Infections in Cancer Patients with Solid Tumors: A Review

This article is based on previously conducted studies and does not involve any new studies of human or animal subjects performed by any of the authors.

Neutropenia is defined as an absolute neutrophil count (ANC) of <500 cells/mm³. The most frequent cause of neutropenia is antineoplastic chemotherapy. Varying degrees of neutropenia also occur after radiation therapy or the administration of other myelosuppressive agents (e.g., ganciclovir), and occasionally after extensive infiltration of the bone marrow by spreading tumor. Unlike patients with hematologic malignancies, most patients with solid tumors have normally functioning neutrophils. Additionally, conventional chemotherapy rarely produces severe neutropenia lasting longer than 7 days. Consequently, the “at risk” period is generally short and many solid tumor patients who develop neutropenic fever are considered low risk [6, 7]. Newer treatment strategies for low-risk neutropenic patients have been developed and include early discharge after a short period of hospitalization, or management of the entire episode of neutropenic fever without hospitalization [8‐10]. Specific guidelines for the management of febrile neutropenic patients with underlying solid tumors have recently been published [11]. These guidelines stress the importance of performing risk assessment in order to identify low-risk patients who can be treated in an ambulatory setting, since hospitalization is associated with several drawbacks including iatrogenic errors and exposure to healthcare associated, multidrug-resistant microflora. Safety, however, is paramount, and ambulatory/outpatient management should only be implemented if the appropriate infrastructure to support this activity around the clock exists [9, 10].

Normal anatomic barriers such as the skin and various mucosal surfaces (oro-pharyngeal, gastro-intestinal, respiratory, and genito-urinary) provide an important natural defense mechanism against invading pathogens. Cancer chemotherapy often damages mucosal surfaces, thereby increasing the risk of infections caused by organisms that colonize these surfaces [e.g., viridans group streptococci (VGS), Streptococcus pneumoniae, Stomatococcus mucilaginosus, enteric Gram-negative bacilli, and anaerobes]. Agents that frequently cause mucositis include 5-fluorouracil (5-FC), capecitabine (a pro-drug of 5-FU), cyclophosphamide, ifosfamide, cisplatin and carboplatin. The taxanes (docetaxel and paclitaxel) and vinorelbine have also been associated with significant mucositis. Damage to mucosal barriers is also caused by radiation therapy, surgical procedures, and the use of medical devices. Tumors may cause local erosion and fistula formation (e.g., broncho-pleural, trachea-esophageal, vesico-vaginal or recto-vaginal). Protection provided by the skin is also breached by surgical procedures and radiation, and by medical devices such as catheters and percutaneous endoscopic gastrostomy (PEG)-tubes [12].

Obstruction caused by expanding tumors is relatively common in solid tumor patients. Bronchogenic carcinomas (or metastatic pulmonary lesions) often cause airways obstruction leading to the development of post-obstructive pneumonia, which may occasionally be the initial manifestation of these tumors [13]. As obstruction increases, lung abscess, fistula formation, or empyema may occur [14]. Biliary tract obstruction in patients with hepato-biliary and pancreatic tumors results in ascending cholangitis and hepatic abscess formation. Ureteral obstruction resulting in hydronephrosis and complicated urinary tract infection is commonplace in patients with carcinoma of the cervix and other gynecologic tumors. Patients with prostatic carcinoma also develop prostatitis, complicated urinary tract infections, and occasionally prostatic abscesses. Intestinal tumors can lead to partial or complete bowel obstruction, ileus, perforation, peritonitis, hemorrhage, and/or abdominal/pelvic abscess formation. In these situations, mixed or polymicrobial infections are the norm, and the etiologic agents are generally those that colonize the site of obstruction.

Surgery, medical procedures, radiation therapy, and the widespread and increasing use of catheters and other devices is often associated with the development of infection [15]. The use of multiple-lumen vascular access catheters has become commonplace and greatly facilitates the drawing of blood and the administration of various entities such as chemotherapy, antimicrobial agents, blood and blood products, and fluids. The major complication associated with these catheters is infection. The organisms causing catheter-related infections are predominantly those that colonize human skin. Approximately 70–80% are Gram-positive, with Staphylococcus species being isolated most often. Gram-negative organisms and fungi (mostly Candida spp.) are much less common, and 5–10% of these infections are polymicrobial. Urinary catheters are used when obstruction or urinary incontinence is present. Occasionally, local involvement of the ureters or urinary bladder may require the creation of surgical diversions into ileal or colonic segments. Acute or chronic pyelonephritis, sometimes progressing to bacteremia (urosepsis), may occur. The use of nephrostomy tubes may be associated with similar complications [16]. Many patients with central nervous system (CNS) tumors require the placement of shunts in order to relieve intracranial pressure. When infected, the CNS end of these shunts produce symptoms such as headache, mental status changes, and meningismus, whereas the distal ends of these shunts (which are generally located in the pleural or peritoneal cavities) give rise to symptoms of pleuritis or peritonitis. Surgically implanted prosthetic devices are used often in patients with osteosarcoma or other bone/cartilage tumors. Infection is the most common complication associated with these devices, and may require removal of the device for resolution of the infection. Patients with head and neck and esophageal cancers often require the placement of PEG-tubes in order to ensure adequate nutrition. Insertion site infections, abdominal wall infections/abscesses, perforation with peritonitis, and occasionally bacteremic infections may occur, but are uncommon [12].

Patients with CNS tumors often develop partial loss of the gag reflex which predisposes them to aspirate oro-pharyngeal secretions. Neurologic abnormalities resulting in impaired micturition can also occur. Radiation can damage ciliary function resulting in aspiration and pneumonia. In elderly patients, immunologic deficits caused by ageing, malnutrition, and cancer cachexia may also have an impact on the frequency and severity of infection and the overall response to therapy. Prior or concurrent antimicrobial usage can result in the selection of resistant organisms. Antimicrobial stewardship and strict adherence to infection control recommendations and policies are important tools in limiting the emergence and spread of such infections.

Bloodstream infections occur predominantly in patients with indwelling central venous catheters and other vascular access devices as well as in patients with significant oral or intestinal mucositis. Bloodstream infections are more common in such patients when they develop episodes of neutropenia. Unlike patients with hematologic malignancies, most patients with solid tumors do not receive antimicrobial prophylaxis following chemotherapy. Such prophylaxis is directed primarily against Gram-negative organisms. Consequently, in the absence of prophylaxis, Gram-negative BSIs are more common than Gram-positive BSIs in patients with solid tumors. [18]. Escherichia coli, Klebsiella species, and Pseudomonas aeruginosa are the most common Gram-negative species isolated [22]. Non-fermentative Gram-negative bacilli are emerging as significant pathogens at some institutions. These include Acinetobacter species, Stenotrophomonas maltophilia, Achromobacter species, and non-aeruginosa Pseudomonas species, many of which are multidrug-resistant [23]. Staphylococci, streptococci, and enterococci are the predominant Gram-positive pathogens isolated. At many institutions, more than 90% of coagulase-negative staphylococci (CoNS) and more than 50% of S. aureus are methicillin-resistant, and 15–20% of Enterococcus species are vancomycin-resistant. A minority of BSIs are fungal, caused almost exclusively by Candida species. Anaerobes are seldom isolated from blood cultures.

Post-obstructive pneumonia is defined as infection of the lung parenchyma caused by bronchial obstruction [24]. In most cases, the obstruction is caused by a neoplasm, and post-obstructive pneumonia may be the initial manifestation of malignancy in 40–50% of patients with this diagnosis [13]. Fever, cough, sputum production, and weight loss are common. Leucocytosis is also common unless chemotherapy-induced myelosuppression is present. Other symptoms include dyspnea, pleuritic chest pain, and hemoptysis. Symptoms persist and worsen as the degree of obstruction increases. Since the infection is located below the level of obstruction, respiratory samples from above this level are often negative. In many cases, Invasive diagnostic procedures such as percutaneous lung aspiration/biopsy may be the most accurate way of determining the etiology. Microbiologic data are often difficult to interpret, and generally reveal polymicrobial flora [25, 26]. These include Streptococcus species such as S. pneumoniae, beta-haemolytic streptococci, and viridans group streptococci; Staphylococcus species including methicillin-resistant isolates, Gram-negative bacilli such as the Enterobacteriaceae and Pseudomonas aeruginosa, and some anaerobes. Candida species are also frequently isolated, but their role in this infection is unclear. Most patients are treated with broad spectrum antimicrobial regimens directed against the pathogens outlined above. Despite such therapy, responses are often slow, and complete defervescence generally does not occur, with persistent or recurrent infections being common. Approximately 10–15% of patients with chronic or progressive post-obstructive pneumonia develop serious complications such as lung abscess, hemorrhage, empyema, and fistula formation (broncho-pleural or trachea-esophageal). A vicious cycle often ensues, as these complications frequently cause delays in the administration of antineoplastic therapy, which can lead to worsening of the obstruction. Consequently, full attention should be focused on treating the lesion(s) causing obstruction. Several options to accomplish this are available including low- or high-dose-rate brachytherapy, cryotherapy, laser therapy, electro-cautery, and the placement of airways stents [27, 28]. Unfortunately, despite these measures, progressive, ultimately fatal, disease is the norm [14].

Breast cancer is the most common cancer in women worldwide and its frequency has been increasing in recent years [1, 29‐31]. Most of these patients undergo some surgical procedure of the involved breast along with ipsilateral lymph node dissection. Several forms of breast reconstruction are also frequently performed. These include autologous reconstruction using a transverse rectus abdominis musculo-cutaneous flap, or a deep inferior epigastric artery perforator flap [31]. Prosthetic reconstruction using silicone or saline implants is also widely used. Although a detailed discussion of the various surgical/reconstruction procedures is beyond the scope of this review, all these procedures are associated with an infection rate that ranges between 2.5% and 24% [32, 33]. Infection is a leading cause of hospital admission in such patients, and can result in devastating medical/surgical, psycho-social, and financial consequences. Factors that increase the risk of infection include increased body mass index, radiation therapy (which also retards healing), axillary lymph node dissection, the use of surgical drains, adjuvant chemotherapy, and possibly tobacco use [34‐37]. Staphylococci (CoNS and S. aureus) are involved in almost all such infections, with the majority of isolates being methicillin-resistant. However, several recent studies indicate that a small but significant proportion of these infections are caused by Gram-negative bacilli such as E. coli, P. aeruginosa, and Klebsiella species [38‐40]. Non-tuberculous mycobacterial and polymicrobial infections are less common but are difficult to manage [41]. With a significant rate of, and changing epidemiology of, infection in this setting, infection prevention has become extremely important. Antimicrobial prophylaxis is an important infection prevention strategy. Breast surgery is considered clean surgery by the Center for Disease Control and Prevention (CDC) and the Surgical Care Improvement Project, and current guidelines suggest a maximum of 24 h of peri-operative antibiotics [42]. Agents commonly used for antimicrobial prophylaxis (predominantly first- and second-generation cephalosporin) were chosen several decades ago and do not provide adequate coverage against organisms (MRSA, P. aeruginosa) mentioned above [39, 43]. Several investigators have recommended alternative regimens based on local epidemiology and susceptibility/resistance patterns [44‐46]. Since most of the procedures are elective, some recommend screening patients for MRSA and P. aeruginosa and providing targeted prophylaxis when these organisms are detected, or using agents with activity against these organisms in empiric regimens [47‐49].

Obstruction of the biliary tract as a result of hepato-biliary or pancreatic tumors results in the development of ascending cholangitis [50]. Less frequently, single or multiple liver abscesses develop, especially in patients with persistent obstruction [51]. These are being documented with increasing frequency due to improved imaging techniques. As with lung neoplasms and post-obstructive pneumonia, ascending cholangitis may be the initial manifestation of local neoplastic disease, and may lead to its discovery during evaluation. Hepatic abscesses have also been reported after invasive procedures for hepatocellular carcinoma, such as the administration of intra-arterial chemotherapy [52, 53]. Most of these infections are polymicrobial, with enteric Gram-negative bacilli, Enterococcus species (including VRE), and anaerobes being predominant [54]. Broad spectrum antimicrobial therapy and percutaneous drainage are often necessary in order to achieve adequate responses. Patients with hepatocellular carcinoma and pancreatic head tumors often develop obstructive jaundice, which can progress to hepatic failure. In this setting, percutaneous transhepatic biliary drainage (PTBD) has been used to treat obstructive jaundice [55]. More recently, endoscopic biliary stenting (EBS) is replacing PTBD as the treatment of choice in this setting [56]. Several studies have shown that internal biliary drainage increases microbial colonization of stents and the formation of sludge which also contains intestinal microorganisms [57]. The frequency of cholangitis appears to be increased in such circumstances [57, 58].

The intestinal tract is a common site of infection in patients with solid tumors. Several well-recognized syndromes have been described in such patients, including appendicitis, intestinal perforation with peritonitis and/or local abscess formation, Clostridium difficile-associated colitis, cytomegalovirus (CMV) colitis, and typhlitis or neutropenic enterocolitis [20]. The clinical manifestations associated with most of these syndromes are similar, and include abdominal symptoms (cramping, pain, tenderness, distension), fever, diarrhea, and intestinal hemorrhage. These manifestations are not typical nor pathognomonic of any single entity. Therefore, clinical features, radiographic imaging findings, microbiologic, serologic, and histopathologic data need to be considered in order to make a specific diagnosis. Conservative medical management (fluid and electrolyte support, bowel rest, broad-spectrum parenteral antibiotic therapy) is generally effective. Surgical intervention is usually needed when complications such as intestinal perforation or bleeding develop.

In years gone by, neutropenic enterocolitis (NEC) was seen primarily in patients with acute leukemia receiving intensive cytotoxic chemotherapy with agents such as cytosine arabinoside or idarubicin [59‐61]. NEC was documented much less often in patients with solid tumors. Recent reports have highlighted an association between NEC and therapy with taxanes (docetaxel, paclitaxel) and vinorelbine [62‐64]. These agents are often used to treat solid tumors such as breast, lung, and ovarian cancers. Pre-existing bowel abnormalities such as diverticulosis/diverticulitis, bowel infiltration with the underlying tumor, and prior surgery or radiation may also increase the risk of development of NEC following cytotoxic chemotherapy. The onset of NEC usually occurs in the third week of neutropenia (median 17 days) and coincides with maximal mucosal damage. However, there are reports suggesting earlier or later onset, sometimes even after resolution of neutropenia. In patients with the abdominal symptoms outlined above, imaging studies are the most reliable and accurate tools for making a diagnosis of NEC. Computerized tomography (CT) is the imaging option of choice [65]. The most characteristic CT finding is bowel wall thickening, usually around 7 mm (range 4–15 mm). An important prognostic finding is the presence of bowel wall thickening of >10 mm which is associated with severe disease and poorer outcomes [66]. As mentioned previously, general supportive measures such as bowel rest with nasogastric suction and parenteral nutrition if necessary, along with fluid and electrolyte replenishment, are generally effective, with surgical intervention being reserved for more serious complications.

Risk factors associated with C. difficile colonization and disease include antibiotic usage, proton-pump inhibitors or H2 blockers, previous hospitalization, and antineoplastic chemotherapy [67]. Up to 6% of patients receiving cisplatin therapy for ovarian carcinoma develop C. difficile-associated colitis [68]. Such therapy should subsequently be avoided since relapse or recurrent infection can occur [69]. Recent data suggest that vancomycin is superior to metronidazole therapy for moderate to severe infection. Fidaxomicin, a new macrocyclic agent, is similar to vancomycin with regards to clinical response, but produces more sustained responses and fewer relapses [70‐72]. Fecal microbiota transplantation has been shown to be efficacious in patients with multiple recurrences [73].

CMV disease has not been well studied in solid tumor patients. Although infrequently reported, CMV testing is not routinely performed in such patients, consequently reactivation of CMV or active disease is probably often unrecognized and underreported. One retrospective analysis reported that at least 50% of patients with solid tumors with a positive CMV polymerase chain reaction also had clinically relevant CMV disease requiring antiviral therapy [74]. Although gastrointestinal CMV disease is uncommon in patients with solid tumors, it is associated with high morbidity and mortality [75].

Hepatitis virus infections (both hepatitis B virus, HBV, and hepatitis C virus, HCV) are relatively common worldwide. Recent estimates suggest that more than 350 million individuals globally have HBV infection and 130–170 million are infected with HCV [76‐78]. In oncology settings, HBV reactivation rates vary between 30% and 80% depending on the HBV serologic status and the specific chemotherapy regimen [79]. Whilst reactivation can be asymptomatic, it can lead to severe hepatitis, liver failure and death [80]. It often leads to delays in antineoplastic chemotherapy which can result in increased tumor-related mortality. Patients with solid tumors who are hepatitis B surface antigen (HBsAg)- or hepatitis B core antibody (HBcAb)-positive are at risk for HBV reactivation after the administration of cytotoxic chemotherapy. The CDC recommends universal screening of individuals prior to the administration of cytotoxic chemotherapy or immunosuppressive therapy [81]. A recent systematic review and meta-analysis of HBV reactivation and prophylaxis during chemotherapy for solid tumors concluded that, in patients with chronic HBV receiving such chemotherapy, the risk of reactivation was similar to other types of immunosuppressive therapy, and that there was strong support for HBV screening and antiviral prophylaxis prior to initiating such therapy [82]. Other studies/groups have confirmed these findings [83, 84]. Preferred agents for HBV prophylaxis include lamivudine, entecavir, and tenofovir. Additionally, monitoring of viral load and hepatic transaminases is recommended for patients who do not have active HBV infection and are not receiving prophylaxis [85].

HCV reactivation in cancer patients has not been as well studied as HBV reactivation. The overall prevalence of HCV infection in cancer patients ranges from 1.5% to 32% [86, 87]. However, very little is known about its natural history, prophylaxis, treatment, and outcomes in this patient population. HCV-positive patients with cancer have a higher risk of developing cirrhosis, progress to fibrosis more rapidly, and have poorer virologic responses [88]. Increased mortality has been reported in patients with cancer who have HCV infection compared to those who do not [89]. Additionally, increased risk of reactivation has also been reported in patients receiving targeted therapies [90]. Although treatment and outcomes data in cancer patients are limited, in the general population HCV therapy can cure infection, prevent reactivation, delay progression to cirrhosis, and reduce overall mortality [91, 92]. Guidelines recently issued by the National Comprehensive Cancer Network state that all patients receiving chemotherapy or immunosuppressive therapy should be screened for HCV [85]. Although no specific treatment guidelines for cancer patients exist, HCV therapy in this setting has been shown to be feasible and to prevent or decrease progression of liver disease. An algorithm for the management of patients with cancer and HCV infection has recently been published [86].

Obstructive uropathy is common in patients with solid tumors [16]. The resultant urinary stasis leads to bacterial colonization and can progress to the development of complicated urinary tract infection and urosepsis. Acute or chronic ureteral obstruction (most often unilateral but occasionally bilateral) is a complication of advancing retroperitoneal or pelvic malignancy. Prompt decompression of the obstruction is required. Ureteral stents have been used for the management of ureteral obstruction in this setting. Silicone or polyurethane stents are most often used but may be associated with significant failure rates. Metallic stents have also been evaluated and are considered to be effective [16, 93‐95]. Alternatively, obstructions can be dealt with the placement of percutaneous nephrostomy tubes. The use of stents and nephrostomy tubes is associated with a significant rate of pyelonephritis [16]. Organisms causing these infections include Staphylococcus species, Enterococcus species, E. coli, P. aeruginosa, S. maltophilia, Klebsiella species, and Candida species [16]. Eradication of such infections is difficult to accomplish and recurrent infections are the norm. Long-term suppressive antibiotic therapy may be necessary in patients who develop frequent bouts of urosepsis.