W. Lance George
I. BACKGROUND. The development of infection in patients undergoing treatment for malignancies is a complex interplay of a number of factors. These include alterations in the host’s natural mechanical barriers to infection, reduction in the number and function of “professional” phagocytes (particularly neutrophils), and alterations in both humoral and cell-mediated immunity. These various alterations may be a consequence of the malignancy itself or of the treatment (chemotherapy and radiation therapy).
Certain patterns of infection have been recognized and form the basis for empirical management. For example, neutropenia is a major predisposition to bacterial infection, yet it is clear that chemotherapy-induced neutropenia typically occurs in association with alterations in the hosts mechanical barriers to infection and alterations in both humoral and cell-mediated immunity. These interactions likely account both for the different infectious complications that occur during therapy of malignancies and for the types of infections that may be seen with different malignancies.
II. NEUTROPENIA AND FEVER
A. Principles. Development of fever in neutropenic patients should always be regarded as a medical emergency caused by infection. The patient who has signs or symptoms of infection, in the absence of fever, should still be treated in a manner similar to that of the febrile patient.
Early in the period of neutropenia, bacterial infections predominate; hence, management of suspected infection is usually directed initially toward bacterial processes. Diagnosis of a specific infectious process is not possible, however, in a significant proportion of febrile neutropenic patients; much of the clinical uncertainty in treating patients with neutropenia is related to the lack of a specific diagnosis. This should not, however, deter the physician from performing a thorough evaluation and continuing to reassess the patient. Management of infection in the neutropenic patient continues to evolve as new diagnostic tests and antimicrobial therapies (particularly antifungal) are developed.
1. Definitions
a. Fever. A single oral temperature measurement of ≥101°F (38.3°C) or a temperature of ≥100.4°F (38.0°C) for >1 hour constitutes fever.
b. Neutropenia. Although an absolute neutrophil count (ANC) of ≤1,000 cells/has long been the cutoff for the term “neutropenia,” the increased risk of infection with ANC > 500 cells/µL is minimal. The risk of infection increases substantially when the ANC is ≤500 cells/µL, and it is quite high when the ANC is ≤100 cells/μL; “profound neutropenia” is frequendy used to refer to ANC ≤100 cells/µL. “Functional neutropenia” refers to impaired function (e.g., phagocytosis) of circulating neutrophils that can occur with certain hematologic malignancies.
2. Prevention of infection in neutropenic patients
a. General measures
(1) Skin care is important in preventing infections with Staphylococcus aureus and other pathogens. Occlusive antiperspirants should be avoided. Electric shavers are preferred; not shaving at all may be best.
(2) Procedures involving the use of tubes, tapes, and instruments should be minimized because they may be sources of infection.
(3) Fresh flowers, dried flowers, and plants should not be present in the rooms of neutropenic patients because they may carry molds such as Aspergillus.
(4) Avoidance of foods with high bacterial contents (e.g., fresh fruits, uncooked foods, and tap water) is commonly practiced but has no established value.
(5) Pet therapy, the use of household pets at the bedside, should be avoided.
b. Isolation methods
(1) Appropriate hand hygiene is the single most important means to prevent infection in hospitalized patients.
(2) Standard barrier precautions should be employed for all patients; infection-specific isolation should be employed as indicated by the hospital infection control policy.
(3) Reverse or neutropenic isolation (caps, masks, gloves, and gowns) has no established benefit. In addition, it deters good patient care by limiting patient contact with the hospital staff and family.
(4) High-efficiency particulate air filters and laminar airflow rooms, which are expensive, are of questionable benefit.
c. Prophylactic antibiotics. Using absorbable, orally administered antibiotics in neutropenic patients alters the indigenous microbial flora, particularly of the gastrointestinal (GI) tract. Many have advocated this as a form of prophylaxis in the neutropenic patient. The disadvantage of routine oral prophylaxis is the risk of inducing significant resistance of the bacterial and fungal flora to the agents being used for prophylaxis and perhaps other agents; this, in turn, would limit the availability of effective agents to treat infection.
(1) Prophylaxis with fluoroquinolones (e.g., ciprofloxacin or levofloxacin) can be considered in patients who are high risk (see Section II.C.1 for definition of high and low risk) for infection and are expected to be profoundly neutropenic for more than 7 days. The greater gram-positive activity of levofloxacin over ciprofloxacin is potentially an advantage for patients with mucositis. Fluoroquinolone prophylaxis reduces the incidence of fever, “probable” infection, and hospitalization but does not reduce overall mortality. Subsequent infections are more likely to be the result of resistant organisms. Significant concern exists regarding the rising incidence of resistance to fluoroquinolones and the relationship of this resistance to Clostridium difficile diarrhea and colitis. If routine prophylactic antimicrobial therapy is adopted at a cancer center, it should be done in association with rigorous infection control practices and monitoring for emergence of resistant microorganisms.
(2) The routine use of sulfamethoxazole–trimethoprim (Bactrim or Septra) for bacterial prophylaxis in neutropenic patients is of limited benefit and possesses some of the same risks associated with fluoroquinolone prophylaxis. Patients at appreciable risk for Pneumocystis carinii or PCP (renamed P. jiroveci) infection, such as those with acquired immunodeficiency syndrome (AIDS) and CD4 lymphocyte counts <200 cells/µL, should, however, receive prophylaxis in the form of one double-strength tablet (800 mg of sulfamethoxazole plus 160 mg of trimethoprim) once daily. Data documenting the benefit of PCP prophylaxis in patients with leukemia, lymphoma, and certain solid tumors receiving chemotherapy are much less robust than for HIV infection. Sulfamethoxazole–trimethoprim is not recommended for bacterial prophylaxis.
(3) Intravenous vancomycin prophylaxis has been used to prevent catheter-associated gram-positive infections; it has sometimes been given as combination prophylaxis with quinolones. This practice is strongly discouraged.
(4) Linezolid, daptomycin, and quinupristin–dalfopristin (Zyvox, Cubicin, and Synercid, respectively) are newer agents with activity against some resistant gram-positive organisms; they should not be usedas prophylactic agents.
(5) Antifungal agents. Posaconazole prophylaxis was recently shown to improve survival when compared with fluconazole and itraconazole in patients with certain types of immunosuppression. Patients studied were those who received chemotherapy for acute myelogenous leukemia or myelodysplastic syndrome and those undergoing allogeneic hematopoietic stem cell transplantation with graft versus host disease (GVHD). The benefit was largely a lower incidence of invasive Aspergillus infection; serious side effects of prophylaxis were noted. Although there is debate regarding the overall benefit of antifungal prophylaxis in severely immunosuppressed patients, antifungal prophylaxis in patients with lesser degrees of immunosuppression is not recommended.
3. Predisposition to infection
a. The degree and the duration of neutropenia are the most important and easily measured risk factors that predispose to the development of infection. Infection that develops in the setting of neutropenia of relatively brief duration (5 to 7 days) is most likely to be associated with bacterial infection, reflecting the important role of granulocytes in the prevention or control of bacterial infection. Defects in granulocyte function, humoral immunity, and cell-mediated immunity are likely contributing factors, particularly when neutropenia is of longer duration, but these defects are difficult to assess clinically; in patients with profound neutropenia lasting longer than 7 days, fungal infections become a major concern.
b. Defects in the normal mechanical barriers of the host to infection are important predispositions to infection.
(1) Defects in mechanical barriers related to treatment of malignancy are major predisposing factors. The most common sites of such breaches are the skin, the paranasal sinuses, and the alimentary tract; breaches of these barriers allow for local and disseminated infection by the indigenous (normal) and colonizing (environmental) flora of the skin and alimentary tract. Placement of vascular access devices creates a portal for infection of the surrounding soft tissues and bloodstream by microorganisms. Other invasive procedures pose risks for infection that relate to the site of the procedure.
(2) Other types of impairment of the host’s normal barriers to infection include tumor invasion of mucosal surfaces and of the integument; loss of protective reflexes, such as cough; and obstruction to drainage of hollow organs, such as the urinary bladder and the gall bladder.
c. Hospitalization, per se, does not increase the risk of infection, but it does influence the types of infecting organisms and their antimicrobial susceptibility.
4. Infecting organisms
a. Early in the course of neutropenia, bacteria predominate as the microbiologically documented pathogens. Gram-positive bacteria now account for approximately two-thirds of isolates, gram-negative bacilli account for approximately one-fourth, and Candida species and other fungi are occasional pathogens; fungi other than Candida (molds) are usually not of major concern early in neutropenia. Gram-negative bacilli that are encountered frequently include Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and, more recently, Acinetobacter baumannii.
Increasing antimicrobial resistance among gram-positive bacteria has made management difficult. Approximately 50% of Staphylococcus aureus are resistant to traditional antimicrobial agents (penicillins and cephalosporins) and can produce rapidly fatal infection. Other gram-positive organisms may also display significant antimicrobial resistance but typically have a more indolent course; these include coagulase-negative staphylococci, enterococci, including vancomycin-resistant enterococci, and Corynebacterium jeikeium.
b. Later in the course of neutropenia, fungi, particularly yeast (Candida species) and molds (particularly Aspergillus species), must be considered as potential pathogens. In addition, multiply drug-resistant bacteria must be considered.
c. Clostridium difficile–associated diarrhea or colitis is now frequently hospital acquired; it is often associated with fever and almost invariably follows antimicrobial therapy. Of note, onset of symptoms may occur during antimicrobial treatment or as many as 6 weeks after cessation of antimicrobial therapy.
B. Diagnosis
1. History and physical examination. A careful history should be taken, with a focus on new symptoms and on sites that are most commonly infected. Classic signs of inflammation may not be present because of the absence of neutrophilic exudates in infected tissues, although the presence of localized pain may be an important clue. A detailed examination should be performed of the ocular fundus; oropharynx, including teeth and supporting structures; lungs; perineum and perianal areas; and the skin, including vascular access catheter sites and other breaks in the integument related to diagnostic procedures. Digital rectal examination and pelvic examination are usually not performed because trauma to the mucosa during the examination may cause bacteremia.
2. Laboratory evaluation. In addition to routine laboratory tests, at least two samples of blood for bacterial and fungal culture should be obtained promptly by percutaneous collection. The benefit of obtaining blood cultures via a central venous catheter (CVC) is debated; if microorganisms are present in blood, they will be detected by percutaneously collected cultures. Recovery of organisms from cultures collected from a CVC may reflect true infection but frequently reflects contamination of the external port or connection hardware of the CVC; this often leads to much confusion, unnecessary use of antimicrobial agents, with the attendant risks of adverse side effects and colonization of the patient by increasingly resistant microorganisms.
If a CVC is present, the skin exit site should be carefully inspected. If there is drainage from the CVC exit site, the exudate should be submitted to the laboratory for Gram stain, bacterial culture, and fungal culture and microscopic examination.
Cutaneous lesions should be either aspirated or biopsied for bacterial and fungal cultures and histopathologic examination. Sputum for bacterial culture should be obtained if pulmonary symptoms are present or radiographic abnormalities are seen. Urine culture is indicated if there are symptoms, a bladder catheter is present, or the urinalysis is abnormal. If diarrhea is present, then samples should be submitted for C. difficiletoxin test and routine bacterial cultures; if diarrhea has been present for >7 days, tests for Giardia, Cryptosporidium, Cyclospora, and Isospora should be submitted.
3. Surveillance cultures. No clinical value is seen in obtaining surveillance cultures from sites such as the anterior nares, pharynx, urine, and rectum or perianal area.
4. Imaging studies. A baseline chest radiograph (posteroanterior and lateral views) should always be done as part of the initial evaluation. In the case of persistent fever and neutropenia, CT, MRI, 67Ga scanning, and other isotopic scans and imaging studies may occasionally be of diagnostic value, depending on the particular clinical circumstances. CT scanning of the lungs and paranasal sinuses may be particularly useful.
C. Empiric therapy
1. Initial empiric antimicrobial therapy: high- and low-risk patients. Subject to the definitions of fever and neutropenia given above, febrile neutropenic patients should be rapidly assessed for evidence of infection. Even if there is no evidence of infection other than fever, prompt institution of empiric antimicrobial therapy is essentially always indicated.
In order to facilitate management, febrile neutropenic patients can be subdivided in those who are at low risk and those who are at high risk for serious infection. Low-risk patients are individuals whose period of neutropenia is expected to be brief (<7 days) and who lack significant medical comorbidities; they can be safely treated with either oral or intravenous antimicrobial therapy as outpatients. High-risk patients are those who are anticipated to have prolonged (>7 days) and profound neutropenia (ANC ≤ 100 cells/µL). The presence of significant medical comorbidities such as hypotension, pneumonia, abdominal pain, and change in neurologic status would obviously warrant hospitalization and intravenous antibiotic treatment, regardless of the anticipated duration and severity of neutropenia.
Useful antibacterial and antifungal agents for the treatment of neutropenic fever are shown in Table 35.1.
Table 35.1 Useful Antibiotics for Neutropenic Fever
NF, neutropenic fever; CNS, central nervous system; FDA, U.S. Food and Drug Administration.
aAll of the agents listed require dose adjustment for impairment of renal function. Many of these agents are available as generic products.
b1.0 g q8h to q6h may be given in life-threatening situations or for infections by organisms that are only moderately susceptible to imipenem-cilastatin (primarily some strains of P. aeruginosa) and resistant to most other agents.
cMonitoring of blood levels (peak and trough) and adjustment of dosing of aminoglycosides are indicated to ensure efficacy and to minimize oto- and nephrotoxicity. Once-daily aminoglycoside dosing should not be done unless a β-lactam or carbapenem is also being administered; dose adjustments are needed in the case of renal dysfunction and obesity, regardless of the dosing regimen.
dOf the three echinocandins, only caspofungin has an FDA indication for treatment of NF. Many hospitals will maintain a supply of only one echinocandin. Based on available data, it is reasonable to use one of the other echinocandins for treatment of NF, if caspofungin is not available.
eOf the three lipid preparations of amphotericin, only LAmB has an FDA indication for treatment of NF. Because most hospitals will only maintain a supply of AmBD and one of the three lipid formulations, it is reasonable to use the available lipid formulation if AmBD cannot be used. All amphotericin-containing products possess multiple toxicities, including nephrotoxicity.
2. Intravenous antimicrobial therapy. Most patients will likely fall into the so-called “high risk” category. In the past, several different antibiotic combinations were employed for empirical treatment. Empirical treatment has been greatly simplified but requires knowledge of the antimicrobial susceptibility patterns of bacteria isolates at the facility where the patient has been receiving care as well as consideration of the particular infection. Information regarding antimicrobial susceptibility, often termed the hospital “antibiogram,” can usually be obtained from the microbiology laboratory.
The goal of empiric therapy is to provide coverage against likely pathogens pending receipt of culture results. Information from the antibiogram can be used to tailor empiric treatment based on local resistance patterns. In the past decade, initial empiric treatment has been simplified to the use of one of several broad-spectrum agents; this approach has been highly effective.
a. A main goal of initial empiric therapy is coverage of gram-negative bacilli, including Pseudomonas aeruginosa; this coverage can usually be accomplished by monotherapy with a beta-lactam antimicrobial. Agents appropriate for this goal include piperacillin–tazobactam, cefepime, and selected carbapenems (either meropenem or imipenem–cilastatin). These antimicrobial agents also provide moderate to excellent coverage for many (but not all) gram-positive organisms and anaerobic bacteria and are often used as monotherapy for fever in the setting of neutropenia.
Generally, these agents are appropriate when the patient has not been exposed repeatedly to antimicrobial therapy, and the microbiology laboratory at the treatment facility has not recorded appreciable resistance to these agents. If the patient is not clinically stable or there is concern about infection with more resistant bacteria, addition of other agents to the regimen may be warranted; these agents would include vancomycin, daptomycin, linezolid, fluoroquinolones (ciprofloxacin and levofloxacin), aminoglycosides (particularly amikacin), colistin, and tigecycline (see below).
b. A history of uncomplicated penicillin-induced skin rash is not a contraindication to the use of these beta-lactam agents (penicillins, cephalosporins, and carbapenems). However, these drugs should be avoided in patients with a history of immediate hypersensitivity to penicillins (or other beta-lactam agents) or history of penicillin-associated Stevens-Johnson syndrome or toxic epidermal necrolysis. In the occasional situation in which a beta-lactam agent is clearly contraindicated because of risk of serious allergic reaction, alternative empiric regimens include ciprofloxacin–clindamycin or aztreonam–vancomycin; data regarding efficacy of these alternative regimens are limited.
c. The initial empiric use of vancomycin is indicated in patients who are suspected of having CVC-related infection, bacterial pneumonia, skin and soft tissues infection, or who are hemodynamically unstable, in addition to the gram-negative coverage listed above.
d. Modifications to the initial empiric antibiotic regimen are appropriate for patients who are at risk for infection with resistant organisms or who are bacteremic or are clinically unstable. A significant degree of expertise with regard to local hospital bacterial resistance patterns is often needed to address these issues; infectious diseases consultation should be considered.
3. Modifications (additions) to the recommended initial empiric antibiotic regimen is warranted whenever there is concern regarding the following: Staphylococcus aureus, vancomycin-resistant Enterococcus, or extended-spectrum beta-lactamase production.
a. Staphylococcus aureus. Effective treatment of infection due to Staphylococcus aureus has changed substantially in the past decade and likely will continue to change.
(1) Methicillin-resistant Staphylococcus aureus (MRSA) now accounts for an appreciable portion (>50%) of all infections due to S. aureus. Agents to be considered for treatment of suspected or documented infections due to S. aureus include vancomycin, daptomycin, and line-zolid. The greatest clinical experience for treatment of MRSA is with vancomycin; it is considered by most experts to be the drug of choice. However, progressively rising concentrations of vancomycin (“MIC creep”) that are now required to treat MRSA infection have many experts concerned that this drug may eventually be lost as a first-line agent. Recommendations for treatment of serious MRSA infections include a target serum trough level of 15 to 20 µg of vancomycin/mL of blood.
(2) Daptomycin also has good activity against MRSA and has been used with success. Potential concerns regarding daptomycin are several, however. The drug is significantly bound by pulmonary surfactant; daptomycin is not indicated for treatment of pneumonia. In addition, the vancomycin “MIC creep” noted above appears often to also be associated with a daptomycin MIC creep as well; the clinical significance of this finding is unclear but definitely concerning.
(3) Linezolid is a bacteriostatic agent with good activity against most gram-positive organisms, including MRSA. The major concerns about linezolid are its bacteriostatic nature and potential hematologic toxicity. The latter includes thrombocytopenia, anemia, and myelosuppression. Thrombocytopenia, the most concerning hematologic adverse effect, is thought to be an immune-mediated process that is particularly associated with linezolid therapy of >2 weeks duration.
(4) Ceftaroline is a new agent with activity against a variety of microorganisms, including MRSA. It was recently approved by the FDA for treatment of acute skin and soft tissue infections and community-acquired pneumonia due to susceptible organisms. Data to support ceftaroline’s efficacy for infections in immunosuppressed patients are lacking. In addition, it is unclear whether it will become another useful agent to treat most infections caused by MRSA (aside from skin/soft tissue infection).
b. Vancomycin/ampicillin-resistant Enterococcus (VRE) has become an important pathogen in many centers. The recommended empiric therapy for suspected VRE is either linezolid or daptomycin.
c. Multidrug-resistant gram-negative bacilli (GNB) are becoming increasingly common isolates and present major clinical challenges. They are extended spectrum beta-lactamase (ESBL) producing organisms (the most common form of multidrug resistant GNB) and carbapenemase-producing organisms (a relatively uncommon form).
(1) ESBL-producing GNB are relatively commonly isolated from hospitalized patients, whereas carbapenemase-producing GNB are uncommon. ESBL-producing GNB are considered to be resistant to penicillins (including piperacillin–tazobactam) and cephalosporins (including cefepime). Because there is not a single standardized clinical laboratory test for ESBL production, microbiology experts and the FDA have proposed a revision of laboratory susceptibility interpretation. This should eliminate testing for ESBL and provide a more uniform interpretation of antimicrobial activity.
At present, this field is in a state of flux. In general, GNB that produce ESBLs are often resistant to other classes of antibiotics, such as aminoglycosides and fluoroquinolones. Most experts recommend use of a carbapenem (imipenem or meropenem) if the patient is clinically unstable or has cultures that are suspicious for resistant GNB because of the high incidence of ESBL production.
(2) Carbapenemase-producing GNB are uncommon, but there is significant concern regarding widespread dissemination of these organisms. In general, most experts would consider adding either colistin or tigecycline to the regimen if the patient is clinically unstable or if culture results are suspicious for a carbapenemase-producing GNB. Clinical data regarding the efficacy of these agents for treatment of infection in neutropenic patients are extremely sparse. Infectious diseases consultation would be prudent in such situations.
4. Oral antimicrobial therapy. Oral antimicrobial therapy with ciprofloxacin (Cipro), 750 mg q12h, plus amoxicillin/clavulanate (Augmentin), 875 mg/125 mg q12h, has been shown to be safe and appropriate, when limited to adult patients who are at low risk for infectious complications of neutropenia. Such patients do not have an identifiable focus of infection and lack clinical findings of systemic infection other than fever.
A number of factors that favor a low risk for severe infection have been identified and a scoring index has been developed to identify low-risk subjects who would be suitable for oral therapy (see Hughes, et al. 2002 and Freifeld, 2010 in Suggested Reading). These patients, however, still require careful observation and immediate access to medical care. Outpatient oral antibiotic therapy may not be suitable for many patients and health care facilities, but likely greater use will be seen in the future as additional experience is gained with this form of management.
Other options available to the clinician are initial hospitalization for administration of intravenous antibiotics, followed by switch to oral therapy and discharge, or discharge home on IV antibiotic therapy. Patients with febrile neutropenia, regardless of route of antimicrobial therapy, should be seen and evaluated on a daily basis.
D. Empiric therapy. Management of antimicrobial therapy during the first 7 days. Response of fever to initiation of empiric antimicrobial therapy, if it is to occur, sometimes requires 3 to 5 days. After initiation of antimicrobial therapy, several possible outcomes exist: deterioration during the ensuing 1 to 3 days, resolution of fever during the first 3 to 5 days, or persistence of fever during the first 3 to 5 days. In the event of clinical instability, immediate reassessment of the patient and the treatment regimen is essential.
In many studies, the median time to defervescence after initiation of therapy is approximately 5 days. Therefore, in a patient who is clinically stable, except for persistent fever, the physician should consider waiting approximately 5 days before entertaining changes in the antimicrobial regimen, unless initial cultures yield an organism resistant to the treatment regimen. Changes in antimicrobial therapy should generally be made for specific reasons; an unintended consequence of aggressive, unjustifiably escalating antimicrobial therapy is the promotion of subsequent infection by more highly resistant microorganisms.
1. In patients who become afebrile within 3 days, broad-spectrum therapy should be maintained throughout the period of neutropenia, with appropriate modifications to the regimen based on results of cultures and other diagnostic tests. Cessation of therapy is appropriate when cultures and clinical assessment indicate eradication of infection and the ANC is >500 cells/µL. A switch from IV to oral antibiotic therapy is reasonable if the patient is clinically stable and impaired absorption of antibiotics from the gastrointestinal tract is not a concern. Clinically documented infection should be treated in a manner that is appropriate for the type of infection, irrespective of the rapidity with which neutropenia resolves.
2. In patients whose fever persists during the first 4 to 7 days of empiric therapy and in whom a specific infectious process has not been identified, a number of possibilities exist. In the event of persistent fever of unknown cause for more than 4 days, the most appropriate actions are (1) continue treatment with the initial regimen, (2) change or add antibacterial agents to the original regimen, or (3) add an antifungal agent to the regimen (with or without making changes to the antibacterial regimen).
a. Causes of persistent fever include
(1) Slow response to the treatment regimen
(2) Bacterial infection resistant to the treatment regimen
(3) Development of a second infection
(4) Inadequate antibiotic levels owing to suboptimal dosing
(5) Inadequate penetration of drugs into an infected site, such as infected necrotic tissue, an abscess, or a CVC site
(6) A nonbacterial infection
(7) Fever not of infectious origin, such as drug fever or pulmonary emboli
b. Reevaluation. In reevaluating the patient’s status after 3 to 4 days of therapy, the physician should repeat the initial diagnostic evaluation, review results of culture, obtain additional cultures, and consider obtaining radiographic imaging studies, if new localizing symptoms or signs are present. Any changes in therapy should be dictated by findings on reevaluation.
c. If the patient has remained clinically stable and the reevaluation was unrevealing, continuation of the initial regimen is reasonable. If neutropenia is expected to resolve within 5 days, this approach is quite appropriate.
d. With evidence of progressive disease, consideration should be given to changes in the antimicrobial regimen. The nature of these changes should be dictated by findings made during clinical reassessment and the components of the initial antimicrobial regimen. Examples of new findings include development of abdominal pain (suggesting cecitis, enterocolitis, or other intra-abdominal processes), development of diarrhea (suggesting C. difficile disease), detection of pulmonary infiltrates, drainage or inflammation at catheter entry sites, worsening stomatitis, and detection of sinus opacities on CT scanning.
e. Addition of antifungal therapy to the treatment regimens of patients who are febrile after initial antimicrobial therapy has been controversial, particularly with regard to the timing of such therapy and the particular antifungal agent to be used. The availability of newer, less toxic anti-fungal agents have facilitated a more uniform approach. Most experts believe that a patient with persistent fever and profound neutropenia after 4 days of empiric antimicrobial therapy should be considered for antifungal therapy. A thorough evaluation to detect systemic fungal infection should be done; this should include consideration of biopsy of suspicious lesions, chest radiographs, sinus radiographs or CT, and CT of the chest and abdomen. If a focus of bacterial infection is not found, fungal infection should strongly be considered. The fungi most likely to cause fever relatively early in the course of neutropenia are Candida species.
Detailed discussion of treatment of fungal infections is provided in Section VII. The use of antifungal agents in patients with prolonged neutropenic fever is discussed in Section VII.B.
E. Empiric therapy: Duration of therapy
1. Antibacterial therapy
a. The most important indicator in deciding to discontinue antibacterial therapy is the neutrophil count. If the ANC is ≥500 cells/µL and the patient has been afebrile for 2 consecutive days, therapy may be stopped unless more prolonged therapy is indicated for treatment of a specific, documented infection (e.g., pneumonia or bacteremia).
b. For the patient who becomes afebrile but is persistently neutropenic, most experts recommend continuation of therapy until the ANC is ≥500 cells/µL. Some experts would change to oral therapy if the patient were at low risk. In the completely healthy-appearing patient, some would discontinue antimicrobial therapy and engage in close monitoring, particularly with early evidence of bone marrow recovery.
c. For the patient who remains profoundly neutropenic (ANC ≤ 100 cells/µL), IV antimicrobial treatment should be continued.
2. Antifungal therapy
a. If a specific fungal infection has been documented, then the duration of antifungal therapy will be determined by the pathogen and the nature of the infection. Because of the differing activities of the three main groups of antifungal agents commonly given to patients with neutropenic fever (echinocandins, triazoles, and amphotericin preparations), a greater need now exists for establishing an etiologic diagnosis. Knowledge of the infecting fungus should allow for selection of the most effective therapeutic agent and facilitate limitation of toxicity.
b. If a fungal infection is not documented but empiric antifungal therapy is given, it is not clear how long antifungal therapy should be given. Antifungal therapy can be discontinued if neutropenia and fever have resolved, the patient appears well, cultures are negative, and imaging studies do not reveal lesions suspicious for fungal infection.
3. Persistent fever after resolution of neutropenia. The persistence of fever after broad-spectrum antimicrobial therapy and recovery of bone marrow function (ANC ≥ 500 cells/µL) suggests drug fever, deep-seated bacterial infection, or infection with a mycobacterium or fungus (e.g., aspergillosis or systemic candidiasis).
F. Further issues involving neutropenic fever
1. Antiviral therapy. Empiric use of antiviral agents is not recommended. Localized lesions caused by herpes simplex or varicella-zoster virus may provide a portal of entry for other pathogens and can be treated with oral acyclovir, valacyclovir, or famciclovir. Disseminated cytomegalovirus (CMV) infection is rare in the absence of profound immunosuppression that occurs in patients with AIDS or stem cell transplantation.
2. Granulocyte transfusion. The routine use of granulocyte transfusions is not recommended. Some investigators believe that patients with severe bacterial or fungal infections may benefit from granulocyte transfusion. This procedure should still be considered investigational (see Chapter 34, Section V.B in “Cytopenia”).
3. Use of colony-stimulating factors (CSF). The hematopoietic growth factors granulocyte CSF (filgrastim) and granulocyte-macrophage CSF (sargramostim) have long been used for the treatment of patients with febrile neutropenia. Although they may reduce the period of neutropenia, they do not reliably reduce the duration of fever, the need for antimicrobial therapy, the duration of hospitalization, or other measures of febrile morbidity. The American Society of Clinical Oncology, through an update of its clinical practice guidelines (see Smith, et al. in Suggested Reading), has recommended the routine use of CSF when the risk of febrile neutropenia is approximately 20%, based on the conclusion that reduction of febrile neutropenia was, per se, an important clinical outcome.
III. SPECIFIC INFECTIONS IN THE COMPROMISED HOST
A. Pulmonary infections
1. Differential diagnosis
a. Noninfectious causes. About 25% to 30% of cases of fever with pulmonary infiltrates in cancer patients are owing to noninfectious causes, which include radiation pneumonitis, drug-induced pneumonitis, pulmonary emboli and hemorrhage, and leukoagglutinin transfusion reaction.
b. Predicting the infecting agent. Acute, severe symptoms that progress in 1 to 2 days suggest a common bacterial pathogen, a virus, or a noninfectious process (pulmonary emboli, pulmonary hemorrhage). A subacute course (5 to 14 days) suggests pneumocystis, or, occasionally, aspergillosis or nocardiosis. A chronic course (over several weeks) is more typical of mycobacterial or fungal infections, radiation fibrosis, or drug-induced pneumonitis.
(1) Infection acquired outside the hospital. Despite the susceptibility of cancer patients to opportunistic pathogens, S. pneumoniae and influenza virus are the most likely causes of pulmonary infections in the outpatient setting.
(2) Infection acquired in the hospital. E. coli, K. pneumoniae, Serratia marcescens, P. aeruginosa, Acinetobacter sp., and S. aureus are the most frequently acquired nosocomial bacterial pathogens. Aspergillussp., Legionella pneumophila, and P. carinii can be hospital acquired.
(3) The association between lung carcinoma and pulmonary tuberculosis is related to the increased susceptibility to opportunistic infections and tuberculosis in cancer patients. Erosion of tumor into a quiescent tuberculous focus likely accounts for some cases. Diagnosis of tuberculosis requires pathologic evidence from biopsies or bacteriology samples. Surgical treatment of early stage bronchopulmonary carcinoma may have to be postponed and may even be contraindicated in the presence of active tuberculosis. Chemotherapy and radiotherapy may result in extension of the tuberculosis.
2. Diagnostic approach
a. Sputum examination. If the sputum contains neutrophils or macrophages and <10 epithelial cells per low-power field, the sputum culture results are probably valid. Problems with interpretation include the following:
(1) Neutropenic patients usually have no neutrophils in the sputum.
(2) Aspiration pneumonia is usually caused by mouth flora, which renders routine culture meaningless in this condition.
(3) S. pneumoniae is a fastidious organism that is difficult to recover from sputum, although approximately 25% of pneumococcal pneumonias are associated with concomitant bacteremia.
(4) Many opportunistic organisms that produce pneumonia are infrequently retrieved from sputum (e.g., Nocardia asteroides and Aspergillus species and other molds).
(5) Sputum cultures of hospitalized patients, particularly those receiving antibiotics, often yield Candida on culture. Although candidemia and disseminated candidiasis are frequent and serious complications of immunosuppression, pneumonia because of Candida is remarkably uncommon. Therefore, recovery of Candida from sputum should not be considered to be diagnostic of infection.
b. Serology may be useful for identifying infection caused by Coccidioides immitis. Serology is less useful for diagnosis of infections caused by Aspergillus species, L. pneumophila, Mycoplasma pneumoniae, Toxoplasma gondii, and CMV. There is a delay associated with most serologic tests, and some are not highly sensitive or specific.
c. Antigen tests. Blood antigen tests are useful for diagnosis of infections caused by C. neoformans. Urinary antigen tests are valuable tools for diagnosis of infections caused by S. pneumoniae; L. pneumophila, serogroup 1; and Histoplasma capsulatum. The detection of cryptococcal antigen in any body fluid is considered diagnostic of infection.
The use of nonculture tests for diagnosis of other fungal infections has been disappointing. Detection of Candida species depends primarily on culture.
The serum galactomannan test for aspergillosis has not proven to be particularly helpful. A meta-analysis found the test sensitivity ranged from 61% to 71% and specificity from 89% to 93%; the positive predictive values ranged from 26% to 53%, whereas the negative predicative values ranged from 95% to 98%.
The serum beta-D-glucan assay can detect a cell wall component (1,3-beta-D-glucan) of many fungi but also has the limitations of the galactomannan—variable sensitivity and specificity.
d. Blood cultures should be obtained in all patients.
e. CT and high-resolution CT (HRCT). A normal chest radiograph makes pneumonia unlikely, but plain radiographs of the lungs may be too insensitive to detect early disease. Neutropenic patients with persistent fever and normal chest radiographs should undergo CT scanning (and perhaps HRCT) to detect occult inflammatory pulmonary disease. CT is of particular value for diagnosis of invasive pulmonary mycoses, such as aspergillosis.
f. Thoracentesis should be performed in patients with pleural effusion.
g. Lung biopsy procedures. Diagnosis is paramount in the immunocompromised host. The highest yield and best control of bleeding is by direct visualization with open-lung biopsy or video-assisted thoracoscopic surgery (VATS). This approach may be mandatory when the patient is rapidly deteriorating. If the pneumonic process is less rapid, then bronchoscopy with lavage appears to be the best approach. When a mass or consolidation is present, fine needle biopsy is more frequently performed because of less chance of complications.
Invasive techniques are often not justified late in the course of malignancy because they often add morbidity with little hope of benefit. Empiric antibiotic therapy directed at the most likely pathogen(s) may be justified in these cases.
3. Therapy for acute pneumonia should be initiated immediately after cultures are obtained. Patients with acid-fast bacilli, N. asteroides, Cryptococcus, or Aspergillus species in sputum should not be regarded as colonized and should be treated.
B. Central nervous system infections. Infections of the CNS can present either with simple changes to mentation or motor skills or with seizures and coma. Meningismus is a hallmark of disease, but this condition may be absent. MRI is indicated when cerebral edema, abscess, or demyelinating encephalitis is suspected. This scan is particularly useful in defining viral encephalitis and areas where enhanced foci are seen, such as in toxoplasmosis.
Special considerations in cancer patients suspected or proved to have CNS infections are as follows:
1. Meningitis. Cancer patients have an increased incidence of atypical pathogens. These can occur as a direct result of immune suppression, CNS involvement by the malignancy, or opportunistic infections after craniofacial surgery.
a. Neutropenic patients rarely develop gram-negative meningitis despite a relatively high incidence of gram-negative bacteremia. However, when meningitis does develop, the pathogens usually are members of the family Enterobacteriaceae (e.g., E. coli, Klebsiella), P. aeruginosa, or Listeria monocytogenes. Meningitis caused by aspergillosis or zygomycosis has also been described.
b. Patients with defects in cell-mediated immunity. L. monocytogenes and C. neoformans are relatively likely pathogens in these patients. Meningitis and meningoencephalitis from varicella zoster virus (VZV), herpes simplex virus (HSV), JC virus (progressive multifocal leukoencephalopathy), human immunodeficiency virus (HIV), CMV, T. gondii, and Strongyloides stercoralis also occur.
2. Brain abscesses are most likely caused by mixed aerobic and anaerobic bacteria. In the immunocompromised patient, brain abscesses are also caused by Aspergillus species, the agents of mucormycosis, N. asteroides, or T. gondii. Toxoplasma can produce meningitis, necrotizing encephalitis, or abscess. In atypical cases, brain biopsy should be performed at the time of surgical drainage.
3. Lumbar puncture (LP)
a. Papilledema. An emergency CT scan of the brain must be performed first. Patients with space-occupying lesions seen on CT scan should have LP or cisternal puncture performed by a qualified neurologist or neuroradiologist.
b. Thrombocytopenia. Spinal subdural hematoma occasionally complicates LP in patients with severe thrombocytopenia. Clinical evidence of CNS infection, however, supersedes consideration of risks. The following guidelines are recommended:
(1) If the platelet count is <50,000/µL, transfuse platelets just before performing LP. Transfuse additional platelets if back pain or neurologic signs develop.
(2) A highly skilled physician should perform the LP using a 22-gauge needle and the patient should be observed closely afterward. The role of needle aspiration and surgical intervention in patients with spinal subdural hematomas induced by LP is not known.
c. Cerebrospinal fluid should be evaluated for the following:
(1) Glucose and protein concentrations, cell counts, routine bacterial culture and sensitivity, Gram stain, and cytology. The WBC count in the cerebrospinal fluid is >100/µL in about 90% of patients with bacterial meningitis and >1,000/µL in 15% to 20%. Neutrophils constitute >80% of the WBC count in 80% to 90% of patients; occasionally, lymphocytes predominate in the cerebrospinal fluid, especially in neutropenic patients and in about 25% of patients with meningitis caused by L. monocytogenes.
(2) Acid-fast culture and stain, fungal stains of smears and fungal cultures, India ink preparation, cryptococcal antigen, and “screening” and complement fixation serology for Coccidioides immitis (depending on geography and predominant soil fungus) should be done.
(3) Polymerase chain reaction (PCR) assays for HIV, JC virus, herpesviruses, Toxoplasma, Mycobacterium tuberculosis, Listeria, and other pathogens should be performed only if clinical or laboratory findings suggest the likelihood of that specific infection.
C. Skin infections
1. Neoplasms invading the skin (e.g., mycosis fungoides) are associated with infections involving common pathogens such as S. aureus and Streptococcus pyogenes.
2. Cell-mediated immunity deficiencies are typically associated with skin infection by VZV or HSV.
3. Neutropenic patients may have skin infections with atypical or few physical findings. S. aureus and Streptococcus pyogenes are common. More serious manifestations represent systemic infections; these include bullae formation, raised ecchymotic plaques or nodules, black necrotic ulcers, or ecthyma gangrenosum. These more pronounced cutaneous manifestations of systemic infection are typically caused by gram-negative bacilli, such as P. aeruginosa, Aeromonas hydrophila, members of the family Enterobacteriaceae, and fungi, including Candida species, Aspergillus species, and members of the class Zygomycetes (the latter infections are often referred to as mucormycosis or zygomycosis).
D. Alimentary tract and intra-abdominal infections
1. Esophagitis may be caused by Candida or HSV.
2. Colitis with ulceration is occasionally produced by CMV. Aspergillus and zygomycosis may also involve the GI tract. In most medical centers, colonic infection due to Clostridium difficile is common.
3. Cecitis and ileocolitis are processes that probably develop as a consequence of several factors that include mucosal injury, neutropenia, and the resident bowel flora. They can usually be appreciated on CT scan of the abdomen and may be confused with Clostridium difficile–induced colitis when colonic wall thickening is present.
4. Intra-abdominal abscesses develop when the bowel or genital tract becomes obstructed, necrotic, or perforated because of tumor. Mixed infections derived from colonic flora involve gram-negative enteric bacilli; various species of streptococci and members of the Bacteroides fragilis family are common. Streptococcus bovis abscess and sepsis may occur with colonic, pancreatic, or oropharyngeal carcinoma.
5. Perirectal abscesses frequently develop in neutropenic patients, especially those with acute leukemia; usually, they are caused by mixtures of aerobic and anaerobic bacteria. The hallmark of perirectal abscess in neutropenic patients is pain.
6. Liver infections. Multiple abscesses secondary to systemic bacterial or fungal infection also occur. Hepatosplenic candidiasis can be an extremely difficult infection to diagnose and treat, and it is often found at autopsy to involve other organs; it may not become clinically evident until there is recovery from neutropenia. Even herpesviruses, such as VZV, HSV, HHV-8 (human herpesvirus 8), CMV, and Epstein-Barr virus (EBV), can present as mass or necrotic lesions in the liver of immunocompromised patients.
E. Urinary tract infections are frequent in cancer patients because of obstructive uropathies, the use of urinary catheters, and prolonged and repeated hospitalizations. These infections are often caused by resistant gram-negative bacteria or Candida species. Candida species often colonize the urinary tract of patients who have indwelling catheters or diabetes mellitus, particularly in the setting of recent antibacterial therapy. Recovery of Candida from urine may occasionally represent significant infection of the urinary tract (rather than colonization that resolves with changing of the bladder catheter) but should always lead to consideration of occult fungemia.
F. Infection of bone marrow usually reflects systemic or disseminated disease, particularly with M. tuberculosis, Mycobacterium avium complex, fungi, Salmonella, and Listeria. Bone marrow biopsy for culture can be a useful diagnostic tool. Bone marrow suppression mimicking aplastic anemia occurs with parvovirus B19, mycobacterial infection, histoplasmosis, and brucellosis.
G. Central-line infections. The incidence of infection of IV catheters, including nontunneled central lines, tunneled silicone catheters (e.g., Hickman, Broviac, or Groshong), or implantable devices (e.g., Portacath), is significant and often poses a major challenge for the clinician.
1. Most central-line infections are caused by S. aureus (coagulase-positive Staphylococcus) or coagulase-negative Staphylococcus species (often incorrectly referred to as “Staph epi” or “Staph epidermidis”). The neutropenic patient is also at risk for infection of venous catheters by a variety of gram-negative bacilli, including P. aeruginosa and by a variety of Candida species and other fungi.
2. In almost all instances, infected peripheral vascular catheters and nontunneled CVC should be removed and appropriate antimicrobial therapy administered. In addition, CVC in which there is a tunnel (pocket) infection or a periport abscess should always be removed. Attempts at salvage of the CVC can sometimes be made, if the organism is of low virulence (e.g., coagulase-negative staphylococci), by the use of appropriate IV antibiotics. Clinical guidelines have been developed to assist clinicians with this vexing problem (see Mermel, et al. 2009 in Suggested Reading).
3. Vancomycin, with dosage adjustment for renal dysfunction, should be used for initial therapy of infection due to gram-positive organisms; alternatives include daptomycin and linezolid. If the organism is subsequently found to be “methicillin susceptible” then high-dose oxacillin should be used.
4. “Antibiotic lock therapy,” in which the catheter is filled with a high concentration of an appropriate antibiotic and then capped for varying periods of time, has been advocated by some, but controlled clinical studies are insufficient to permit conclusions to the utility of this method in the setting of neutropenia.
5. All venous catheters must be removed in the following circumstances:
a. All nontunneled peripheral and central catheters (the latter are often referred to colloquially as “PICC lines”) if bacteremia has been documented or there is evidence of insertion site infection
b. All tunnel infections or periport abscesses
c. All catheter infections caused by fungi
d. Persistence of infection after 48 to 72 hours of treatment, regardless of the pathogen
e. Bacteremia caused by S. aureus, vancomycin-resistant Enterococcus, Bacillus species, Corynebacterium jeikeium, or gram-negative bacilli
f. Infections associated with thrombophlebitis, septic emboli, or hypotension
g. Nonpatent (i.e., plugged) catheter
IV. VACCINATION OF IMMUNOSUPPRESSED PATIENTS
A. Vaccines contraindicated in immunosuppressed patients are those that contain living organisms. These include the viral vaccines for rubeola (measles), varicella, rubella, mumps, oral poliovirus, smallpox, yellow fever, shingles, and live, attenuated, intranasally administered influenza vaccine (FluMist).
B. Permissible vaccines. Immunosuppressed patients often do not attain an effective response to active immunization. Permissible vaccines, however, are those for diphtheria, tetanus, pertussis, typhoid, cholera, plague, influenza, hepatitis A and B, and S. pneumoniae. Influenza immunization should be done on an annual basis because immunity is short lived, and antigenic drift of the “epidemic” strain(s) occurs each year. Pneumococcal vaccination is strongly indicated for all cancer patients. Although the efficacy is diminished in severely immunosuppressed patients, a potential benefit still exists. Reimmunization every 5 years is recommended for patients with AIDS and is reasonable in non-AIDS subjects who have cancer.
V. VIRAL INFECTIONS
A. Cytomegalovirus often presents as EBV-negative mononucleosis. Fever, interstitial pneumonia, and alimentary canal ulcerative disease are the most common manifestations of CMV in adults with neoplasms. CMV, which is tropic for endothelial cells, also causes retinitis, encephalitis, and peripheral neuropathy. CMV can suppress cell-mediated immunity, reticuloendothelial cell function, and granulocyte reserves.
1. Infection, latency, and recurrence. Primary CMV infection can occur perinatally or later in life and inevitably results in latent infection. Infection is especially likely after transfusions of blood that contains granulocytes. Latent CMV burden and risk for recurrence are related to the extent of virus multiplication during primary infection. The risk for CMV recurrence is relatively high in severely immunocompromised patients.
2. CMV infection of the GI tract can cause serious inflammatory or ulcerative disease in immunocompromised patients. Manifestations include pain, ulceration, bleeding, diarrhea, and perforation. All levels of the GI tract, particularly the stomach and colon, may be involved. Pathologic examination reveals diffuse ulcerations and necrosis with scattered CMV inclusions.
3. Diagnosis
a. Culture. CMV is slow growing (up to 6 weeks), and culture is generally not practical. Early antibody detected by application of enzyme-linked immunosorbent assay (ELISA) in cultures may accelerate identification.
b. Histocytology shows the characteristic enlarged cells with dense nuclear inclusions and wide peri-inclusion halos. Cytoplasmic inclusions are frequent, but multinucleation is absent.
c. Serologic assays
(1) Seropositivity for antibodies against CMV is indicative of latent infection but is insufficient as a predictor for the risk for recurrence.
(2) Elevated IgM antibody showing fourfold titer increases is highly suggestive of acute disease.
(3) Anticomplementary immunofluorescence assay, ELISA, and indirect fluorescent antibody (FA) assays are sensitive indicators of infection. IgG antibody occurs during the acute phase of the illness and persists for life, whereas IgM antibodies occur early and often disappear after 4 to 8 weeks. Recurrent IgM spikes occur in certain patients, indicating either partial immunity to CMV or exposure to new variants of the virus.
d. PCR assay, both in situ and in DNA extracted from gross specimens, is the most useful tool to isolate and identify the presence and location of CMV in clinical disease. Interpretation of the PCR assay results is sometimes difficult, given that shedding of low levels of CMV does not necessarily indicate clinical infection.
4. Management
a. Ganciclovir
(1) The efficacy of this drug for CMV retinitis and colitis is well documented, but it is less effective with CMV pneumonia or meningoencephalitis. After stem cell transplantation, the prophylactic administration of ganciclovir or valganciclovir abrogates CMV pneumonitis and considerably reduces the incidence of CMV infection.
(2) Ganciclovir is given for 14 days at a dose of 5 mg/kg IV q12h. Patients with AIDS often require maintenance treatment (5 mg/kg/d). Dosage is modified according to the predicted creatinine clearance and ANC.
(3) Valganciclovir, a derivative of ganciclovir, is effective when given orally. The usual treatment is 900 mg b.i.d. for 21 days, followed by 900 mg daily for suppression.
b. Foscarnet and cidofovir are other agents that may be useful for treatment of CMV infection.
B. Varicella-Zoster virus (VZV). Chickenpox is often associated with extensive visceral dissemination and appreciable mortality in immunocompromised patients, particularly stem cell transplant recipients. Shingles is characterized by the development of vesicles in clusters on erythematous bases, usually distributed along one to three dermatomes. Although disseminated VZV infection does occur, the presence of several lesions outside a dermatomal distribution does not necessarily indicate dissemination. Disseminated VZV infections may be manifested by encephalopathy, Guillain-Barré syndrome, transverse myelitis, myositis, pneumonia, thrombocytopenia, hepatitis, and arthritis.
1. Diagnosis. VZV can usually be diagnosed on physical examination.
a. Histocytology. Multinucleated cells with intranuclear inclusions is suggestive.
b. Culture. Inoculate early vesicular fluid.
2. Management. VZV is transmissible; patients should be isolated.
a. IV acyclovir is the treatment of choice for ophthalmic zoster and disseminated VZV infection in immunocompromised patients (10 mg/kg IV every 8 hours for 7 to 10 days; renal function should be monitored for evidence of nephrotoxicity). “Localized” or nondisseminated zoster can be treated with IV acyclovir initially and then with oral agents to complete 7 to 10 days of treatment: acyclovir (800 mg five times daily), valacyclovir (1,000 mg t.i.d. or q.i.d.), or famciclovir (500 mg t.i.d.).
b. Ganciclovir has considerable activity for VZV as well as for CMV.
c. VZV live vaccines are available for primary immunization against chicken pox and prevention of recurrent VZV infection (shingles) but have no role in the immunocompromised patient.
d. VZV immune globulin or plasma may prevent or ameliorate the severity of infection in nonimmunocompromised subjects if given soon after exposure but are only sporadically available.
C. Herpes simplex virus. Patients with reticuloendothelial neoplasms, T-lymphocyte defects, or cytotoxic chemotherapy treatment may develop HSV viremia. The viremia often produces alimentary tract ulceration and hemorrhage, hepatitis (occasionally manifested by abscess like lesions), and respiratory tract infections. Patients with Sézary syndrome or atopic dermatitis can develop progressive fulminant mucocutaneous disease (eczema herpeticum), which can recur and disseminate to visceral organs.
1. Diagnosis
a. Histocytology demonstrates the characteristic intranuclear mass surrounded by marginated chromatosis and often a peri-inclusion halo. Cytoplasmic inclusions are absent. Electron microscopy analysis of vesicular fluid, which can be performed in <30 minutes, strongly suggests the diagnosis. Immunofluorescence for HSV antigen is also rapid and specific.
b. Culture. HSV grows rapidly in tissue cultures (24 to 72 hours) and produces a unique cytopathologic picture.
c. Assays. Hemagglutination and indirect FA titers are useful if fourfold increases are demonstrated. Differentiation of IgG from IgM antibody assists in clarifying recent infection. An HSV IgG-capture ELISA has demonstrated intrathecal synthesis of antibodies to the virus. Furthermore, a PCR assay has demonstrated amplification of HSV DNA in cerebrospinal fluid. Both ELISA and PCR assay are rapid, noninvasive means of diagnosing HSV encephalitis in a very early stage of the disease.
2. Management
a. Topical idoxuridine, especially using dimethyl sulfoxide as a carrier, is effective for HSV keratitis.
b. Acyclovir is safe, effective treatment for HSV infections in normal and immunocompromised patients. The dose is 200 mg PO five times daily for 7 to 10 days. As an ointment, acyclovir is useful for primary local infections but does not appear to prevent recurrent disease. Famciclovir and valacyclovir are now superseding acyclovir because they have easier dosing regimens of 500 mg PO t.i.d. and have evidence of better penetration into tissue. Serious infections requiring IV therapy should be treated with acyclovir, 10 mg/kg IV q8h for 7 to 10 days.
c. Ganciclovir has excellent activity against HSV, although its primary usefulness has been directed at CMV.
d. Vidarabine is effective topically for keratitis.
VI. BACTERIAL INFECTIONS
A. Mycobacteria. Active tuberculosis (TB) develops in 0.5% to 1% of patients with malignancies. Infection is predominantly pulmonary in 70%, is widely disseminated in 20%, and involves lymph nodes or other nonpulmonary sites in 10% of cases.
1. The incidence of atypical Mycobacterium infection (particularly with M. kansasii and M. avium complex [MAC]) is significantly higher in patients with cancer, HIV, or AIDS than in the general population. M. kansasii infection has been associated with hairy cell leukemia. M. malmoense is an opportunistic pathogen mainly isolated in northern Europe, most often in patients with pulmonary infections. All of these organisms are commonly resistant to isoniazid or rifampin. A variety of other atypical mycobacteria is occasionally isolated from patients with malignancy.
2. Pathogenesis. Cutaneous anergy and treatment with corticosteroids, cytotoxic agents, or irradiation predispose to reactivation of quiescent M. tuberculosis. It is now appreciated, however, that some cases of tuberculosis in adults represent new acquisition of infection rather than reactivation.
3. Resistant TB. Immigration from high-prevalence countries, coinfection with HIV, and outbreaks in congregative facilities are primarily responsible for the increased incidence of TB cases during the past decade. Coincident with the increase in TB, outbreaks of multidrug-resistant (MDR) TB have occurred. MDR TB occurs late in the course of HIV infection and is refractory to treatment. A history of antituberculous therapy is the strongest predictor of the presence of resistance.
4. Diagnosis
a. Chest radiographic evidence of infiltrates in apical or posterior segments of the upper lobe or superior segment of the lower lobe is the most frequent manifestations of postprimary TB. Radiographic features may be confusing in immunosuppressed patients, however, in whom intrathoracic lymphadenopathy, pleural effusions, miliary infiltrates, or cavities may be lacking. Chest radiographs are normal in 10% to 15% of immunosuppressed patients with TB.
b. Smears and cultures. The tuberculin skin test is often negative in immunocompromised patients with TB and is not helpful in evaluating patients thought to have active TB. The diagnosis of TB can be established by visualizing the organism in stained sputum smears or culturing M. tuberculosis from sputum or from extrapulmonary sites; blood cultures may be occasionally be positive when blood is sampled utilizing specialized media or techniques. Three sputum cultures from separate days are necessary for routine culturing; more samples do not increase the yield. Expectorated sputum may be adequate for smears and culture. Aerosol-induced sputum is superior to expectorated sputum or gastric juice aspiration in patients who produce little sputum, however, and it is the preferred means for sputum collection. Bronchoalveolar lavage or transbronchial biopsy may be required when other material is not diagnostic.
c. Effusions. Pleural fluid samples may yield the organism in up to 30% of cases, and percutaneous needle pleural biopsies (three biopsies in three locations) provide up to a 75% yield. Culture of pericardial fluid may be positive in up to 50% of cases, and pericardial biopsy yields 80% positive results on either histology or culture. Analysis of ascitic fluid findings is not helpful unless the fluid is concentrated; peritoneal biopsy is preferred. PCR assay and detection of elevated adenosine deaminase levels in fluids are occasionally useful, but neither is highly sensitive.
d. TB meningitis. Spinal fluid analysis is variable, although mononuclear cell pleocytosis and low glucose concentrations are common. Concentrated spinal fluid reveals TB bacillus on smear in 30% to 50% of cases in some reports and on culture in about 50%. Most often, however, the diagnosis is made on clinical grounds and treatment is empiric. PCR assay has been disappointing for diagnosing tuberculous meningitis.
5. Management
a. TB prophylaxis in cancer patients. Any patient who is to receive immunosuppressive therapy should be skin tested for TB and anergy. Prophylaxis with isoniazid (INH), 300 mg/d for 9 months, should be given to any cancer patient who has a positive tuberculin skin test.
b. Active TB. Because of increasing drug resistance, the U.S. Public Health Service has issued new guidelines for the initial treatment of TB. Until drug susceptibility data are available, patients with active TB should be treated with daily administration of isoniazid, rifampin, pyrazinamide, and ethambutol. After 2 months of therapy, the regimen for patients with drug-sensitive organisms should be changed to isoniazid and rifampin administered daily for an additional 4 months or until sputum cultures are negative for 3 months. Alternative regimens are recommended for patients who require directly observed therapy to ensure compliance.
c. MDR TB, defined as resistance to at least isoniazid and rifampin, is readily transmitted among hospitalized patients with AIDS. The management of MDR TB is exceedingly difficult, and early diagnosis with individualized therapy is crucial. To interrupt the transmission of MDR TB, stringent isolation procedures and aggressive chemotherapy with a combination of drugs are essential. The choice of agents depends on susceptibility testing, but until such results are available, the drugs most likely to be effective include pyrazinamide, streptomycin, ciprofloxacin, ofloxacin, cycloserine, and ethambutol.
The treatment of patients exposed to MDR TB is also difficult. Such patients should be evaluated for the closeness of their contact with infected patients and their immune status. People at high risk are candidates for chemoprophylaxis.
d. MAC. Treatment for dissemination should include clarithromycin (alternative is azithromycin) and ethambutol. Some experts would add rifabutin to clarithromycin and ethambutol to treat widely disseminated infection; this is largely based on studies of bloodstream dissemination in HIV-infected patients. When resistance to a two-drug regimen develops, one or two additional drugs should be selected from the following: rifabutin, a fluoroquinolone, or, in some instances, amikacin.
B. Nocardia asteroides infection (nocardiosis). Several types of cell-mediated immune defects have been described in association with nocardiosis. About 20% of cases occur in patients receiving corticosteroids. In immunocompromised subjects, 75% of nocardiosis involves the lung.
Nocardiosis can be asymptomatic, heal spontaneously, or produce a lower lobe bronchopneumonia with cavities, abscesses, or empyema. Disseminated nocardiosis typically involves subcutaneous tissue, muscle, and brain.
1. Diagnosis. Gram stain of sputum reveals gram-positive, beaded, branching filaments. Sputum should also be examined with modified Ziehl-Neelsen stain, because the organism is typically weakly acid-fast.
2. Management. Sulfa drugs have been the mainstay of therapy for Nocardia; in recent years, the convenience, safety, and efficacy of the combination of sulfamethoxazole and trimethoprim (Bactrim or Septra) have led most experts to consider this combination as the first line of therapy. High initial daily doses (15 mg/kg of trimethoprim and 75 mg/kg of sulfamethoxazole per day) are used for severe infection, such as disseminated infection or cerebral abscess. Several different species are found in the Nocardia asteroides complex. Poor response to therapy in some patients in the past may have been because of differing antimicrobial susceptibilities of these organisms. In addition, a number of other conventional antibacterial agents are active against many Nocardia isolates, and their use may be beneficial, depending on the nature of the specific infection.
C. Listeria monocytogenes may be confused with gram-positive cocci, H. influenzae, or diphtheroids on Gram stain of specimens. Infections are more common in patients with defects in cell-mediated immunity.
Listeria monocytogenes is the most common cause of bacterial meningitis in patients with carcinoma and in patients receiving corticosteroids or other immunosuppressive therapy, especially for lymphoma. CNS infection with cerebritis or brain abscess accounts for 80% of cases. The mortality rate for CNS infections is 15% to 45%. Bacteremia or sepsis accounts for 20% of cases in adults. Pulmonary involvement is always in the form of an empyema.
1. Diagnosis
a. Culture. After L. monocytogenes is isolated, the organisms have a unique tumbling motion when viewed in a hanging drop, thereby allowing for rapid tentative identification.
b. Spinal fluid. Either lymphocytes or polymorphonuclear neutrophils are predominant. Spinal fluid protein concentration ranges from normal to 1 g/dL. Glucose levels are low in only half of the cases.
2. Management
a. Sepsis. Ampicillin, 200 mg/kg/d, is given IV in six divided doses. Most experts recommend adding gentamicin to ampicillin for synergy. In patients who cannot tolerate ampicillin, the best alternative appears to be high-dose sulfamethoxazole–trimethoprim.
b. Meningoencephalitis is treated in the same manner as sepsis. Intrathecal gentamicin, 3 to 5 mg every 24 hours, may be synergistic with IV antibiotics.
D. Legionella pneumophila. Legionnaires disease can affect normal and immunosuppressed hosts, especially patients receiving glucocorticoids. The disease typically produces lobar pulmonic consolidation evolving from patchy infiltrates. Features that suggest Legionnaires disease include nonproductive cough, pulmonary consolidation, diarrhea, hyponatremia, and confusion.
1. Diagnosis
a. Cultures on specialized media developed specifically for recovery of Legionella should be requested.
b. Legionella urine antigen should be obtained. This test only detects Legionella pneumophila serogroup 1; however, serogroup 1 organisms cause the most severe forms of disease in humans.
c. Tissue examination. Dieterle staining can be used to detect bacteria in tissue. Positive direct FA examination of tissue strongly suggests Legionnaires disease.
d. Serology. Antibody titers do not help early in the disease course.
2. Management
a. Newer macrolides, such as clarithromycin and azithromycin, and the so-called respiratory fluoroquinolones (e.g., levofloxacin) have efficacy. Either azithromycin, 500 mg/d, or levofloxacin, 750 mg/d, are effective and well-tolerated agents.
b. Rifampin 300 to 600 mg/d PO may be effective as adjunctive therapy and can be added if the patient does not respond to initial therapy.
E. Clostridium difficile. This toxin-mediated diarrheal disease of the colon is almost invariably associated with recent or concurrent use of antimicrobial therapy. Horizontal spread of C. difficile within health care facilities has become extremely common.
An epidemic clonal strain (NAP1) of C. difficile was found to be associated with increased morbidity and mortality. The spread of this strain may be owing to resistance to newer fluoroquinolones, whereas the apparent increase in virulence may result from dysregulation of toxin production. Preliminary data suggest this strain has spread globally.
Clinical correlates of infection with the NAP1 strain appear to be more severe disease as manifested by high fever (>102.5°F), marked leukocytosis (>25,000 cells/µL) in the absence of bone marrow suppression, protein-losing enteropathy, extensive colitis on CT scanning, and more frequent need for emergent colectomy because of loss of colonic wall integrity or toxic dilation of the colon.
1. Diagnosis. Of the number of tests for C. difficile toxins in feces, the most rapidly available has been an enzyme immunoassay (EIA) for toxins A and B. The sensitivity of this and other EIA for C. difficile toxins is often relatively poor (ranges are from approximately 65% to 90%), however. Tissue culture cytotoxin assay for toxin B is appreciably more sensitive but is not a rapid test, is expensive, and is not widely available. Many centers are now performing PCR for toxin B; this assay is extremely sensitive, and a positive PCR, in the setting of acute diarrhea, is diagnostic. Stool culture alone for C. difficile is not clinically useful. The presence of colonic pseudomembranes or characteristic plaques is considered diagnostic, but these findings are present in no more than 50% of patients and require lower GI endoscopy for detection. “Screening” or surveillance for C. difficile infection is not recommended because intestinal carriage (in the absence of diarrhea) is common and detection of carriage is not clinically meaningful.
2. Management. Nosocomial diarrhea that is not attributable to hyperosmolar nutritional supplements or tube feeding preparations suggests the presence of symptomatic C. difficile disease. Such patients should be placed in contact isolation, a test for C. difficile toxin ordered, and empiric treatment considered.
a. If the diarrhea is trivial and the offending antimicrobial agent can be stopped, resolution of diarrhea occurs in approximately 90% of patients without significant risk of relapse or recurrence.
b. If the illness is mild to moderate (high fever, marked leukocytosis, and abdominal pain or tenderness are absent), then treatment with metronidazole is appropriate. Standard doses of metronidazole for C. difficile–associated diarrhea are 250 mg q.i.d. or 500 mg t.i.d. daily orally for 10 to 14 days, although higher doses (2 to 2.25 g/d) are recommended for treatment of other anaerobic infections. Intravenously administered metronidazole penetrates the colonic lumen poorly and has not been established as reliably effective therapy for C. difficile diarrhea.
c. If the illness is severe, then oral vancomycin, 125 mg q.i.d. for 10 to 14 days, is appropriate.
d. Oral fidaxomicin was recently approved by the FDA for treatment of C. difficile–associated diarrhea. Fidaxomicin was not found to be superior to oral vancomycin but did have a somewhat lower relapse rate.
e. Surgical consultation for consideration for colectomy is indicated with clinical evidence of progressive toxicity, radiographic evidence of progressive colonic dilation, or concern regarding loss of bowel wall integrity.
f. Approximately 25% of patients treated for C. difficile diarrhea with oral metronidazole or vancomycin have a relapse or recurrence of diarrhea. Generally, retreatment is effective, although multiple relapses are not uncommon and may require a tapering schedule of drug.
VII. FUNGAL INFECTIONS. The profoundly immunosuppressed host, particularly if there is prolonged neutropenia, is at risk for infection by a variety of fungi, many of which rarely cause infection in healthy hosts. Some fungi cause infection in humans so rarely that identification of genus and species by a clinical microbiology laboratory may not be possible, and if identified by the laboratory, they may not be familiar, even to many clinically astute infectious diseases clinicians.
In this section is a review of the more common fungal pathogens, rather than an encyclopedic review of the literature. Recovery of “nonpathogenic” fungi (or members of other classes of “nonpathogenic” microorganisms) from normally sterile body fluids, such as spinal fluid or blood, or from biopsy samples should prompt the clinician to consider that “nonpathogenic” organism might be a pathogen.
Unfortunately, the greatest problem faced by clinicians is the inability to detect fungal infection in neutropenic patients. The assumption that infection by Candida spp. is present can be inferred relatively early in neutropenia and empiric treatment is thought to be relatively effective and benign. Infection by molds (generally a phenomenon that occurs after a more prolonged period of neutropenia) is far more difficult to diagnose, cultures are typically negative, and empiric therapeutic regimens simply cannot cover all possibilities without incurring unacceptable toxicity.
A. Antifungal agents. The three major classes of antifungal agents that are useful in the patient with neutropenia and persistent fever are echinocandins, triazoles, and amphotericin B (AmB) preparations. Detailed information is available via the package inserts, including dosing instructions, specific FDA-approved indications, and warnings regarding potential adverse reactions. Dosages are shown in Table 35.1.
1. Echinocandins. The echinocandins are the newest group of antifungal agents; those currently marketed are caspofungin (Cancidas), anidulafungin (Eraxis), and micafungin (Mycamine). Although the greatest clinical experience is with caspofungin, many experts believe these three agents have similar antifungal activities and toxicities. The echinocandins have excellent in vitro activity against most species of Candida (including fluconazole-resistant C. glabrata) and Aspergillus.
2. Triazoles are clinically useful antifungal agents that have substantially differing spectra of activity, adverse effects, and potential for drug–drug interactions. All are effective for treatment of infections caused by Candida albicans.The four agents with potential clinical utility in cancer patients are
a. Fluconazole (Diflucan). Although highly effective against C. albicans, fluconazole has much less activity against non-albicans Candida than do the newer triazoles. In the past, fluconazole had been considered an acceptable alternative to AmB at institutions in which infections with certain Candida species (C. krusei and some isolates of C. glabrata) and molds (e.g., Aspergillus species) were relatively uncommon. The main value of fluconazole in neutropenic patients is for treatment of mucocutaneous Candida infection and systemic infection documented to be caused by C. albicans in patients for whom broader-spectrum antifungal agents are not indicated.
b. Itraconazole (Sporanox) has a broader spectrum of activity than fluconazole. Its main clinical utility is against the agents of histoplasmosis and blastomycosis. It also has only modest activity against Aspergillus.
c. Voriconazole (VFEND) has an appreciably broader spectrum of activity than fluconazole or itraconazole and is active against most species of Candida, Aspergillus, and several less common fungi. It is the most useful of the triazoles for empiric and pathogen-specific treatment of fungal infection in neutropenic patients. The potential for drug–drug interactions can be a problem with the use of voriconazole.
(1) Adverse reactions. The most common adverse reactions are several different types of visual disturbances that usually do not require discontinuation of therapy and skin reactions. IV voriconazole is solubilized in sulfobutylether-β-cyclodextrin (SBECD), which accumulates with moderate renal dysfunction; it is recommended that the IV preparation not be used if the creatinine clearance is <50 mL/min.
(2) Bioavailability of oral voriconazole is excellent, and the oral preparation does not contain SBECD. In selected patients with appreciably impaired renal function, a change to oral therapy with voriconazole may be feasible.
d. Posaconazole (Noxafil), available only in an oral formulation, appears useful as an agent for prophylaxis of infection in severely immunosuppressed patients, such as those with GVHD. Additional study of this agent is needed to define its role in treatment of fungal infections in cancer patients.
e. Drug–drug interactions. Of importance, a number of important drug–drug interactions involve voriconazole and the other triazoles. Most of these interactions involve cytochrome P450 isoforms and may result in significantly increased or decreased concentrations of voriconazole or of the interacting drug, resulting in either potential toxicity or lack of efficacy, respectively.
3. AmB preparations
a. Amphotericin B deoxycholate (AmBD, Fungizone) had been the gold standard for treatment of fungal infections, but there is reluctance to use it in nonneutropenic patients because of nephrotoxicity. In neutropenic patients, this concern is heightened by the frequent concomitant use of nephrotoxic chemotherapeutic agents and antimicrobial agents.
b. Lipid formulations of AmB have not been shown to be more effective than AmBD for treatment of fungal infections, but they are much less likely to cause nephrotoxicity. Their major drawbacks have been other potential side effects and their much greater cost. These lipid preparations include
(1) Amphotericin B lipid complex (ABLC, Abelcet)
(2) Amphotericin B colloidal dispersion (ABCD, Amphotec)
(3) Liposomal amphotericin B (LAmB, AmBisome), which currently is the only U.S. Food and Drug Administration (FDA)-approved lipid formulation for empiric therapy for presumed fungal infections in febrile neutropenic patients.
B. Antifungal agents in patients with neutropenic fever. Reasonably clear guidelines have been developed for antifungal therapy early in the course of neutropenia, largely because the greatest concern is for disseminated candidiasis. With prolonged broad-spectrum antibacterial therapy and empiric anti-fungal therapy, increasing opportunity and selective pressure tend to result in unusual infections. The availability of the newer triazoles and echinocandins has provided greater therapeutic options with reduced toxicity; it has also created more opportunity for administration of an antifungal agent that is not active against the patient’s present fungal pathogen. This makes microbiologic diagnosis of infection imperative and may require invasive procedures to procure biopsy material for culture and fungal staining.
The strategy for providing empiric antifungal therapy in cancer patients with neutropenia is based on the following principles:
1. During the first several days of neutropenic fever, the likely pathogens are bacteria; diagnostic approaches and empiric treatment, therefore, are not focused primarily on fungal pathogens.
2. During the first 4 to 7 days of neutropenic fever, the fungal pathogens most likely to be encountered are Candida spp. and, much less frequently, Aspergillus spp. The echinocandins and newer triazoles have excellent in vitro activity against most Candida spp. and most Aspergillus spp., and they possess limited toxicity. Unfortunately for the clinician, the FDA-approved indications for these agents vary based on the patient populations and types of fungal infection that were studied prior to FDA approval.
As the duration of neutropenia and fever increases beyond 7 to 10 days, the likelihood of infection by a more resistant mold (not Aspergillus) increases. This should prompt an aggressive search for occult infection and consideration of more aggressive antifungal therapy (including the use of an amphotericin lipid preparation).
3. AmBD and the lipid formulations of AmB possess the broadest spectrum of antifungal activity of all groups of antifungal agents. The echinocandins may lack the broader activity of AmB preparations and of the newer triazoles against genera of clinically important fungi that may cause infection later in neutropenia.
4. Among the echinocandins, the greatest clinical experience is with caspofungin; however, many experts believe that micafungin and anidulafungin are likely to have similar clinical efficacies, based on in vitro and limited in vivo data. It is important to note that echinocandins are inactive against Cryptococcus neoformans, the endemic mycoses (e.g., Coccidioides spp., Histoplasma capsulatum), and many molds (e.g., Fusariumspp., Scedosporium apiospermum, Zygomyces). Drug–drug interactions are generally less than those seen with triazoles.
5. Among the triazoles, voriconazole may be a reasonable alternative to an echinocandin or AmB preparation. With voriconazole, attention must be paid to potential side effects and drug–drug interactions; also, it is recommended that the drug not be given intravenously, if at all possible, when the creatinine clearance is <50 mL/min to avoid accumulation of the diluent used to solubilize the drug. Of the other azoles, fluconazole and itraconazole are thought not to have a sufficiently broad spectrum of activity against all Candida spp. Clinical experience with posaconazole is quite limited, and this drug is not currently available in an IV formulation.
6. If an AmB preparation were to be used for empiric antifungal coverage of the febrile neutropenic patient, most clinicians would use one of the more expensive lipid preparations to avoid the potentially more severe nephrotoxicity of AmBD.
7. Substantial variation exists in the costs of all of the all antifungal agents. Cost plus an institution’s clinical experience with fungal infections may determine the choice of an initial antifungal agent within each group of drugs.
8. Recommendations:
a. After 4 to 7 days of persistent fever and neutropenia despite antibiotics, initiate empirical treatment with a lipid formulation of amphotericin B or caspofungin or voriconazole.
b. Do not use voriconazole if there was prior azole (i.e., fluconazole, itraconazole, voriconazole, or posaconazole) prophylaxis or treatment.
c. For patients receiving antimold prophylaxis, consider switching to another class of antimold agents given intravenously because of potential selection of a resistant mold by the prophylactic agent. Antimold agents include
(1) Amphotericin (all preparations are active against many molds)
(2) Echinocandins (anidulafungin, caspofungin and micafungin have good in vitro activity against some molds, including the most common Aspergillus species, A. fumigatus).
(3) Azoles: Voriconazole and posaconazole have differing but broad activity against molds. Voriconazole has broad in vitro activity against most clinical species of Aspergillus, including A. fumigatus.Fluconazole and itraconazole lack clinically useful activity against molds.
9. Summary. With concerns regarding renal function (pre-existing impairment of renal function, concomitant use of nephrotoxic agents, or development of renal dysfunction during AmB administration), use of an echinocandin (preferably caspofungin) or voriconazole is frequently reasonable and appropriate. With substantial clinical deterioration that might be caused by fungal infection, the initiation of antifungal therapy with an AmB lipid preparation would be prudent.
C. Cryptococcus. Patients receiving corticosteroids and those with AIDS or Hodgkin lymphoma have the highest incidence of infection with C. neoformans.
1. Clinical presentation. Pulmonary infection can be asymptomatic. Chest radiographs reveal local bronchopneumonia, lobar involvement, or discrete nodules that may cavitate. CNS infection usually presents as insidious meningoencephalitis without evidence of infection outside the meninges. A variety of skin findings, ranging from maculopapular or nodular lesions to cellulitis, can be seen in disseminated infection.
2. Diagnosis
a. Culture. C. neoformans, an encapsulated yeast that replicates by budding, can easily be grown from blood, respiratory secretions, spinal fluid, and skin biopsies on common laboratory media.
b. Cerebrospinal fluid typically reveals an elevated opening pressure and lymphocytic pleocytosis in cryptococcal meningoencephalitis. A low glucose concentration is found in half of the cases. The India ink preparation is positive in approximately 40% of cases.
c. Serology. The presence of cryptococcal polysaccharide antigen in spinal fluid is diagnostic and is detected in cerebrospinal fluid in >90% of meningitis cases. The presence of cryptococcal antigen in serum documents infection and can be used as a rapid screen. Antibody assays are not useful.
3. Management. The major difficulty the clinician faces with management of cryptococcal infection is determining whether meningeal infection exists. The greatest clinical experience with treatment of cryptococcal infection is that from HIV-infected patients; this experience heavily influences management algorithms. All echinocandins lack activity against Cryptococcus.
a. Meningitis or disseminated disease is treated with AmBD, 0.7 mg/kg/d, with adjunctive flucytosine for 2 weeks. Amphotericin lipid preparations are sometimes substituted. This 2-week induction is followed by fluconazole given at a dose of 400 mg/d (after a 400-mg loading dose) either PO or IV. In patients with intracranial hypertension, depressed sensorium, or other ominous CNS findings, AmB should be given in a dose of 1.0 mg/kg/d. Intracranial hypertension in the absence of intracranial mass lesions may require repeated lumbar puncture to reduce intracranial pressure and ensure adequate perfusion of the brain.
b. Extrameningeal infection. Most patients with extrameningeal infection can be treated with fluconazole (400 to 800 mg/d), if meningeal infection has been excluded.
D. Candidiasis. The major risk factors for systemic candidiasis include treatment with immunosuppressive agents, antibiotics, glucocorticoids, or parenteral hyperalimentation. Indwelling central venous catheters, IV drug abuse, and underlying diseases that produce defects in polymorphonuclear neutrophil function or cell-mediated immunity (e.g., leukemia, lymphoma, diabetes mellitus) also are associated with this infection.
1. Clinical presentation. Localized candidiasis can involve the skin, mouth, esophagus, rectum, or vagina. Disseminated candidiasis can present with fever alone, sepsis, endophthalmitis, skin nodules, renal disease, arthritis, or myositis. With dissemination, C. albicans and occasionally other Candida species may produce discrete, yellow–white retinal lesions of Candida endophthalmitis. Visceral involvement (hepatosplenic candidiasis) is another sequela of dissemination and typically becomes evident following resolution of neutropenia.
2. Diagnosis
a. Cultures. Although studies have shown that blood cultures were positive in only 50% of patients with disseminated candidiasis at autopsy, the yield using modern culture media is undoubtedly higher. Recovery of Candida in the laboratory allows for speciation; this may have implications for selection of therapeutic agents. Documentation of disseminated candidiasis may also avoid a continued search for causes of fever.
b. Serology. A useful test for diagnosis of candidiasis has yet to be developed.
c. Esophagogram shows a typical shaggy, moth-eaten appearance in cases of esophageal candidiasis; the diagnosis can also be made by esophagoscopy.
3. Management. Infected foreign bodies, such as CVC, should be promptly removed.
a. Local therapy. Nystatin liquid suspension (100,000 U/mL) is used to treat oropharyngeal candidiasis; the usual regimen is 500,000 to 2,000,000 U every 4 to 6 hours (“swish and swallow”). If this fails, clotrimazole (Mycelex troches) five times daily or fluconazole, 50 to 100 mg once daily, should be used.
b. Prophylaxis. Topical agents such as nystatin or clotrimazole may be used for prophylaxis, although no good data support a clear-cut benefit. The prophylactic use of fluconazole (or other triazole antifungal agents) is not recommended because of the risk of selecting resistant organisms that would preclude fluconazole and possibly other triazoles as therapeutic agents for subsequent treatment of suspected or documented infections.
c. Systemic therapy. If a Candida species is isolated from a neutropenic patient, then treatment with an echinocandin would be appropriate. When the isolate has been speciated or susceptibility testing has been done, changing to a triazole might be appropriate, depending on the species of Candida recovered (see Pappas et al. in Selected Reading), whether the patient is tolerating the echinocandin, and whether there has been resolution of neutropenia.
E. Aspergillosis. Infection usually occurs via inhalation of spores leading to infection of lung parenchyma or of the paranasal sinuses; dissemination usually occurs from the lung. Approximately 70% to 80% of isolates are Aspergillus fumigatus.
The typical presentation for pulmonary aspergillosis in immunosuppressed patients is fever and pulmonary nodules or infiltrates; as disease progresses, there may be infarction, hemoptysis, and gangrene from vascular invasion. Nearly one-third of patients have no radiologic abnormalities early in the disease.
Dissemination complicates pulmonary disease in 25% to 50% of cases. Various skin lesions, multiple abscesses, brain infarction, or GI ulceration with hemorrhage can result. Aspergillosis is the second most frequent fungal infection that affects the face and mouth of patients receiving chemotherapy. In these patients, bone marrow recovery may lead to the liquefaction of pulmonary foci. Potentially lethal erosion and bleeding may then occur because of the vasculotropic nature of the infection.
1. Diagnosis. The “gold standard” for diagnosis is recovery of the organism by the laboratory from an appropriate clinical sample; this invariably involves culture of a biopsy specimen. Aspergillus species are infrequently recovered from tracheobronchial secretions and essentially never from blood cultures. The galactomannan assay, which detects a cell wall polysaccharide of Aspergillus species, has poor sensitivity, poor specificity, and poor positive predictive value.
The diagnosis of aspergillosis is often based on demonstration of septate, acutely branching hyphae in tissue. Other fungi (e.g., Scedosporium apiospermum, Fusarium species, Penicillium species), however, may not be distinguishable from Aspergillus in tissue section and other fungi (e.g., the Zygomycetes) may require an experienced microscopist to recognize their distinct morphology. Chest radiographic studies may reveal nodules, with or without cavitation, or pleural-based infiltrates. The presence of a “halo sign” (low attenuation surrounding a nodular lesion) on high-resolution CT may be seen in early pulmonary aspergillosis. Later, an “air-crescent” sign indicative of cavitation may be noted. Similar radiographic findings may, however, be present with other vasculotropic organisms. Hence, the emphasis should be on biopsy and culture, whenever possible.
2. Management
a. Optimal antifungal treatment of invasive aspergillosis is unclear at this time. The main difficulties are that no single antifungal agent is active against all species and isolates of Aspergillus and that reliable, reproducible means of susceptibility testing of antifungal agents against Aspergillus do not exist. The greatest experience is with AmBD, given in a dose of 1.0 to 1.5 mg/kg/d; this dose regimen almost invariably results in significant renal dysfunction. The lipid preparations of AmB (ABLC and LAmB) are better tolerated and are usually given in a daily dose of at least 5 mg/kg/d; some patients with refractory disease have been treated with doses as high as 15 mg/kg/d.
b. Voriconazole has FDA approval for treatment of invasive aspergillosis and has become a mainstay of treatment of invasive aspergillosis. Recent reports of in vitro resistance of Aspergillus to voriconazole are of concern, although the clinical impact of these findings is unclear. Therapy should be initiated with two doses of 6 mg/kg given IV 12 hours apart, followed by 4 mg/kg every 12 hours. Patients who respond to this treatment can be switched to oral drugs at 7 days (see Section VII.A.2 for adverse reactions, bioavailability, and drug interactions).
c. The other triazoles (fluconazole, itraconazole, and posaconazole) are either not active against Aspergillus or offer no advantage over voriconazole.
d. Caspofungin has FDA approval for treatment of aspergillosis in patients who cannot tolerate or who have failed other forms of therapy (the so-called “salvage therapy”). The other echinocandins, anidulafungin and micafungin, possess in vitro activity against Aspergillus, but clinical data are limited.
e. Data to support the use of combination therapy for aspergillosis are extremely limited. Triazoles have been shown to be antagonistic when given in conjunction with AmB preparations. Although the combined use of caspofungin and voriconazole has biologic plausibility, insufficient clinical data exist regarding efficacy and toxicity to support their use.
f. Surgical resection of localized invasive pulmonary aspergillosis with a cavitating lesion may prevent hemoptysis and recurrence in selected patients. In leukemic patients, the achievement of complete remission combined with aggressive antifungal therapy has led to markedly increased cure rates for aspergillosis.
F. Zygomycosis. Members of the taxonomic class Zygomycetes are a complicated group of organisms. Infection has been recognized with increasing frequency in patients who have leukemia or lymphoma, immunoincompetence, glucocorticoid therapy, diabetes mellitus, malnutrition, burns, stem cell transplantation, or solid-organ transplantation.
1. Manifestations. The genera Rhizopus, Absidia, and Mucor produce similar pathologic and clinical manifestations because of neutrophil exudation, tissue necrosis, and vascular invasion that results in thrombosis and infarction.
a. Pneumonia can be associated with a dry cough or hemoptysis. Radiographs may show interstitial infiltrates, lobar consolidation, or cavitation.
b. Cerebral disease is usually secondary to pulmonary involvement and presents as brain infarcts or abscesses. Spinal fluid studies are not usually helpful. In contrast, rhinocerebral mucormycosis occurs most frequently in uncontrolled diabetes mellitus.
c. Disseminated disease can result in gastroenteritis, bowel perforation or hemorrhage, peritonitis, or abscess in any organ.
2. Diagnosis. Zygomycetes organisms have broad, nonseptate hyphae, often with right-angle branching in tissue specimens. The agents of zygomycosis may be difficult to recover by culture. Diagnosis is made by demonstrating the organism by culture or, more commonly, by special stains of tissue sections.
3. Management. A high dose of either AmBD or one of the AmB lipid formulations is recommended, although these drugs are largely adjunctive. Reversal of the predisposing condition and resection of infected tissue, if feasible, are the mainstays of therapy. Posaconazole appears to provide some benefit following treatment with an AmB preparation, but experience is quite limited. Mortality is high.
G. Other systemic mycoses
1. Histoplasma capsulatum, Coccidioides immitis, and Blastomyces dermatitidis can readily be recovered from tissues and display typical (pathognomonic) histopathologies. These common human pathogens can present as opportunistic infections in patients who are immunocompromised. Dissemination is often associated with cutaneous anergy.
2. Trichosporon beigelii refers to a group of fungi that cannot readily be distinguished without the use of molecular techniques. Trichosporon beigelii causes white piedra, an infection of hair shafts; is an emerging opportunistic mycosis that is can be difficult to diagnose; and has a high attributable mortality rate. Systemic infection has been most frequently described in neutropenic patients receiving chemotherapy.
a. Cutaneous involvement occurs in about 30% of patients and frequently presents as purpuric papules and nodules with central necrosis or ulceration. Biopsy specimens of these lesions reveal dermal invasion by fungal elements. Culture is positive in >90% of cases.
b. Resolution of disseminated infection appears to require resolution of neutropenia. The antifungal triazoles are most active. AmBD, liposomal AmB, and the echinocandins appear not to be very effective.
3. Scedosporiosis is caused by the asexual form Scedosporium apiospermum (Pseudallescheria boydii); it is an increasingly common cause of opportunistic infection and may cause CNS disease and fungemia in patients with leukemia. Although infections are usually resistant to AmB, the triazoles may be effective, with voriconazole being preferred.
4. Fusariosis. Members of the genus Fusarium are ubiquitous fungi uncommonly associated with infection. Disseminated fusariosis typically occurs in neutropenic patients, carries a high mortality rate, and presents with fever and diffuse cutaneous macules, papules, and nodules. Fusarium species can be isolated from biopsy of skin lesions (hyphae are often observed on direct microscopy) or bronchial aspirates of lung lesions. AmBD and AmB lipid formulations may eradicate this infection; voriconazole is indicated for those with fusariosis who are intolerant of, or refractory to, other therapy. Some clinicians prefer a lipid preparation of AmB plus voriconazole.
5. Fungemic shock. As the use of empiric antibiotics for bacteria has increased, the likelihood has increased that fungi, particularly Candida species, can cause a septic shock-type picture.
VIII. PARASITIC INFECTIONS
A. Toxoplasmosis. The incidence of asymptomatic disease based on serology ranges from 10% to 40% in the United States to 96% in Western Europe. Of those patients with AIDS who are seropositive for T. gondii, about 25% to 50% originally developed Toxoplasma encephalitis. This has decreased dramatically because of the use of trimethoprim–sulfamethoxazole for Pneumocystis prophylaxis in severely CD4 lymphocytopenic patients and the availability of highly active antiretroviral therapy.
Patients with symptomatic disease present with a low-grade febrile illness characterized by localized or generalized lymphadenopathy, hepatosplenomegaly, malaise, and fatigue. Any organ may become involved. Infection in patients with abnormal cellular immunity may mimic brain tumor or lymphoproliferative disorder.
1. Diagnosis
a. Histology. Identification of trophozoites rather than cysts is important because cysts can persist for decades. Lymph node pathology is characteristic of toxoplasmosis.
b. Culture is rarely used.
c. Serology suggests the disease. IgM antibody is suggestive of recent infection. Many patients, however, develop symptomatic disease as a result of reactivation of a quiescent infection. In the latter instance, only IgG antibody will likely be detectable.
2. Management. Pyrimethamine (a folic acid antagonist) and a sulfa derivative are given in divided doses for 3 to 6 weeks. The development of hematologic toxicity often interrupts treatment. Leucovorin is also given to minimize marrow suppressive effects.
a. Pyrimethamine is given as a loading dose of 200 mg PO followed by maintenance of 50 to 75 mg/d in association with leucovorin, 10 to 20 mg/d orally.
b. Sulfadiazine, 1.0 to 1.5 g q.i.d. is given in conjunction with pyrimethamine.
c. Another combination for acute disease is pyrimethamine (100 mg/d PO) and leucovorin plus clindamycin (1.2 g/d IV in divided doses).
B. Pneumocystis. P. carinii (which has been reclassified as a fungus and renamed P. jiroveci) causes pneumonia in patients with immunodeficiency, including those with AIDS. Children with acute lymphoblastic leukemia in remission and patients in whom corticosteroid therapy is being tapered are particularly susceptible to infection. Manifestations include dyspnea, fever, nonproductive cough, pulmonary rales, hypoxemia, and hypocapnia. Chest radiographs early in the disease may appear benign, whereas blood gases often demonstrate hypoxemia. Chest radiographs most often show diffuse symmetric, bilateral, perihilar infiltrates that progress at variable rates.
1. Diagnosis. In patients infected with HIV, the organism is usually easily visualized because of the large numbers often present; in patients with other forms of immunosuppression, detection of cysts is much more difficult. The most commonly used diagnostic techniques are direct fluorescent antibody (DFA) stain or methenamine silver stain of pulmonary secretions or lung biopsy material. Giemsa stain detects sporozoites within the cyst wall but not the wall.
In patients who are critically ill or severely thrombocytopenic, lung biopsy should be deferred. Less invasive procedures or possibly an empiric trial of therapy may be considered because the biopsy procedure has high morbidity and mortality rates.
2. Management. In patients with significant respiratory difficulties (arterial oxygen pressure <70 mm Hg or an alveolar–arterial oxygen gradient >35 mm Hg), corticosteroids (prednisone 40 mg b.i.d., tapering over a 21-day course) should be added to the antimicrobial treatment for pneumocystis. Treatment is normally given for 21 days and options include the following:
a. Sulfamethoxazole–trimethoprim (Bactrim or Septra), two double-strength tablets PO or two ampoules IV every 6 to 8 hours; this schedule is considered to be the therapy of choice.
b. Pentamidine, 4 mg/kg IM daily, can be used in patients intolerant to sulfa drugs.
c. Trimetrexate in combination with leucovorin may be effective when other regimens have failed. Trimetrexate is relatively toxic and does not offer any advantages over sulfamethoxazole–trimethoprim or pentamidine. This drug is no longer available in the United States.
d. Atovaquone or the combination of clindamycin–primaquine is sometimes used for mild cases in patients infected with HIV, but these are definitely second-line therapies and less likely to produce a good outcome in the severely ill patient.
C. Strongyloidiasis. Humans are infected by both filariform larvae and adult forms, resulting in self-perpetuating autoinfection. Defective cell-mediated immunity, high-dose corticosteroid therapy, and decreased bowel motility enhance the chance of massive GI tract, pulmonary, or CNS infection. The characteristics of Strongyloides stercoralis allow it to be harbored within a host for prolonged periods, only to disseminate after cell-mediated immunity is suppressed.
1. Diagnosis. A diagnosis of strongyloidiasis should be considered in an immunocompromised patient with a petechial rash. Larvae can be recovered from the stool in 25% to 60% of patients and from duodenal aspirates in 40% to 90%. Peripheral eosinophilia is typical but may be absent in the hyperinfected state.
2. Management. Prompt diagnosis and initiation of thiabendazole therapy, 1.5 g PO twice daily for 2 to 4 days, provides the greatest opportunity for patient survival. Secondary bacterial infections should be aggressively sought. The mortality rate from disseminated strongyloidiasis approaches 80%.
D. Other parasites
1. Giardia lamblia infection is associated with hypogammaglobulinemia, small bowel lymphoma, and pancreatic carcinoma. Manifestations include diarrhea, nausea, flatulence, and cramps.
2. Malaria and babesiosis may infect immunosuppressed hosts, especially after splenectomy. Infection results in high fever and hemolysis.
Suggested Reading
Freifeld AG, at 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 2011:52:e56.
Hughes WT, et al. 2002 guidelines for the use of antimicrobial agents in neutropenic patients with cancer. Clin Infect Dis 2002;34:730.
Marr KA, et al. Combination antifungal therapy for invasive aspergillosis. Clin Infect Dis 2004;39:797.
Mermel LA, et al. Clinical practice guidelines for the diagnosis and management of intravascular catheter–related infection: 2009 update by the Infectious Diseases Society of America. Clin Infect Dis 2009;49:1.
Ostrosky-Zeichner L, et al. Amphotericin B: Time for a new “gold standard.” Clin Infect Dis 2003;37:415.
Pappas PG, et al. Clinical practice guidelines for the management of candidiasis. Clin Infect Dis 2009;48:503.
Pfeiffer CD, et al. Diagnosis of invasive aspergillosis using a galactomannan assay: a meta-analysis. Clin Infect Dis 2006;42:1417.
Smith TJ, et al. 2006 update of recommendations for use of white blood cell growth factors: an evidence-based clinical practice guideline. J Clin Oncol 2006;24:3187.
Spellberg BJ, et al. Current treatment strategies for disseminated candidiasis. Clin Infect Dis 2006;42:244.