clear role in increasing the infection risk because it is associated with long-lasting and profound lymphopenia. Bacteremias, invasive fungal diseases (including pneumocystosis), several viral diseases, and tuberculosis have been all described in association with this drug. A low CD4⁺ T-lymphocyte count (with a possible cutoff of 200 CD4⁺/mm³) has been indicated as one of the most important factors related to the development of infectious complications. Obviously, infections seem to be more common (with more severe clinical pictures) in patients previously treated with other antineoplastic protocols. Rituximab is an anti-CD20 (B-cell) antibody that causes a prolonged (2 to 6 months median, but sometimes more) suppression of immunoglobulin production. It has been associated with reactivation or acute exacerbation of viral hepatitis (both hepatitis B virus [HBV] and C virus [HCV]) and, more rarely, with disseminated parvovirus infections, enteroviral meningitis, progressive multifocal leukoencephalopathy, babesiosis, and pneumocystosis.⁴¹ Bacterial and fungal diseases have also been described, usually when rituximab was administered in combination with other chemotherapeutic agents. For other anti-CD20 monoclonal antibodies, such as ibritumomab, tositumomab, ofatumumab, and ocrelizumab, less data on infectious complications exist. Such monoclonal antibodies were reported to cause severe myelosuppression, with a spectrum of infectious complications somewhat similar to those associated with classic cytostatic drugs. It is noteworthy that patients receiving antilymphocytic monoclonal antibodies (anti-CD52 and/or anti-CD20) for relapsing diseases (i.e., after previous prolonged chemotherapy cycles) present more frequent and severe complications compared with those who receive front-line therapies. Bevacizumab is another monoclonal antibody that targets vascular endothelial growth factor and is used in colon, kidney, brain, or lung cancer. Febrile neutropenia and bacterial infections have been reported in approximately 10% of patients, usually when the drug was used in combination with other chemotherapeutic agents. Cetuximab (approved for colon, head, and neck cancer) and panitumumab (approved for colon cancer) both have the epidermal growth factor receptor as their main target of activity and cause important dermatologic toxicity, such as rash, skin drying and fissuring, or paronychial inflammation, with infectious complications in up to 30% of patients, including sepsis caused by S. aureus. Trastuzumab reacts with the human epidermal growth factor receptor 2 (HER2) and is administered, usually in combination with standard chemotherapies, for treatment of HER2-positive breast or gastric cancers. Infections associated with this compound are generally mild, though not infrequent, and they may exacerbate chemotherapy-induced neutropenia. Small molecules with protein kinase activity targeting oncogenic tyrosine kinase BCR-ABL (breakpoint cluster region–Abelson murine leukemia), such as imatinib, desatinib, and nilotinib, are used in patients with both acute and chronic leukemia and solid tumors, even for very long periods of time. Infectious complications seem to be similar to those observed with other immunosuppressive drugs affecting mechanisms of cell-mediated immunity, such as pneumocystosis and viral diseases, including reactivation of hepatitis. Because of the absence of major myelosuppression, there is no apparent increase in the rates of bacterial or fungal infections.²⁶ Finally, there are kinase inhibitors, such as sunitinib and sorafenib, that are used before nephrectomy for renal cell carcinoma and for hepatocellular carcinoma. These drugs apparently do not increase the risk of surgical infections, although one of them (sunitinib) has been associated with necrotizing fasciitis, respiratory infections, and sepsis.

Several problems impair our ability to understand the exact role of these new compounds on the risk of infection in cancer patients. Even in randomized, placebo-controlled trials and in large open-label studies, it is difficult to establish the rate of infectious complications. The main reason is that these trials were powered to measure efficacy but not safety, and if the effect is very rare, it might go undetected. Second, there are many confounding factors because new drugs are usually used together with old or classic therapies, making it difficult, if not impossible, to evaluate their respective role. In addition, the trials did not use the same definitions of infectious complications or simply did not pay enough attention to diagnosing them. Sadly, in some cases, there was a tendency toward minimization and covering. Finally, in some cases, there was not enough attention to forecast the risk of infection. This is the case of eculizumab used for paroxysmal nocturnal hemoglobinuria, which targets the C5 complement component. As widely known among infectious disease physicians dealing with infections in immunocompromised hosts, the inherited deficiency of the C5 complement component is associated with repeated episodes of meningococcal disease. Thus, this risk might have been forecast.

Oncologic Surgery

Bacteremia, usually associated with surgical site infection and deep organ abscess, is not uncommon in urologic, gynecologic, and abdominal surgery in cancer patients, but it is difficult to say with certainty if this happens significantly more often among oncologic versus non-oncologic patients.^42,43 Several studies reported the rates of postsurgery infections in different cancer populations. For example, among patients with peritoneal carcinomatosis undergoing peritonectomy and intraperitoneal hyperthermic chemotherapy, the proportion of infectious complications was rather high, varying from 24% to 36%,^42–44 with more than two infectious episodes per patient. The rate of infectious complications is lower in other oncologic surgeries. In breast cancer, surgical site infection is a complication in 4% to 8% of cases, depending whether breast reconstruction is performed in one or two steps and whether surgery follows previous chemotherapy cycles.^45,46 In case of malignant biliary obstruction, early infectious complications after percutaneous biliary stent insertion were present in 6.5% of patients.⁴⁷ Similar incidence was reported in patients undergoing surgery for hepatocellular or metastatic carcinoma (3% to 11%), and this incidence was apparently lower than in surgery for nonmalignant conditions such as hepatolithiasis (24%).⁴⁸ The rate of infectious complications after hepatectomy for hepatocarcinoma was associated with surgical risk factors such as bile leakage and blood loss.⁴⁹ A similar incidence of surgical site infections was reported after elective colon and rectal surgery (9% and 18%, respectively),⁵⁰ and after orthopedic surgery (9.5%).⁵¹ Of interest, in the latter study, the use of an implant or allograft did not represent a risk factor for infectious complications.⁵¹ Finally, postoperative respiratory infections have been reported in nearly 4% of patients undergoing surgery for lung cancer, and they occurred more frequently in the presence of advanced age, impaired respiratory function, advanced pathologic stage, and induction chemotherapy.

In conclusion, although not many data are available on infectious complications after surgery in solid tumors, it seems that surgical and ICU-related factors are more important than previous antineoplastic chemotherapy in determining the risk of infection. However, it must be noted that in patients with solid tumors, surgery, together with long hospital stay and use of third-generation cephalosporins and glycopeptides, has been associated with an increased risk of infections caused by MDR pathogens.⁵²

Bacterial Infections

In the last 30 years, gram-positive bacteria have been the most frequent pathogens in bloodstream infections in cancer patients. However, more recently, an increase in the frequency of bacteremias caused by gram-negative rods has been reported in many centers worldwide, with gram-negative pathogens becoming either predominant or at least as frequent as gram-positive pathogens. This trend has been observed also in the results from a recent literature review and European surveillance study performed in 2011 in 39 hematology centers from 18 countries for the Fourth European Conference of Infections in Leukemia (ECIL-4).^52a As shown in Figure 310-1, gram-negative pathogens are almost as frequent as gram-positive ones, with the gram-positive versus gram-negative ratio in bloodstream infections at 60% versus 40% and 55% versus 45% in the literature review and ECIL-4 surveillance, respectively. The detailed etiology was similar (see Fig. 310-1) in the literature review and surveillance study, with slightly increased rates of enterococci and Enterobacteriaceae and a decreased rate of P. aeruginosa in the ECIL-4 surveillance study. These changes in etiology seemed to be accompanied by an important and alarming increase in the proportion of resistant pathogens, such as ESBL-producing Enterobacteriaceae, VRE, or, the most worrisome, carbapenem-resistant gram-negative pathogens, both P. aeruginosa and Enterobacteriaceae—mostly Klebsiella pneumoniae. Last but not least, in leukemia patients, most of staphylococci are resistant to methicillin, whereas most of gram-negative pathogens are fluoroquinolone resistant. Of note, the rates of resistance were generally higher in southern and eastern Europe than in northern and western Europe.

Anaerobic bacteria are isolated in less than 1% of positive blood cultures in cancer patients, but the proportion may increase to 3% among those undergoing abdominal surgery.⁴² Anaerobes are usually isolated in polymicrobial bacteremias, especially together with gram-negative rods,⁵³ with a rate that seems to be higher than that observed in nononcologic patients undergoing similar surgery (0.597/1000 vs. 0.033/1000 hospital days, respectively). Of interest, in non-neutropenic febrile cancer patients, gram-negative pathogens are the most frequently isolated, followed by gram-positive pathogens, yeasts, and filamentous fungi, probably in relation to severe gastrointestinal mucositis.⁵⁴ CVC-related bacteremias are generally caused by gram-positive cocci (especially coagulase-negative staphylococci) that are isolated in more than 50% of the episodes, compared with the rate of 25% to 40% for gram-negative rods. The source of infection is likely to be partially different between gram-positive and negative CVC-related bacteremias. In both cases, contamination of skin or hub caused by incorrect catheter management is pivotal, although many gram-positive cocci come directly from the patient’s skin flora. Infusate contamination is a rare but possible event, and in this case, gram-negative rods, such as Klebsiella, Enterobacter, Citrobacter, Achromobacter, Serratia, and Pseudomonas (other than P. aeruginosa), are more likely involved. Polymicrobial infections are not rare (8% to 49% of the episodes), with a predominance of gram-negative bacteria, whereas fungi (mainly Candida spp.) are usually isolated in no more than 10% of CVC-related bloodstream infections.^{20,29–35,38}

Bacterial gastroenteritis caused by classic enteric pathogens (Salmonella and Shigella) is a rare event in patients with acute leukemia, involving less than 1% of acute enteritis after chemotherapy.⁵⁵ On the contrary, Clostridium difficile is not unusual in cancer patients, with an incidence that is twofold higher than in the noncancer population.⁵⁶ Helicobacter pylori has also been described as possible cause of gastrointestinal (GI) disease in cancer patients.

Mycoplasma pneumoniae and Chlamydia pneumoniae have been rarely described as a cause of pneumonia in cancer patients, but it is possible that their incidence is underreported. Similarly, tuberculosis is probably underestimated and underdiagnosed in cancer populations, although there are data showing that the rate approximates 90 cases per 100,000 persons (i.e., ninefold higher than in the general population in developed countries).⁵⁷ Patients from high-endemicity countries or belonging to racial and ethnic minorities account for most of the cases. On the contrary, infections caused by nontubercular mycobacteria are rare. Of note, disseminated tuberculosis caused by Mycobacterium bovis may occur in patients receiving Calmette-Guérin bacillus immunotherapy for bladder cancer.

Fungal Infections

The etiology of fungal infections in cancer patients is shown in Table 310-3. Aspergillus spp. and Candida spp. are the most common fungal pathogens, with the former now being seen more frequently than the latter. Other fungal pathogens include P. jirovecii, cryptococci, and molds, such as Mucorales or Fusarium.

Among yeasts, Candida is the most frequently isolated organism, usually in bloodstream infections. There is an increasing proportion of non-albicans strains, at least partly in correlation with the extensive use of prophylactic fluconazole, to which some non-albicans strains are resistant or less susceptible. Already, in a 1999 European Organisation for Research and Treatment of Cancer (EORTC) study, C. albicans was responsible for only 35% of candidemias in patients with hematologic malignancies and for 70% of episodes in those with solid tumors.⁵⁸ Similarly, recent EORTC data from 297 patients with fungemia, presented at the 2012 European Congress of Clinical Microbiology and Infectious Diseases, reported an overall incidence of 2.3%, with C. albicans responsible for only 40% of monomicrobial infections.^58a Of note, only 38% of fungemias occurred during neutropenia.

In general, yeasts belonging to the Candida parapsilosis complex are usually associated with CVC contamination, whereas the other Candida species are supposed to come from the GI tract after selection and translocation.

Among molds, Aspergillus represents the most frequently isolated or suspected organism. The majority of episodes are caused by Aspergillus fumigatus, although some centers report a predominance of infections caused by Aspergillus flavus and Aspergillus terreus.^23,59 Aspergillus species are ubiquitous molds whose primary ecologic niche is represented by decomposing vegetable material, including potted plants, soil, flowers, and carpets. In healthy individuals, Aspergillus conidia are trapped in the upper respiratory tract, and only a small proportion of them enter the lower airways, where Aspergillus may become an allergen. In immunocompromised patients, especially those with hematologic malignancies or after allogeneic transplantation, spores can germinate and cause an invasive disease. Thus, invasive aspergillosis in patients with malignancy or receiving HSCT is an endemic disease, which is usually community acquired and endogenous, although epidemic outbreaks of exogenous infection associated with massive environmental exposures (in and outside the hospital) can occur. The incidence of invasive aspergillosis depends on the patient’s age (lower in those younger than 10 years), the underlying malignancy, and its treatment, being the highest in patients with prolonged neutropenia, followed by those receiving high doses of steroid therapy. In a multicenter Italian study, the incidence of aspergillosis among hematologic patients varied from 7.9% in acute nonlymphoblastic leukemia; 4.3% in acute lymphoblastic leukemia; 2.3% in chronic myelogenous leukemia; to less than 1% in chronic lymphocytic leukemia, Hodgkin’s disease, non–Hodgkin’s lymphoma, and multiple myeloma.²³ A recently described risk group is represented by patients with chronic lymphoproliferative disorders, probably resulting from more intensive treatment protocols.⁵⁹ The incidence of invasive aspergillosis after autologous HSCT is low (0.3% to 2%), and it occurs during neutropenia preceding the engraftment.^23,60–62

P. jirovecii is a well-known cause of pneumonia in cancer patients not receiving specific prophylaxis, especially in association with high-dose and prolonged steroid therapy. Attack rates vary from 6.5% to 43% in acute lymphoblastic leukemia, 4% to 25% in rhabdomyosarcomas, and nearly 1% in Hodgkin’s disease and primary or metastatic central nervous system tumors.⁶³

In some centers, there have been increasing reports of mucormycosis; however, it is unclear whether this represents a general trend, is influenced by local factors, or that these infections are simply diagnosed more often because of an increased clinical awareness. Other fungi, such as Cryptococcus, Fusarium, Blastoschizomyces, Trichosporon, and Scedosporium, have been reported sporadically. Finally, infections or reactivations of dimorphic fungi, such as Histoplasma or Coccidioides, are possible in patients who live or used to live in endemic areas.