Infectious Complications

Overview

Infections are among the most common, potentially serious complications of cancer and its treatment. This chapter discusses infections from a syndromic approach: that is, infections present to the clinician as a complex of signs and symptoms. The syndromes addressed include febrile neutropenia, pneumonia, catheter-associated infections, and gastrointestinal infections (Clostridium difficile–associated diarrhea and typhlitis). Special sections focus on fungal and viral infections.

Infection During Febrile Neutropenia

It has long been recognized that the incidence of infection is high in patients who develop a fever during neutropenia and that empiric antimicrobial therapy is warranted in such patients.

Definitions

Fever

Fever is usually defined as a temperature ≥ 38.3°C (about 101°F).

Neutropenia

Neutropenia is defined as an absolute neutrophil count (ANC) of < 500/μL, although patients with a neutrophil count between 500 and 1,000/μL in whom a decrease is anticipated are considered to be neutropenic. Patients with a neutrophil count < 100/μL are at greatest risk for infection, as are those with a rapid decrease in neutrophil count and those with protracted neutropenia (> 7 days).

Etiology

Bacterial infections

Bacterial infections occurring during episodes of febrile neutropenia are caused predominantly by aerobic gram-negative bacilli (especially Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa) and gram-positive cocci (coagulase-negative staphylococci, β-hemolytic streptococci, viridans streptococci, enterococci, and Staphylococcus aureus). In recent years, multidrug-resistant organisms have become more prominent.

Fungi

Fungal infections usually occur after a patient has received broad-spectrum antimicrobial therapy and/or steroids. The most common fungal pathogens are Candida species (predominantly C albicans and C glabrata) and Aspergillus species. Less common are Mucorales (Zygomycetes), Fusarium, and Scedosporium infections (see also section on “Fungal infections”).

Viruses

Viral infections occurring during neutropenia are caused predominantly by herpesviruses and respiratory viruses. The herpesviruses include herpes simplex virus (HSV), varicella zoster virus (VZV), cytomegalovirus (CMV), human herpes virus 6 (HHV-6), and Epstein-Barr virus (EBV). The respiratory viruses include adenovirus, respiratory syncytial virus (RSV), parainfluenza virus, influenza A and B viruses, human metapneumovirus, and rhinovirus (see also section on “Viral infections”).

Signs and Symptoms

The most remarkable aspect of the febrile, neutropenic patient is the lack of physical findings. This is due to the neutropenia and the absence of an inflammatory response at the infection site. The patient may have only a fever, with or without chills or rigors. Even if the patient has pneumonia, there may be few respiratory symptoms. Likewise, a perirectal abscess may be relatively asymptomatic.

Diagnosis

An initial evaluation and diagnostic workup of any fever in a neutropenic patient should begin immediately but should not delay the initiation of empiric therapy. A complete history (exposures, past infections, rashes, cough, abdominal pain, diarrhea) should be taken and a physical examination (of skin lesions, exit site and tunnel of central venous catheters, oropharynx, abdomen, perineum) should be performed.

Diagnostic workup

Diagnostic workup should include:

- at least two sets of blood cultures: one from a peripheral vein and one from each port of a central venous catheter. If fever persists in the face of negative cultures, blood cultures for fungi and acid-fast bacilli should be considered.

- culture of any drainage from a catheter exit site

- stool examination for C difficile and other bacterial/protozoal agents, especially if diarrhea is present

- urine culture and urinalysis

- chest radiograph

- respiratory samples for culture

- cerebrospinal fluid exam and culture if meningitis is suspected

- aspiration or biopsy of any skin lesions.

CT

CT of sinus, chest, abdomen, and pelvis can be performed, as per clinical judgement. If central nervous system infection is suspected, CT of the brain can be performed (followed by lumbar puncture).

Laboratory tests

Determination of serum transaminases, complete blood count, and serum creatinine levels is also recommended. Other useful serologies include Aspergillus galactomannan, beta-D-glucan, Coccidioides antibody panel, and histoplasmosis antigen, depending on the region.

Treatment

FIGURE 1

Guide to the initial management of the febrile neutropenic patient.

Initial empiric antibiotic therapy

The choice of initial empiric antibiotic therapy for the febrile, neutropenic patient should be broad spectrum and is dictated in part by the susceptibility pattern of blood isolates seen at a particular cancer center (Figure 1).

If the prevalence of extended-spectrum beta-lactamase (ESBL) gram-negative bacteria is high, for example, one probably would not want to use a third-generation cephalosporin such as ceftazidime as initial empiric monotherapy. Some data suggest that prolonged use of ceftazidime monotherapy in this setting promotes the emergence of ESBL bacteria. City of Hope has used ceftazidime as initial monotherapy for the past 15 years, however, without a significant rise in the incidence of resistant gram-negative infections, and this experience has been shared by other centers. Finally, any special circumstance, such as the suspicion of an indwelling IV catheter–associated infection, may influence the antibiotic choice.

When choosing an antibiotic, the clinician should take into consideration the patient’s allergies and other drugs administered that may interact with the empiric antimicrobial agent. The clinician should adjust for hepatic and renal function to limit toxicity, ie, seizures with beta-lactams such as cefepime.

TABLE 1

Dosing schedules of selected antimicrobials

Either a single antibiotic or antibiotic combinations can be used for initial empiric therapy (see Table 1 for dosage regimens).

High-risk patients. High-risk patients require hospitalization for IV empirical antibiotic therapy. Monotherapy with an antipseudomonal β-lactam (cefepime, imipenem-cilastatin, meropenem, or piperacillin-tazobactam) is recommended. Other antimicrobials (aminoglycosides, fluoroquinolones, and/or vancomycin) may be added for management of complications (eg, hypotension and pneumonia) or if antimicrobial resistance is suspected or proven (Figure 1).

Vancomycin. Vancomycin or other agents active against aerobic gram-positive cocci are not recommended as a standard part of the initial regimen for fever and neutropenia. These agents should only be considered empirically for clinical situations such as the following:

- hemodynamic instability or other evidence of severe sepsis

- pneumonia documented radiographically

- positive blood culture for gram-positive bacteria, before the identification and susceptibility testing results are available

- clinically suspected serious catheter-related infection (eg, chills or rigors with infusion through a catheter and cellulitis around the catheter entry/exit site)

- skin or soft-tissue infection at any site

- colonization with methicillin-resistant S aureus, vancomycin-resistant enterococcus, or penicillin-resistant Streptococcus pneumoniae

- severe mucositis, if fluoroquinolone prophylaxis has been given and ceftazidime is employed as empirical therapy

Modifications to initial empiric therapy. Modifications to initial empiric therapy may be considered for patients at risk for infection with the following antibiotic-resistant organisms, particularly if the patient’s condition is unstable or if the patient has positive blood cultures suspicious for resistant bacteria. These include methicillin-resistant S aureus (MRSA), vancomycin-resistant enterococci (VRE), ESBL-producing gram-negative bacteria, and carbapenem-resistant enterobacteriaceae (CRE) (including K pneumoniae carbapenemase [KPC] or metallo-beta-lactamase producers [MBLs]). Risk factors include previous infection or colonization with the organism and treatment in a hospital with high rates of endemicity. Recommended management is as follows:

- MRSA: Consider early addition of vancomycin, linezolid, or daptomycin (daptomycin is not recommended for patients with respiratory infection, ie, pneumonia, due to inactivation by surfactant).

- VRE: Consider early addition of linezolid or daptomycin.

- ESBLs: Consider early use of carbapenem

- KPCs, MBLs: Consider early use of colistin or tigecycline (Tygacil). Caution: monotherapy with colistin has been associated with treatment failures.

Most penicillin-allergic patients. Most penicillin-allergic patients tolerate cephalosporins, but those with a history of immediate-type hypersensitivity reaction (eg, hives and bronchospams) should be treated with a combination that avoids penicillins or cephalosporins, such as ciprofloxacin plus clindamycin or aztreonam plus vancomycin.

Afebrile neutropenic patients. Afebrile neutropenic patients who have new signs or symptoms suggestive of infection should be evaluated and treated as high-risk patients.

Low-risk patients. Low-risk patients should receive initial oral or IV empirical antibiotic doses in a clinic or hospital setting. They may be transitioned to outpatient oral or IV treatment if they meet specific clinical criteria. Criteria for the low-risk designation include neutropenia expected to resolve within 7 days and no active medical comorbidity, as well as stable and adequate hepatic and renal function.

- Ciprofloxacin plus amoxicillin-clavulanate in combination is recommended for oral empirical treatment. Other oral regimens, including levofloxacin or ciprofloxacin monotherapy, or ciprofloxacin plus clindamycin, are less well studied but are commonly used.

- Patients receiving fluoroquinolone prophylaxis should not receive oral empirical therapy with a fluoroquinolone.

- Hospital readmission or continued stay in the hospital is required for patients with persistent fever or signs and symptoms of worsening infection.

Double β-lactam therapy. Double β-lactam therapy is discouraged because of concerns about increased expense and toxicity without added benefit, and the possibility of antagonism.

Changes in initial therapy

Modifications to the initial antibiotic regimen should be guided by clinical and microbiologic data (Figure 2).

Unexplained persistent fever. Unexplained persistent fever in a patient whose condition is otherwise stable rarely requires an empirical change to the initial antibiotic regimen. If an infection is identified, antibiotics should be adjusted accordingly.

Documented infections. Documented infections, confirmed either clinically and/or microbiologically, should be treated with antibiotics appropriate for the site and for the susceptibilities of any isolated organism.

• Vancomycin-If vancomycin or other antibiotic for gram-positive organisms was initiated, it may be stopped after 2 days if there is no evidence of a gram-positive infection.

• Patients who remain hemodynamically unstable-Patients who remain hemodynamically unstable after initial doses with standard agents for neutropenic fever should have their antimicrobial regimen broadened to include coverage for resistant gram-negative, gram-positive, and anaerobic bacteria and fungi.

• Low-risk patients-Low-risk patients who have initiated IV or oral antibiotics in the hospital may have their treatment approach simplified if they are clinically stable.

- An IV-to-oral switch in the antibiotic regimen may be made if patients are clinically stable and their gastrointestinal absorption is believed to be adequate.

- Selected hospitalized patients who meet criteria for being at low risk may be transitioned to the outpatient setting to receive either IV or oral antibiotics, as long as adequate daily follow-up is ensured. If fever persists or recurs within 48 hours in outpatients, hospitalization is recommended, with management as for high-risk patients.

• Empirical antifungal coverage-Empirical antifungal coverage should be considered in high-risk patients who have persistent fever without an identifiable source after 4 to 7 days of treatment with a broad-spectrum antibacterial regimen (Figure 3).

FIGURE 2

Reassess after 2 to 4 days of empirical antibiotic therapy.FIGURE 3

High-risk patient with fever after 4 days of empirical antibiotics.

Duration of empirical antibiotic therapy

Patients with documented infections. In patients with documented infections, clinically or microbiologically, the duration of therapy is dictated by the isolated organism and site. Appropriate antibiotics should be selected based on culture and sensitivity, and continued for at least the duration of neutropenia (until ANC is ≥ 500/μL) or longer if clinically necessary.

Patients with unexplained fever. In patients with unexplained fever, it is recommended that the initial regimen be continued until there are clear signs of marrow recovery. The traditional endpoint is an increasing ANC that exceeds 500/μL.

If an appropriate treatment course has been completed and all signs and symptoms of a documented infection have resolved, patients who remain neutropenic may resume oral fluoroquinolone prophylaxis until marrow recovery.

Prevention

Attempts to prevent infection in the neutropenic host focus on two broad areas: preventing acquisition of pathogenic organisms and suppressing or eradicating endogenous microbial flora.

Hygienic measures

Hand hygiene. The simplest, most effective, and least expensive way to prevent acquisition of potential pathogens is to institute strict hand-washing precautions.

Food. Food should be well-cooked. Prepared luncheon meat should be avoided. Well-cleaned, uncooked raw fruits and vegetables are acceptable, provided that freshness of ingredients and the means of preparation can be confirmed.

Water purification systems (to eliminate Legionella organisms) and high-efficiency particulate air (HEPA) filtration systems (to eliminate fungal spores) can decrease the rates of acquisition of these pathogens.

Hematopoietic cell transplantation (HCT) recipients should be placed in private (ie, single-patient) rooms. Allogeneic HCT recipients should be placed in rooms with > 12 air exchanges/hour and HEPA filtration.

Plants and dried or fresh flowers should not be allowed in the rooms of hospitalized neutropenic patients.

Hospital work exclusion policies should be designed to encourage healthcare workers to report their illnesses or exposures.

Antibacterial prophylaxis

Fluoroquinolone prophylaxis should be considered for high-risk patients with expected durations of prolonged and profound neutropenia (ANC ≤ 100/μL for > 7 days). Levofloxacin and ciprofloxacin have been evaluated most comprehensively and are considered roughly equivalent, although levofloxacin is preferred in situations with increased risk for oral mucositis–related invasive viridans group streptococcal infection. A systemic strategy for monitoring the development of fluoroquinolone resistance among gram-negative bacilli is recommended. Levofloxacin use has also been associated with the emergence of hypervirulent C difficile enterocolitis.

Addition of a gram-positive–active agent to fluoroquinolone prophylaxis is generally not recommended.

Antibacterial prophylaxis is not routinely recommended for low-risk patients who are anticipated to remain neutropenic for < 7 days.

Pneumocystis jirovecii pneumonia. In patients at risk for P jirovecii pneumonia (patients undergoing allogeneic HCT, those with lymphoma, or those receiving steroids), trimethoprim-sulfamethoxazole, administered for only 2 or 3 days per week, can reduce the incidence of infection.

Antifungal prophylaxis

High-Risk. Prophylaxis against Candida infections is recommended in patients in whom the risk of invasive candidal infections is substantial, such as allogeneic HCT recipients or those undergoing intensive remission-induction or salvage induction chemotherapy for acute leukemia. Fluconazole, itraconazole, voriconazole (Vfend), posaconazole, micafungin (Mycamine), and caspofungin are acceptable choices.

Prophylaxis against invasive Aspergillus infections with posaconazole (Noxafil) should be considered for selected patients 13 years of age and older who are undergoing intensive chemotherapy for AML (acute myelogenous leukemia)/MDS (myelodysplastic syndrome) in whom the risk of invasive aspergillosis without prophylaxis is substantial.

Prophylaxis against Aspergillus infection in pre-engraftment allogeneic or autologous HCT recipients has not been shown to be efficacious. However, a mold-active agent is recommended in patients with prior invasive aspergillosis, anticipated prolonged neutropenic periods of at least 2 weeks, or a prolonged period of neutropenia immediately prior to HCT (see also the “Prevention” section under “Fungal infections”).

Low-Risk. Antifungal prophylaxis is not recommended for patients in whom the anticipated duration of neutropenia is < 7 days.

Antiviral prophylaxis

Acyclovir. Patients at risk for mucositis (ie, those undergoing induction therapy for leukemia or lymphoma or HCT) who have evidence of prior HSV infection (positive serology) should receive prophylaxis with twice-daily acyclovir (see Table 1 for dose).

Antiviral treatment for HSV or VZV is only indicated if there is clinical or laboratory evidence of active viral disease. Also see section on “Viral Infections.”

Ganciclovir. Ganciclovir has been shown to be effective “preemptively” in preventing CMV interstitial pneumonia in allogeneic HCT recipients who demonstrate evidence of viremia by polymerase chain reaction (PCR), antigen testing, or positive blood cultures (see section on “Viral infections”).

Pneumonia

A significant number of infections in cancer patients are due to pneumonia. For example, 25% of documented infections in patients with nonlymphocytic leukemia are caused by pneumonia. Also, 50% of allogeneic HCT recipients develop pneumonia.

Etiology and Risk Factors

Some of the risk factors that predispose cancer patients to pneumonia are cellular and humoral immune deficiencies, neutropenia, impaired tracheobronchial clearance, use of antibiotics and steroids, and surgery.

Etiologic agents

The etiologic agents responsible for pneumonia in the cancer patient run the gamut of most bacterial, fungal, and viral organisms (Figure 4).

Noninfectious processes mimicking pneumonia

Numerous noninfectious processes can mimic pneumonia in cancer patients. They include congestive heart failure, aseptic emboli, metastatic disease, adult respiratory distress syndrome, diffuse alveolar hemorrhage, a peri-engraftment infiltrate, radiation injury, hypersensitivity disorders and reactions, and trauma.

Pinpointing the pathogen

Certain characteristics of each cancer patient may help predict the specific etiologic agent.

FIGURE 4

Pneumonia in a neutropenic/ immunocompromised host.FIGURE 5

Timing of infectious syndromes after bone marrow transplantation.

Type of immunosuppression. One characteristic that is particularly useful is the type of immunosuppression that the patient is experiencing. This depends on the type of neoplastic disease (eg, lymphoma, leukemia) and, more importantly, the type of therapy (eg, chemotherapy, radiation therapy, allogeneic HCT). For example, certain gram-negative and gram-positive bacteria are more prevalent during neutropenia, whereas other bacteria (S pneumoniae, Haemophilus influenzae) are more common with a humoral immune deficiency, such as occurs after splenectomy.

Timing of pneumonia. Another important characteristic is the timing of the pneumonia; in other words, the phase of the immunosuppression can help predict the etiology. For example, an interstitial pneumonia occurring during the first 30 days after allogeneic HCT would not be expected to be due to CMV (Figure 5).

Other factors

Finally, other factors such as the duration of neutropenia, prior antimicrobial therapy, other agents (such as steroids and alemtuzumab) used, and the specific local microbiota help in prediction. For example, if an allogeneic HCT patient receiving steroids for graft-versus-host disease (GVHD) develops nodular infiltrates after weeks of treatment with broad-spectrum antibacterial antibiotics, an Aspergillus species would be highly suspected.

Signs and Symptoms

Although a productive cough is almost always present in a normal host with pneumonia, often neither a cough nor sputum is seen in an immunocompromised cancer patient with such an infection.

Fever, however, is almost invariably present in the cancer patient with pneumonia and, by itself, should prompt a workup for pneumonia.

Other possible symptoms include shortness of breath, pleuritic chest pain, and hemoptysis.

Diagnosis

Identification of the etiologic agent for pneumonia in immunocompromised host is often difficult. Also, pneumonia can progress rapidly, resulting in high morbidity and mortality. Therefore, aggressive workup and treatment are warranted by the managing clinician.

The diagnosis of pneumonia is most commonly made by a simple chest radiograph. However, there are occasions when a pulmonary infiltrate or small nodular lesion is seen only on a CT scan.

Etiologic diagnosis

An etiologic diagnosis is made by the following procedures: sputum (expectorated or induced) testing, bronchoscopy with bronchoalveolar lavage and transbronchial biopsy, transthoracic needle biopsy/aspiration, and thoracoscopic and open lung biopsy.

Sputum. An adequate sputum specimen is difficult to obtain from cancer patients, especially during neutropenia.

Bronchoscopy with bronchoalveolar lavage. Bronchoscopy with bronchoalveolar lavage is a much more sensitive technique than sputum analysis but may miss the organism when the pulmonary disease is peripheral or nodular.

Transthoracic needle biopsy/aspiration. Transthoracic needle biopsy/aspiration under CT guidance may be helpful if the lesion is distal but may be contraindicated in a severely thrombocytopenic patient. This procedure is indicated when there is a focal/nodular lesion in the periphery.

FIGURE 6

Diagnostic approach to pneumonia.

Open lung biopsy. Open lung biopsy is the most definitive diagnostic procedure but also the most invasive. It is still not clear whether the information obtained by open biopsy improves overall survival. The less invasive thoracoscopic lung biopsy is becoming more popular than open lung biopsy.

Smears and cultures. Both fluid and tissue specimens should be sent for bacterial smears (including acid-fast bacilli and modified acid-fast bacilli) and cultures (including those for anaerobes, acid-fast bacilli, and Legionella organisms), fungal smears (potassium hydroxide) and cultures, direct fluorescent antibody test for viruses, cytology (for viral inclusions and silver stains for fungi and P jirovecii), histopathology, and Aspergillus PCR and Mucor PCR on bronchoalveolar lavage.

Diagnostic approach. The diagnostic approach to pneumonia is depicted in Figure 6 using risk stratification (low vs high risk). Patients with suspected pneumonia should undergo an aggressive etiologic workup along with broad-spectrum empiric antimicrobial treatment. Preemptive antifungal therapy should be based on risk. Treatment is then tailored accordingly.

Treatment

The therapeutic approach to pneumonia in the cancer patient should take into consideration the category of immunosuppression (neoplastic disease and immunosuppressive therapy), as well as the timing of onset and the pattern of the pneumonia.

Empiric antibiotic therapy

In neutropenic patients experiencing their first episode of fever and localized pulmonary infiltrates, one can justify initiating empiric therapy similar to that used for febrile, neutropenic patients (see previous discussion), because the majority of pneumonias in this setting are caused by gram-negative bacteria. However, in other situations-such as pneumonia that has a later onset, develops after empiric antibiotics have been initiated, is more aggressive or severe, occurs in a more severely compromised host (eg, a patient who has had allogeneic HCT), or is characterized by a diffuse or interstitial infiltrate-one should proceed to immediate bronchoscopy with bronchoalveolar lavage (and possibly transbronchial biopsy).

Additions to empiric therapy

If no diagnosis is forthcoming after bronchoscopy and bronchoalveolar lavage, additions to empiric therapy should be made.

Anaerobic, gram-positive, and Legionella coverage. Certainly, anaerobic coverage should be considered, as well as gram-positive coverage. Legionella coverage should be added, especially if warranted by the epidemiologic setting.

Antifungal and antituberculous therapy. Finally, antifungal therapy should be initiated if there is no response to antibacterial therapy and especially if there are nodular or cavitary lesions. In addition, if such lesions are present and/or the epidemiologic setting is compatible, antituberculous therapy should be added.

FIGURE 7

Antimicrobial treatment approach.

Further diagnostic procedures. If bronchoscopy with bronchoalveolar lavage does not reveal an etiology and the pneumonia is progressing despite empiric therapy, consideration should be given to transthoracic needle biopsy/aspiration and open lung biopsy. As mentioned previously, if there is a peripheral, focal lesion, transthoracic needle biopsy/aspiration can be attempted.

The ultimate diagnostic procedure is open biopsy, but because its contribution to increased survival is unknown, the decision to proceed with this most invasive procedure must be undertaken carefully.

Specific antimicrobial therapy

A specific treatment approach is suggested in Figure 7 based on whether treatment is empiric or targeted.

Prevention

Methods to prevent pulmonary infections fall into the following categories: colonization prevention, antimicrobial prophylaxis (and preemptive treatment), vaccination, and immunomodulation.

The simplest method of colonization prevention is hand-washing.

Other colonization-prevention methods, such as protective environments, are discussed in the previous section.

With regard to pulmonary pathogens, HEPA-filtered rooms can eliminate Aspergillus spores from the immediate environment. Water supplies can be checked for Legionella contamination and/or adequate disinfection maintained (eg, chlorination, copper/silver ionization, temperature [60°C]).

Antimicrobial prophylaxis is discussed in the previous section.

The influenza and pneumococcal (killed) vaccines should be administered to cancer patients.

Immunomodulators, such as granulocyte colony-stimulating factor (G-CSF, filgrastim) and granulocyte-macrophage colony-stimulating factor (GM-CSF, sargramostim), may help to reduce infection risk by decreasing the duration of neutropenia.

Catheter-Associated Infections

Chronic indwelling catheters are commonly placed in cancer patients, as they permit frequent, long-term vascular access for drug and blood product administration, hyperalimentation, and blood drawing.

Hickman and Broviac catheters have an exit site on the skin surface, are anchored with a subcutaneous Dacron felt cuff, and have a subcutaneous tunnel entering the venous system (via the subclavian, external jugular, internal jugular, cephalic, saphenous, or femoral veins), where they lead into the superior or inferior vena cava or right atrium. These catheters can have single, double, or triple lumens. Another type of catheter has a totally implanted port (Port-A-Cath) that is accessed percutaneously. Use of peripherally inserted central catheters (PICCs) is becoming more common.

There are four types of catheter-associated infections: exit-site infections, tunnel infections, catheter-associated bacteremia/fungemia, and septic thrombophlebitis.

There are approximately 0.4 infections per 100 catheter-days and 0.26 bacteremias per 100 catheter-days.

Etiology

It is assumed that catheter-associated infections are caused by tracking of organisms from the skin along the catheter, contamination of the lumen during manipulation, or direct seeding during bacteremia/fungemia.

By far, the most common microorganisms associated with catheter-associated infections are coagulase-negative staphylococci. The next most common pathogen is coagulase-positive S aureus.

Less common pathogens include gram-negative bacilli, gram-positive bacilli (such as Corynebacterium JK and Bacillus species), fungi (especially Candida species), and rapidly growing mycobacteria.

Signs and Symptoms

Exit-site infections may be manifested by local erythema, warmth, and tenderness. Purulent drainage may be present.

Tunnel infections are characterized by tenderness along the subcutaneous track.

Catheter-associated bacteremia/fungemia usually displays no local findings. A fever may be the only sign, but other signs and symptoms of sepsis or even full-blown septic shock syndrome may be present.

Likewise, septic thrombophlebitis may have no findings, except those associated with sepsis or venous thrombosis (edema).

Diagnosis

In any cancer patient with a central venous catheter who becomes febrile or is shown to be bacteremic or fungemic, a catheter-associated infection should be suspected. Without the signs or symptoms of an exit-site or tunnel infection, however, a diagnosis may be difficult.

Cultures

Two blood cultures should be drawn: one from the catheter(s) and one from a peripheral vein. There are two methods that may be helpful in making a diagnosis of right atrial catheter infection. Both depend upon drawing both (catheter and peripheral vein) blood cultures simultaneously. In the first method, quantitative colony counts are determined from both cultures. If the catheter colony counts are three-fold higher than the colony count from the peripheral vein, it suggests a catheter-associated infection. The second method, differential time to positivity (DTP), requires an automated continuously monitored blood culture system, which determines the time at which a blood culture turns positive. If the catheter culture turns positive at least 2 hours before the peripheral vein culture, it suggests a catheter-associated infection. A catheter infection should be assumed when the organism isolated is a coagulase-negative Staphylococcus, Corynebacterium, Bacillus, or Candida species or a mycobacterium.

If signs are consistent with an exit-site or tunnel infection, an attempt should be made to culture any exit-site drainage.

Treatment

Catheter removal

Although it was once believed that all catheters had to be removed to eradicate infection, it is now clear that many catheters can be salvaged. An exception to this guideline would be if the organism isolated is Corynebacterium JK, a Bacillus species, a Candida organism, or a rapidly growing mycobacterium. Some physicians would add to this list S aureus, VRE, P aeruginosa, polymicrobial bacteremia, and Fusarium species. The catheter also should be removed in patients with sepsis with hemodynamic instability, septic thrombophlebitis, or evidence of septic emboli. A tunnel infection or pocket-space abscess should prompt catheter removal as well. Finally, fever or bacteremia that persists (72 hours or longer) after therapy has been initiated necessitates removal of the catheter if there is no other source of infection.

Antibiotic therapy

Empiric therapy. If a catheter-associated infection is suspected, vancomycin should be initiated empirically. For institutions that have high rates of MRSA with vancomycin MIC (minimum inhibitory concentration) values > 2 µg/mL, alternative agents should be used, such as linezolid or daptomycin (Cubicin) (do not use daptomycin in respiratory infections; this agent is inactivated by surfactant in the lungs). If the patient is known to be colonized with VRE, then empiric therapy with quinupristin/dalfopristin (for Enterococcus faecium only), linezolid, or daptomycin should be considered.

Specific therapy. When a microorganism has been isolated and tested for sensitivity, specific antimicrobial therapy should be adjusted accordingly. If the catheter is left in place, a minimum of 14 days of parenteral (not oral) therapy should be administered through the catheter (rotating through each port), and follow-up cultures should be obtained.

For documented catheter-related infections caused by coagulase-negative staphylococci, the catheter may be retained using systemic therapy with or without antibiotic-lock therapy.

Prolonged treatment (4 to 6 weeks) is recommended for complicated catheter-related infections, defined as the presence of deep tissue infection, endocarditis, septic thrombosis, or persistent bacteremia or fungemia occurring > 72 hours after catheter removal in a patient who has received appropriate antimicrobials.

Search for infectious metastasis

Whether or not the catheter is removed, if the patient remains febrile, a search for sources of metastatic infection (lungs, liver, spleen, brain, heart valves) should be initiated.

Fibrinolytics and anticoagulants

The use of fibrinolytics and anticoagulation is controversial. Anticoagulation is indicated in cases of septic thrombophlebitis when the deep venous system is involved.

Hand hygeine, maximal sterile barrier precautions, and cutaneous antisepsis with chlorhexidine during central venous catheter insertion are recommended.

C Difficile–Associated Diarrhea

Although many infectious complications involve the GI tract and abdomen in cancer patients, C difficile–associated diarrhea (CDAD) and typhlitis are the most important clinically.

Diarrhea is common in the cancer patient during chemotherapy. One of the most common causes of diarrhea is antibiotic-associated colitis. By far, the predominant etiology of antibiotic-associated colitis is C difficile. C difficile may also be community-acquired. The increasing incidence and severity of C difficile infections have been attributed to emergence of a hypervirulent strain known as North American pulsed-field type 1, restriction-endonuclease analysis type B1, PCR ribotype 027 (NAP1/B1/027).

Etiology and Risk Factors

Antibiotics

The major risk factor for C difficile–associated diarrhea is treatment with antibiotics, in particular broad-spectrum β-lactams with activity against enteric bacteria, quinolones, and clindamycin, especially in the hospital environment. Antibiotic therapy causes a disruption in the normal bacterial flora of the colon. Pathogenic strains then produce toxins that cause diarrhea and pseudomembranous colitis.

Other risk factors include surgery (primarily colonic, gastric, and pelvic), colon carcinoma, leukemia, and uremia. The hospitalized cancer patient undergoing chemotherapy and/or surgery in addition to GVHD in the setting of allogeneic HCT, and receiving broad-spectrum antibiotics is most vulnerable to this infection.

Signs and Symptoms

Infection with C difficile can be asymptomatic. When signs and symptoms do occur, they may range from mild to moderate diarrhea with lower abdominal pain, to colitis without pseudomembranous formation, to pseudomembranous colitis, to fulminant colitis. Fulminant colitis may be associated with toxic megacolon and even perforation of the viscus and peritonitis. On occasion, a patient may present with just abdominal pain or fever and no diarrhea.

Pseudomembranes may be absent in mild disease but usually are present in severe disease and are easily recognized on sigmoidoscopic or colonoscopic examination as adherent yellow plaques that may coalesce over large areas.

A nested case-control study by Alonso et al identified the following as risk factors for C difficile infection among patients receiving allogenic HCTs: chemotherapy prior to conditioning, use of broad-spectrum antimicrobials, and acute GVHD. Early C difficile infection was a risk factor for GVHD and presence of the latter is risk for recurrent C difficile infection.

Diagnosis

The development of diarrhea or even abdominal pain and fever in a cancer patient should prompt a workup for C difficile–associated diarrhea.

The laboratory diagnosis of C difficile infection depends on demonstration of C difficile toxins in the stool. The gold standard is the stool cytotoxin test, a tissue-culture assay that demonstrates cell rounding by C difficile toxin B.

Another test that can demonstrate C difficile toxins (A and/or B) in the stool is an enzyme immunoassay. It is less expensive and faster than the cytotoxin test and does not need to be performed by specially trained laboratory personnel.

More recently, stool C difficile PCR has been introduced as a diagnostic test.

Although a stool culture for C difficile may also be obtained, it has less significance in making the diagnosis.

Treatment

Initial management

The initial step in the management of C difficile–associated diarrhea is to discontinue antibiotic therapy, and patients may not require any other therapy. However, stopping antibiotics in a cancer patient may not be possible or the patient may be severely ill from the colitis. In these instances, specific anti–C difficile therapy is required.

Specific antibiotic therapy.

• Metronidazole and vancomycin-Metronidazole (500 mg PO tid) and vancomycin (125 mg PO qid), both given for 10 to 14 days, are the drugs of choice. Metronidazole is preferred because it is less expensive. However, in the case of moderate to severe enterocolitis, vancomycin is the drug of choice.

For the patient who cannot tolerate oral medications, IV metronidazole (500 mg q8h) can be given. IV vancomycin should not be used, as high intraluminal levels cannot be attained. A vancomycin retention enema may be useful for cases of ileus. For a severe complicated episode (hypotension or shock, ileus, megacolon), it is recommended to use vancomycin (500 mg orally four times per day or by nasogastric tube) plus metronidazole (500 mg every 8 hours intravenously). Vancomycin retention enemas should be added for complete ileus.

Other agents. Fidaxomicin 200 mg PO bid for 10 days is FDA-approved and shown to decrease recurrent infection in non-NAP1/B1/027 C difficile strains.

Rifamixin 400 mg PO tid for 20 days has been effectively used as a “chaser” after standard treatment with metronidazole or vancomycin PO in preventing recurrence in patients with known history of recurrence.

Other agents, including nitazoxanide (500 mg PO bid), bacitracin (25,000 U PO qid), and cholestyramine (4 g PO qid), may be used as adjuncts.

Surgical therapy. Subtotal colectomy with ileostomy may be required for severe C difficile enterocolitis, especially in the setting of toxic megacolon and impending rupture. Monitoring serum lactate and white blood cell counts (non-neutropenic) may help in making the decision to operate.

Probiotics. Probiotics should be avoided in neutropenic patients.

Caution. Use of metronidazole beyond the first relapse is not recommended.

Treatment of relapse

Relapse occurs in 10% to 20% of patients. If treatment is indicated, a repeat 7- to 14-day course of either metronidazole or vancomycin may be administered. If the infection persists after repeated therapy, a longer course (4 to 6 weeks of vancomycin) followed by a gradual tapering of the dose may be helpful.

Prevention

Patients with C difficile–associated diarrhea and those who are known carriers should be placed in “contact isolation”; ie, the use of gloves, gowns, and careful hand-washing should be instituted.

During outbreaks, the use of sodium hypochlorite to disinfect contaminated surfaces has been recommended.

Antibiotic prophylaxis of high-risk patients or carriers is not recommended.

Typhlitis

Typhlitis (neutropenic enterocolitis) occurs in patients who are severely neutropenic, usually in the setting of chemotherapy. Pathologically, the areas of involvement include the cecum and terminal ileum. Typhlitis is a broad-spectrum disease characterized by bowel wall edema, diffuse or patchy necrosis involving the mucosa alone or the full thickness of the bowel wall, mucosal ulcerations, hemorrhage, inflammatory infiltrates, and infiltration of the bowel wall by bacteria or fungi. Mild cases are self-limiting when treated with bowel rest/antibiotics. Death may occur in severe cases.

Signs and Symptoms

Signs and symptoms of typhlitis can be nonspecific but usually include fever, abdominal pain (typically in the right lower quadrant), and abdominal distention. The patient may have diarrhea (sometimes bloody), nausea, and vomiting or may demonstrate signs and symptoms consistent with those of acute appendicitis.

There may be abdominal guarding and rebound tenderness, diminished bowel sounds, or even a mass in the right lower quadrant of the abdomen.

Diagnosis

Radiographs or CT scans of the abdomen may demonstrate a thickened cecum, mass, or even gas within the colon wall.

Treatment

Mortality from typhlitis is high (> 50%), and therapy is controversial. However, broad-spectrum antibiotics covering both gut aerobes and anaerobes, as well as resection of necrotic bowel, are recommended.

Fungal Infections

Fungal infections are a leading cause of morbidity and mortality in cancer patients. These infections pose a formidable management challenge, in that diagnosis is often difficult to make at an early stage, therefore appropriate treatment may be delayed.

Etiology and Risk Factors

Candida species

The most common fungal infections in cancer patients are caused by Candida species. Of the candidal pathogens found in these patients, C albicans is the most common. However, more recently other Candida species, such as C tropicalis, C glabrata, C parapsilosis, C krusei, and C lusitaniae, have become more prevalent. This finding is significant, as many of these species can be resistant to fluconazole (C krusei, C glabrata, C lusitaniae) and echinocandins (C parapsilosis, C guilliermondii).

Major risk factors for candidal infections include neutropenia, a breakdown in physical defense barriers (such as mucositis induced by chemotherapy and radiation therapy), broad-spectrum antibiotics, immune dysfunction (caused by chemotherapy and steroids), surgery (especially gastrointestinal surgery), long-term indwelling vascular catheters, and poor nutritional status/total parenteral nutrition.

Aspergillus species

Aspergillus species are a less common cause of infection in cancer patients than candidal organisms, although Aspergillus infections have surpassed Candida in HCT recipients. The most common of the Aspergillus species is A fumigatus, followed by A flavus, A niger, and A terreus.

Risk factors for Aspergillus infections include severe immunosuppression (primarily allogeneic HCT), steroid therapy, antitumor necrosis factor therapy, GVHD, and environmental exposure.

Other fungi

Other fungal pathogens in the cancer patient include the Mucorales (Zygomycetes) species, Fusarium, and Scedosporium species; Cryptococcus; and the dematiaceous/pigmented fungi (eg, Bipolaris spicifera, Cladosporium bantianum).

Finally, the endemic fungi, Coccidioides immitis and Histoplasma capsulatum, are often more virulent and aggressive than other fungi in the immunocompromised host.

Signs and Symptoms

Candidiasis

Candidiasis can present as a wide spectrum of diseases, from mucosal infection to disseminated and invasive disease.

Oropharyngeal candidiasis can present as classic thrush with beige plaques. It may be painful, as there may be a concurrent mucositis due to the ablative chemotherapy. Oropharyngeal candidiasis may extend into the esophagus, which may manifest as odynophagia. Epiglottitis may present as odynophagia and laryngeal stridor.

Candidemia may present simply as an asymptomatic fever or may result in a full-blown septic shock syndrome (acute disseminated candidiasis). In contrast, chronic disseminated candidiasis is an indolent infection of different organs, such as the liver, spleen, and kidneys, which may be manifested by fever alone.

Aspergillosis

Invasive aspergillosis most commonly involves the lungs and sinuses. However, it can also disseminate to the brain (and may be the most common cause of brain abscesses in HCT patients). Less commonly, Aspergillus can disseminate to other organs, including the skin.

Signs and symptoms of invasive pulmonary aspergillosis include pleuritic pain, pulmonary hemorrhage, hemoptysis, and cavitation. The chest radiograph or CT scan may demonstrate pulmonary nodular infiltration and/or cavitary lesions.

Patients with sinusitis may have few signs (swelling) or symptoms (pain), especially if they are neutropenic.

Patients with brain abscesses may have headaches and neurologic signs consistent with the specific site of the lesion.

Skin involvement may present as necrotizing skin nodules or ulcers.

Other infections

Mucorales (Zygomycetes) infections cause sinopulmonary disease, similar to aspergillosis, and have recently been rising in incidence.

Scedosporium and Fusarium infections are also similar to those of aspergillosis; pulmonary infiltrates and sinusitis are prominent manifestations. They can be found in the bloodstream; additionally, cutaneous lesions can be seen with Fusarium.

C immitis and H capsulatum also target the lungs but can disseminate to other organs.

Cryptococcus infections can cause pneumonia, meningitis, and cellulitis/skin lesions.

Diagnosis

Diagnosis of fungal infection in the cancer patient requires documentation by culture, serology, or histologic examination.

Candidiasis

Although the diagnosis of oropharyngeal candidiasis often is made on clinical grounds, the lesions should be scraped for microscopic examination and culture. Biopsy of esophageal lesions via endoscopy should be performed to confirm Candida (as opposed to HSV or CMV) as the etiology of the infection.

A positive blood culture for Candida (especially a species other than C albicans) should never be considered a “contaminant” and often implies a right atrial catheter infection. A glucan assay [(1,3)-β-D glucan] may be positive in a patient with disseminated candidiasis. Less likely to result in positive blood cultures are chronic, deep-seated infections, such as hepatosplenic candidiasis. Such infections require biopsy for confirmation. New tests may include rapid diagnostics, such as T2 Biosystems’s T2Candida Panel.

Aspergillus species

Aspergillus species, like other fungal species, such as those of the Mucorales order (Zygomycetes) and dematiaceous fungi, are rarely found in the bloodstream and tissue sampling is required for diagnosis. Occasionally, bronchoalveolar lavage fluid or sinus drainage will yield Aspergillus, but often a lung biopsy is required. A galactomannan enzyme immunoassay test has become available for the diagnosis of invasive aspergillosis. Unfortunately, it is not clear that it is a sufficiently sensitive test (especially in patients receiving antifungal agents) or a predictive test for the disease. It can be performed on serum or bronchoalveolar lavage fluid. There are also two other diagnostic tests now available: the glucan assay and the Aspergillus DNA PCR test. The glucan assay suffers from a high incidence of false positives, and the PCR test for Aspergillus has not been standardized among laboratories.

Fusarium and Scedosporium

Fusarium and Scedosporium, in contrast to Aspergillus species, are often isolated from the bloodstream.

Skin lesions

Any skin lesion suspicious for fungal infection should be biopsied, cultured, and examined histologically.

Search for sites of infection

When a fungal infection is suspected or documented, a search for possible sites of infection should ensue. For a blood culture that grows a Candida species, the intravascular catheter should, in most cases, be removed for diagnostic as well as therapeutic reasons, and the catheter tip should be cultured. A CT scan of the abdomen should be obtained. In cases of suspected Aspergillus infection, in addition to a CT scan of the chest, a CT scan of the brain and sinuses should be performed.

Treatment

Antifungal agents

There are now three major groups of antifungal agents: (1) the polyenes (amphotericin B deoxycholate and its lipid formulations [amphotericin B lipid complex, liposomal amphotericin B, amphotericin B cholesteryl sulfate]); (2) the azoles (fluconazole, itraconzaole, voriconazole, posaconazole); and (3) the echinocandins (caspofungin, micafungin, anidulafungin [Eraxis]).

Amphotericin B deoxycholate has been the standard therapy for invasive fungal infection for 50 years. It is fungicidal and has a broad spectrum of activity against yeasts and molds, including the Mucorales (Zygomycetes). It is thought to be less active against A terreus, Scedosporium, C guilliermondii, and C lusitaniae. However, it is limited by its nephrotoxicity and infusional toxicity. The lipid formulations are less nephrotoxic but much more expensive than the other formulations.

The azoles are not nephrotoxic. The first-generation azoles (fluconazole and itraconazole) are considered fungistatic, whereas the extended-spectrum azoles (voriconazole and posaconazole) are considered more fungicidal. Fluconazole is well absorbed orally and can be administered orally or intravenously but is not active against molds and certain Candida species (C krusei). Itraconazole is hepatotoxic and is not well absorbed when orally administered. Voriconazole is well absorbed orally and can also be administered intravenously. It is broadly active against most Candida species and most molds, with the exception of the Mucorales (Zygomycetes). Posaconazole can only be orally administered. The suspension requires ingestion of a high-fat meal and is pH-dependent. The new oral tablet is not pH-dependent. It is broadly active against most Candida species and most molds, including the Mucorales (Zygomycetes). Drawing azole levels should be obtained for itraconazole, voriconazole, and posaconazole. Trough levels are recommended to ensure adequate drug concentrations, and there are increasing data indicating correlation to efficacy.

The echinocandins are the least toxic of the antifungal agents. They can only be administered intravenously. They are said to be fungicidal against yeasts but fungistatic against molds.

An intravenous formulation of posaconazole was approved in March 2014. Isavuconazole is also available, having been approved for both invasive aspergillosis and mucormycosis in March 2015.

Candidiasis.

• Mucosal candidiasis-In patients with local mucosal candidiasis (including esophagitis), oral fluconazole or itraconazole can be used. If the patient has difficulty in taking oral medication, IV fluconazole should be used. If the patient was receiving prophylactic fluconazole when candidiasis developed, there is a high likelihood that the causative Candida species may be azole-resistant, and either an echinocandin or a lipid formulation of amphotericin B should be used.

• Candidemia-If candidemia is documented, the intravascular catheter should be removed. This step should be followed by the administration of an antifungal for at least 2 weeks after the last positive blood culture is obtained and all signs and symptoms have resolved. Although fluconazole has been shown to be an effective and safe agent in the treatment of candidemia, there are certain circumstances in which an alternative (an echinocandin or a lipid formulation of amphotericin B) might be preferable. These situations would include hemodynamic instability, neutropenia, or high suspicion of azole resistance (eg, a patient who is colonized with a resistant Candida species or has been on recent fluconazole prophylaxis or treatment).

• Disseminated, deep-seated candidiasis (eg, hepatosplenic infection)-Although the standard of therapy for deep-seated candidiasis has been long-term therapy with amphotericin deoxycholate, it has been limited by nephrotoxicity. Thus, the lipid formulations of amphotericin B have allowed higher cumulative doses with a lower nephrotoxic potential. The azoles (fluconazole, voriconazole) have the advantage of convenient (ie, oral) administration and good absorption, with little toxicity. The echinocandins also have been shown to be effective against this infection.

Aspergillosis.

• Antifungal therapy-Amphotericin B deoxycholate (1 to 1.5 mg/kg/d) had long been the standard therapy for invasive aspergillosis. However, voriconazole has led to better responses, improved survival, and fewer adverse events compared with amphotericin B when used as initial therapy in patients with invasive aspergillosis. Thus, voriconazole is now the standard therapy for invasive aspergillosis. However, amphotericin B lipid complex, amphotericin B cholesteryl sulfate, liposomal amphotericin B, posaconazole, and caspofungin can be used. All of these formulations are less nephrotoxic than amphotericin B deoxycholate. Although combination therapy with voriconazole and an echinocandin in a double-blind randomized trial did not definitively demonstrate superiority over monotherapy voriconazole, this combination may still be used in some cases.

• Surgical removal of infected sites-In addition to antifungal therapy, it is important to attempt surgical removal of infected sites, if at all feasible. Sinus surgery should be performed. Resection of pulmonary lesions should be attempted if there are only one or two limited, discrete lesions.

Infections with other fungi. Although amphotericin B is the drug of choice for most invasive fungal infections, there are exceptions. Scedosporium and Fusarium species are often resistant to amphotericin B, and voriconazole may be the drug of choice for these infections. Voriconazole, however, is not active against Mucorales (Zygomycetes) species, and if an infection with this organism is suspected, documented, or cannot be ruled out, amphotericin B deoxycholate, an amphotericin B lipid formulation, or posaconazole (only if a polyene cannot be tolerated) should be used. The dematiaceous/pigmented fungi also may be better treated with itraconazole. For Trichosporon infections, voriconazole may be more effective than amphotericin B.

Prevention

Because invasive fungal infection occurs with high frequency in the setting of HCT, most prophylactic studies have been performed in HCT recipients. Thus, the following recommendations apply mainly to this group, although prophylaxis can be justified when the incidence of these infections in any population is high enough.

Fluconazole

Two randomized, placebo-controlled studies using prophylactic fluconazole (400 mg/d) have demonstrated a decrease in invasive and superficial C albicans infections. One study showed a reduction in mortality. As fluconazole is not active against C krusei, C glabrata, or molds such as Aspergillus species, there is concern that its prophylactic use will increase the incidence of these resistant fungi. Some authors have reported such an occurrence.

Micafungin

Micafungin has been approved for use as an antifungal (candidiasis) prophylactic agent in HCT. There was also a trend toward protection against Aspergillus infection with micafungin, although it was not significant.

Itraconazole

Itraconazole has been shown to be an effective antifungal prophylactic agent in HCT, but no survival benefit has been demonstrated, possibly because of the toxic GI effects and hepatotoxicity associated with this agent.

Low-dose amphotericin B

Low-dose amphotericin B was observed, in a retrospective study, to decrease the incidence of Candida infection. However, this regimen only delayed the onset of Aspergillus infections.

Posaconazole

Posaconazole has been shown to be effective antifungal prophylaxis in two settings: (1) patients with neutropenic AML (acute myelogenous leukemia) and MDS (myelodysplastic syndrome); and (2) allogeneic HCT recipients with GVHD.

Voriconazole

Voriconazole has been shown to be as efficacious as fluconazole. However, it has not resulted in a significant prevention of aspergillosis or demonstrated a survival benefit.

Other prophylactic regimens

Other prophylactic regimens have been used in small numbers of patients, with various degrees of success. They include aerosolized amphotericin B, intranasal amphotericin B, and amphotericin B lipid complex.

The prophylactic regimen

The prophylactic regimen of choice in HCT might be an echinocandin (eg, micafungin) initially (while the patient is neutropenic and hospitalized) followed by an oral azole (eg, posaconazole) administered to outpatients who remain at high risk for mold infections.

HEPA filtration

Other than using prophylactic antifungals, there is little that can be done to prevent fungal infections in cancer patients. The one possible exception is the use of HEPA filtration, which can eliminate Aspergillus spores from the environment. However, most patients emerge from this environment still possessing the same risk factors (treatment with steroids, GVHD) for aspergillosis.

Viral Infections

Opportunistic viral infections are a particular problem in cancer patients who undergo HCT and in individuals with hematologic cancers. Accurate diagnosis of viral infections is important, as treatment is available for many of them.

Etiology

As mentioned previously, viral infections in cancer patients are caused predominantly by herpesviruses (HSV, VZV, CMV, HHV-6, and EBV). The herpesvirus infections usually are reactivations of latent infections. CMV, HHV-6, and EBV are mostly encountered in HCT recipients. Respiratory viruses that infect cancer patients include RSV, influenza viruses A and B, parainfluenza virus, rhinovirus, adenovirus, and human metapneumovirus.

Signs and Symptoms

Although all of the herpesviruses can cause fever and a septic picture, HSV usually presents as mucositis or a vesicular rash; VZV presents as a vesicular rash in a dermatomal distribution; and CMV, in the HCT setting, presents as interstitial pneumonia. When HSV or VZV disseminates, each virus can cause disseminated cutaneous lesions or visceral (liver, lung, brain) involvement. VZV infection can present with GI symptoms, such as epigastric or generalized abdominal pain.

Diagnosis

To make a specific viral etiologic diagnosis, tissue or fluid must be obtained from the infected site and processed for histologic/cytologic examination, PCR, and culture.

Vesicular skin lesions

When a cancer patient presents with a vesicular rash, it is invariably due to either HSV or VZV. If the distribution of lesions is in a dermatomal pattern, a clinical diagnosis of VZV can be made. However, if there is cutaneous dissemination, the vesicular lesions should be aspirated (and sent for viral culture/PCR) or scraped down to the base, smeared on a glass slide, and sent for direct fluorescent antibody (DFA) staining (for HSV and VZV).

Visceral involvement

When there is visceral involvement with HSV, VZV, or CMV, biopsy material is examined for inclusions and is submitted for culture.

Respiratory infection

For the respiratory viruses, diagnosis is usually made by examination of nasal/nasopharyngeal washing, bronchoalveolar lavage fluid (obtained by bronchoscopy), or biopsy (obtained by transbronchial, percutaneous thoracic, thoracoscopic, or open lung biopsy). In the special case of CMV interstitial pneumonitis in the HCT setting, diagnosis of infection (prior to disease onset) can be made by detection of antigens or virus in the bloodstream, in addition to evidence of the virus in bronchoalveolar lavage fluid. PCR and DFA are available for various community respiratory viruses (eg, adenovirus, parainfluenza, influenza, RSV, rhinovirus, and metapneumovirus).

CNS involvement

CNS involvement can be determined by PCR performed on the cerebrospinal fluid for the following agents: HSV, VZV, HHV-6, CMV, EBV, and adenovirus.

Antibody testing is of little use in the diagnosis of viral infection in the cancer patient.

Evidence of CMV viremia

Evidence of CMV viremia, which is utilized to initiate preemptive therapy, can be determined by PCR, antigen detection, or blood (shell-vial) culture.

Treatment

HSV infection

Localized HSV infection is usually treated with acyclovir, at 5 mg/kg IV q8h. If there is dissemination, a dose of 10 mg/kg q8h can be used, and if there is CNS involvement, a dose of up to 15 mg/kg IV q8h can be utilized. If acyclovir-resistant HSV is suspected, foscarnet can be used (see Table 1 for doses). However, this is a nephrotoxic drug.

VZV infection

VZV infection is usually treated with acyclovir, administered at a dose of 10 mg/kg IV q8h.

CMV infection

CMV infection is treated with ganciclovir or foscarnet. Ganciclovir is the drug of choice but is toxic to bone marrow.

In the HCT setting, “preemptive” treatment (to prevent disease after evidence of infection is obtained) consists of ganciclovir at 5 mg/kg IV bid for 14 days or until viremia is cleared, whichever is longer, followed by 5 mg/kg/d IV for another 3 to 5 weeks. Actual treatment of CMV interstitial pneumonia consists of ganciclovir at 5 mg/kg IV q12h, along with immunoglobulin at 500 mg/kg IV every other day for 21 days (induction phase). Maintenance therapy consists of ganciclovir at 5 mg/kg/d IV for 5 days each week, and immunoglobulin at 500 mg/kg IV every week.

Foscarnet can be used instead of ganciclovir if there is marrow toxicity, but it poses a potential risk of nephrotoxicity.

For CMV infection resistant to both ganciclovir and foscarnet, cidofovir can be used.

HHV-6

HHV-6 infection/disease can be treated with ganciclovir, foscarnet, or cidofovir.

Respiratory viral infection

Regarding infections with the respiratory viruses, zanamivir and oseltamivir (75 mg PO bid) can be used for both influenza A and B. Rimantadine or amantadine, both 100 mg PO bid, in combination with oseltamivir has been recommended for resistant influenza A dependent on yearly Centers for Disease Control and Prevention (CDC) recommendations. However, since the H1N1 strain has been in circulation, addition of rimantadine or amantadine has not been needed. Clinicians should refer to the CDC for final recommendations anually. Finally, cidofovir has been used (but is not FDA approved) for adenovirus infection.

Prevention

Herpesvirus infections

Acyclovir. HSV and VZV reactivate with great frequency in cancer patients undergoing chemotherapy and/or radiation therapy. This finding is especially true in the HCT population, in which 80% of HSV-seropositive patients and up to 40% of VZV-seropositive patients have a reactivation of HSV or VZV. Therefore, in HSV-seropositive HCT patients, prophylactic acyclovir is indicated. Any HSV infection that occurs during acyclovir prophylaxis should be considered resistant to acyclovir. Acyclovir has also been shown to reduce the incidence of CMV infection after HCT. It is now recommended by some to extend HSV prophylaxis for 1 year or longer for patients with allogeneic HCT or GVHD, that is, those at risk for VZV reactivation. In patients exposed to VZV, acyclovir should be given at a dose of 800 mg (for adults) or 20 mg/kg (for pediatric patients, with a maximum dose of 800 mg) four times daily on days 3 to 22 after exposure.

Ganciclovir. Ganciclovir is generally considered too marrow-toxic to be used as universal prophylaxis against CMV. Thus, the preemptive approach was developed to focus on only treating those who had evidence of CMV infection (viremia) as determined by PCR, antigen detection, or blood (shell-vial) culture. This approach allows treatment of viremia before it evolves into CMV disease (interstitial pneumonitis).

Reduction of CMV infection. In the small group of HCT recipients who are CMV-seronegative, the use of CMV-seronegative blood support has been shown to reduce CMV infection dramatically. In a study by Marty et al, CMX001, an orally bioavailable lipid acyclic nucleoside phosphonate of cidofovir, was reported to significantly reduce CMV events in recipients of hematopoietic stem cells. Further investigations are needed.

Varicella and VZV vaccines. Varicella and VZV vaccines (Varivax) should not be given to patients with hematologic malignancies, malignant neoplasms, or immunodeficiencies. The exception is with varicella vaccine in patients with childhood leukemia in remission for 1 year, when selected criteria are met.

Influenza

Inactivated influenza vaccine. Inactivated influenza vaccine should be administered yearly to all cancer patients, although the efficacy of the influenza vaccine is unknown in the HCT population. Optimal timing of vaccination is not established, but serologic responses may be best between chemotherapy cycles (> 7 days after the last treatment) or > 2 weeks before chemotherapy starts.

Influenza outbreak. Rimantadine, amantadine, zanamivir, or oseltamivir can be given prophylactically during an outbreak of influenza.

Antimicrobial Stewardship

There are a limited number of new antibiotics in the pipeline and a worrysome number of drug-resistant and multidrug-resistant organisms. To preserve the utility of remaining antibiotics, stewardship of antimicrobials is important. The goals of stewardship are to minimize inappropriate use of antimicrobials and development of acquired resistance, improve patient outcomes, reduce toxicity, and decrease costs associated with inappropriate antibiotic use.

Suggested Reading

On Infection During Febrile Neutropenia

Freifeld AG, Bow EJ, Sepkowitz KA, et al: Clinical practice guidelines for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis 52:e56–e93, 2011.

National Comprehensive Cancer Network: Prevention and Treatment of Cancer-related Infections. V.2.2011. Available at http://www.nccn.org/professionals/physician_gls/f_guidelines.asp.

On Pneumonia

American Thoracic Society; Infectious Diseases Society of America: Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med 171:388–416, 2005.

Mandell LA, Wunderink RG, Anzueto A, et al: Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis 44(suppl 2):S27–S72, 2007.

On Catheter-Associated Infections

Freifeld AG, Bow EJ, Sepkowitz KA, et al: Clinical practice guidelines for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis 52:e56–e93, 2011.

O’Grady NP, Alexander M, Burns LA, et al: Guidelines for the prevention of intravascular catheter-related infections. Clin Infect Dis 54:1053–1063, 2012.

On C difficile Infections

Alonso CD, Treadway SB, Hanna DB, et al: Epidemiology and outcomes of Clostridium difficile infections in hematopoietic stem cell transplant recipients. Clin Infect Dis 54:1053–1063, 2012.

Cohen SH, Gerding DN, Johnson S, et al: Clinical practice guidelines for Clostridium difficile infection in adults: 2010 Update by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA). Infect Control Hosp Epidemiol 31:431–455, 2010.

On Fungal Infections

Pappas PG, Kauffman CA, Andes D, et al: Clinical practice guidelines for the management of candidiasis: 2009 update by the Infectious Diseases Society of America. Clin Infect Dis 48:503–535, 2009.

Walsh TJ, Anaissie EJ, Denning DW, et al: Treatment of aspergillosis: Clinical practice guidelines of the Infectious Diseases Society of America. Clin Infect Dis 46:327–360, 2008.

Ito IJ, Kriengkauykiat J, Dadwal SS, et al: Approaches to the early treatment of invasive fungal infection. Leuk Lymphoma 51:1623–1631, 2010.

On Viral Infections

Harper SA, Bradley JS, Englund JA, et al: Seasonal influenza in adults and children-Diagnosis, treatment, chemoprophylaxis, and institutional outbreak management: Clinical practice guidelines of the Infectious Diseases Society of America. Clin Infect Dis 48:1003–1032, 2009.

Marty FM, Winston DJ, Rowley SD, et al: CMX001 to prevent cytomegalovirus disease in hematopoietic-cell transplantation. N Engl J Med 369:1227–1236, 2013.