With the advent of modern therapeutic and prophylactic regimens, bacterial infections have become more effectively controlled, while fungal and viral infections have emerged as more prominent complications in the management of immunocompromised patients.
With the advent of modern therapeutic and prophylactic regimens, bacterial infections have become more effectively controlled, while fungal and viral infections have emerged as more prominent complications in the management of immunocompromised patients. Now that newer antifungal and antiviral drugs are available, early diagnosis and treatment should result in a significant decrease in morbidity and mortality associated with these infections. However, because therapy is still suboptimal, primary prevention remains an important consideration.
Fungal infections have become a leading cause of morbidity and mortality in cancer patients . One particular problem in the management of these infections is that early diagnosis is difficult, so treatment may be delayed, which often leads to a poor clinical outcome .
Cancer patients commonly have neutropenia, cellular immune defects, and indwelling catheters, characteristics that make them an ideal target for the development of fungal infections (Table 1).
|Malignancy/intervention||Defects in host-defense mechanisms||Associated infections|
|Acute leukemia||Neutropenia||Candida, Aspergillus|
|Lymphoma||Cellular immune deficiency||Cryptococcus,|
|Bone marrow transplantation||Increased activity of suppressor T-lymphocytes||CMV, VZV, HSV, adenovirus|
|Cancer chemotherapy||Mucositis, neutropenia, impaired cellular and humoral immunity||Candida, Aspergillus|
|Corticosteroids||Monocytopenia, lymphopenia, decreased inflammation, defective phagocytic function||Adversely affect all infections; prdisposition to|
|Therapeutic irradiation||Impaired lymphocyte function, neutropenia, mucositis||VZV|
|Vascular catheter||Skin breakdown||Candida|
Candidiasis is the most common nosocomial mycosis , with Candida albicans representing half of all fungal isolates in cancer patients . Recently, other species, such as C tropicalis, C parapsilosis, C krusei, and C lusitaniae, have emerged as important pathogens . Possible explanations for the high incidence of candidal infections are mucosal damage resulting from chemotherapy, increased use of broad-spectrum antibiotics, prolonged neutropenia associated with more aggressive chemotherapy, use of corticosteroids, and the presence of central venous catheters [1,5]. Neutropenia is probably the most important of these factors . Currently, it is believed that the majority of candidal infections in cancer patients originate from an endogenous source, such as the gastrointestinal tract. However, there are also exogenous sources. The intensive care unit is a typical setting for exogenous infection, where the transmission of infection through the hands of health-care workers has been demonstrated . Candidiasis includes mucocutaneous candidiasis, candidemia, acute disseminated candidiasis, and chronic disseminated candidiasis . Treatment will depend on these distinctions (Table 2).
|Mucosal||Topical clotrimazole||Ketoconazole (400 mg PO qd) or fluconazole (100 mg PO qd)|
|Genitourinary tract||Amphotericin B (0.5-1 mg/kg/d)||Fluconazole (200 mg PO qd)|
|Candidemia*||Amphotericin B (0.5-1 mg/kg/d) ± flucytosine (100-150 mg/kg PO qd)||Fluconazole (400 mg IV qd)|
|ADC||Amphotericin B (no more than 0.6 mg/kg/d) ± flucytosine (100-150 mg/kg PO qd)||Fluconazole (400 mg IV qd)|
|CDC||Amphotericin B^ (0.7-1 mg/kg/d) ± flucytosine (100-150 mg/kg PO qd)||Fluconazole (400 mg IV qd)|
|Pulmonary||Amphotericin B^ (1-1.5 mg/kg/d)||? Itraconazole (400 mg/d)|
|Extrapulmonary||Amphotericin B^ (1-1.5 mg/kg/d) + flucytosine||? Itraconazole (400 mg/d)|
Mucosal Candidiasis: Oropharyngeal candidiasis is common in patients undergoing chemotherapy, especially if the regimen contains corticosteroids. Classically, the infection presents with creamy white patches and ulcers in the oral mucosa; however, the definitive diagnosis is based on a wet mount or gram stain and culture of the lesions. The initial treatment can be topical clotrimazole (Mycelex). For refractory or more severe cases, ketoconazole (Nizoral), 400 mg orally every day, and fluconazole (Diflucan), 100 mg orally every day, are equally effective .
Esophageal candidiasis also is associated with cytotoxic chemotherapy and corticosteroids. Other important factors are mediastinal radiation and esophageal herpes. Clinically, the infection is manifested as dysphagia. Oral thrush may be absent in up to 30% of patients . The definitive diagnosis is made by esophagoscopy with mucosal brushing or biopsy. In cases in which this procedure is contraindicated, empirical treatment with ketoconazole, 400 to 600 mg orally every day, or fluconazole, 100 to 400 mg orally every day, should be started . Alternatively, amphotericin B (Fungizone), 0.3 to 0.4 mg/kg/d, may be used. Treatment should be continued for at least 2 to 3 weeks after symptoms resolve.
Candidiasis of the genitourinary tract usually starts as candiduria, which can be secondary to either upper or lower urinary tract infection. The presence of candiduria in the neutropenic patient frequently is associated with disseminated infection. Amphotericin B, at a dose of 0.5 to 1 mg/kg/d, is the treatment of choice for neutropenic patients [8,9]. Fluconazole is a good alternative because it concentrates well in the urine. If urinary catheters or stents are present, they should be removed when possible. Washout of the bladder with amphotericin B may be useful, but it is reserved for cases in which disseminated or renal infection has been ruled out .
Candidemia: Candida spp in blood cultures from neutropenic patients are unlikely to be contaminants , and in some cases they can be the manifestation of disseminated infection. Even non-neutropenic patients have an increased mortality rate if candidemia remains untreated. Thus, it is prudent to treat all infected patients with systemic antifungal agents .
In neutropenic patients, the treatment of choice is amphotericin B at a dose of 0.5 to 1 mg/kg/d for 2 weeks or until neutropenia resolves. The drug can cause reversible renal failure (low glomerular filtration rate) and electrolyte abnormalities (hypokalemia and hypomagnesemia). Nephrotoxicity can be decreased with the administration of normal saline before and after infusion. Electrolytes should be monitored and replaced carefully. C tropicalis and C parapsilosis usually require higher doses of amphotericin B (0.75 to 1 mg/kg/d) in association with flucytosine . C lusitaniae tends to be resistant to amphotericin B  but may respond to fluconazole and flucytosine. In-vitro susceptibility tests for fungi do not necessarily correlate with clinical results and so are not recommended as routine tests. However, they may aid in drug selection in patients who do not respond to initial treatment [11,15].
A recent trial performed in non-neutropenic patients with candidemia showed that intravenous fluconazole, 400 mg/d, was as effective as amphotericin B, 0.5 to 0.6 mg/kg/d, and was better tolerated . The most important side effects associated with fluconazole were nausea, vomiting, transient elevation of liver function tests, and skin rash .
The management of candidemia in the presence of a vascular catheter is controversial. In some cases, the catheter may be the primary source of the fungemia, whereas in others it may be secondarily colonized, for example, from a gastrointestinal tract infection. Even in the latter situation, however, the chances of perpetuating the infection are greater if the catheter is not removed , so removing it if possible would seem to be indicated .
Acute Disseminated Candidiasis (ADC): ADC represents the acute involvement of two or more noncontiguous sites by Candida spp . Clinically, it can manifest as a septic syndrome with hypotension, multiorgan failure, macronodular skin lesions, and endophthalmitis. The last symptom is usually absent during neutropenia, but in non-neutropenic patients, it is a reliable way to make the diagnosis. Persistent fungemia is not always present. The treatment of choice is amphotericin B, at a dose no lower than 0.6 mg/kg/d with or without flucytosine. The role of fluconazole has not been clearly established .
Chronic Disseminated Candidiasis (CDC): Also known as hepatosplenic candidiasis, CDC is an indolent process that is established during neutropenia and becomes apparent after neutropenia resolves. Deep-seated abscesses are seen not only in the liver and spleen but also in other organs such as the kidneys, adrenals, and lungs. The clinical course is that of progressive debilitation , and fungemia is rare. Abdominal pain and elevation of the alkaline phosphatase level after white blood cell counts recover should be cues for the diagnosis . Computed tomography and biopsy and culture of the abscesses will provide a definitive diagnosis . The initial treatment consists of amphotericin B with or without flucytosine; however, less than half of patients respond to this treatment . Lipid formulations of amphotericin B are an attractive alternative because higher doses of the drug can be given with less nephrotoxicity . Fluconazole also may be effective; it has been used in some refractory cases, with clinical response rates as high as 88% .
Prophylaxis: It is very important to define the population of patients who may benefit from chemoprophylaxis of candidiasis. Patients with protracted (greater than 3 weeks) and profound (less than 100 cells/mL) neutropenia are at higher risk for invasive fungal infections. This situation usually is seen in patients undergoing bone marrow transplantation and induction therapy for acute leukemia [2,22]. Previous studies have shown that fluconazole, at oral doses of 200 to 400 mg/d, is effective at preventing superficial and disseminated candidiasis and at decreasing mortality directly related to systemic fungal infections in this population [23-25]. Furthermore, fluconazole (400 mg/d) has been compared with intravenous (IV) amphotericin B (0.5 mg/kg three times a week) . Both are equally effective, but fluconazole is better tolerated. Fluconazole is not active against Aspergillus spp, however, and it may select some resistant Candida spp, such as C krusei and Torulopsis glabrata .
Invasive aspergillosis is a significant infection that usually develops in the presence of neutropenia and corticosteroid use . Most commonly, it occurs in bone marrow transplantation (BMT) and leukemia patients, although patients with lymphoma or solid tumors also may be affected. The most common species causing invasive disease are Aspergillusfumigatus and A flavus . Given this infection's high prevalence and poor outcome, a reduction in its incidence should greatly reduce the mortality in susceptible patients.
Invasive Pulmonary Aspergillosis: Invasive pulmonary aspergillosis is the most common form of aspergillosis seen in immunocompromised hosts . Clinically, it may present as pleuritic chest pain, pulmonary hemorrhage, hemoptysis, and cavitation, all as a consequence of blood vessel infiltration . Pulmonary infiltrates may be absent during the initial phase of the disease as a result of the lack of inflammatory response associated with neutropenia. The isolation of Aspergillus spp from respiratory secretions of susceptible patients should be considered evidence of disease because it is rarely a contaminant . Bronchoalveolar lavages frequently is performed to establish the diagnosis, but the yield is quite low. Lung biopsy and culture of this tissue may be required for a definitive diagnosis. Noninvasive techniques, including assays for serum Aspergillus antigen, are currently under investigation .
High doses of amphotericin B (1 to 1.5 mg/kg/d) are required for treatment. The addition of flucytosine may produce a synergistic response (Table 2). If they are combined, serum levels of flucytosine should be monitored and kept below 100 µg/mL to avoid major toxic reactions (mainly hematotoxicity). Lipid formulations of amphotericin B should be considered in protracted cases. Treatment should continue until the Aspergillus lesion disappears or stabilizes, which may take several months. The use of itraconazole (Sporanox) in neutropenic patients remains under investigation . Its absorption may be erratic in patients with achlorhydria or patients receiving histamine (H2) blockers. The drug should be taken with meals, and serum levels should be monitored.
An important cofactor for the treatment of invasive pulmonary aspergillosis is the reversal of immunosuppression. Sometimes, this can be achieved by the discontinuation of steroids and treatment with the granulocyte and macrophage colony-stimulating factors (G-CSF [Neupogen], M-CSF, and GM-CSF [Leukine]). In cases refractory to medical treatment that show a well-localized Aspergillus lesion, surgical excision may be indicated .
Extrapulmonary Aspergillosis: Occasionally, Aspergillus infection may affect the paranasal sinuses and extend locally to the base of the skull and brain. In other cases, the central nervous system can be involved by direct hematogenous dissemination from a lung infection. Whatever the mechanism of infection, neurologic manifestations consist of focal neurologic deficits, including focal seizures, hemiparesis, and cranial nerve palsies . Other possible extrapulmonary infections caused by Aspergillus are pericarditis, endocarditis, endophthalmitis, and cutaneous involvement. As in invasive pulmonary aspergillosis, treatment of extrapulmonary infections consists of high-dose amphotericin B in association with flucytosine (Table 2) and reversal of immunosuppression .
Prophylaxis: The most common nosocomial sources of Aspergillus infection are contaminated air conditioners and construction sites. High-efficiency particulate air (HEPA) filters have been shown to be effective in decreasing the environmental source of infection . Chemoprophylaxis for aspergillosis is not a well-established practice. Intranasal administration of amphotericin B decreases the colonization of the nasal mucosa but does not decrease the frequency of invasive pulmonary aspergillosis . Itraconazole may play a role in the primary prevention of aspergillosis, but this has not been clearly defined. IV amphotericin B is effective as secondary prophylaxis, because it decreases the risk of relapse among patients who have a previous history of invasive aspergillosis and are undergoing further cytotoxic chemotherapy .
Fungi considered to represent contamination or harmless colonization in immunocompetent individuals have been shown to be serious pathogens in the immunocompromised patient with cancer. Trichosporon spp, Curvularia spp, Alternaria spp, and Fusarium spp are some of the fungi reported with an increasing frequency . In general, these infections are difficult to treat, and the final prognosis depends on the recovery of immune status. Successful treatment of disseminated fusariosis with amphotericin B in combination with granulocyte transfusions and GM-CSF has been reported.
Cryptococcus is another fungus that should be considered in cancer patients with defects in cellular immunity. Unlike the fungal infections previously described, neutropenia does not seem to be a risk factor. Cryptococcosis usually affects patients with acquired immunodeficiency syndrome (AIDS) or lymphomas or patients who have received bone marrow transplants or corticosteroids [1,34]. Commonly, it presents as fever and severe headache in cases of meningitis.
The diagnosis can be made by latex agglutination of cryptococcal antigen (from serum or cerebrospinal fluid) or by culture . The treatment of choice for meningeal and disseminated cryptococcosis is amphotericin B in combination with flucytosine. In patients who have meningeal cryptococcosis and normal mental status, fluconazole, 400 mg/d, is considered safe as initial treatment. As long as the patient remains immunocompromised, as in patients with AIDS, chronic suppressive therapy is required. For this purpose, fluconazole seems to be superior to amphotericin B .
Empirical Antifungal Treatment
The empirical use of antifungal treatment in neutropenic patients who remain febrile (usually for more than 7 days) in spite of broad-spectrum antibiotics has reduced invasive fungal infections and the morbidity and mortality associated with them . In this circumstance, amphotericin B, at a dose of 0.5 mg/kg/d, is recommended. Triazoles such as fluconazole and itraconazole are potential alternatives, but further studies are needed to establish their efficacy as empirical treatments .
Other Therapeutic Modalities
A reduction in the duration of neutropenia reduces the incidence of invasive fungal infections . Use of cytokines such as G-CSF, GM-CSF, M-CSF, and gamma interferon (IFN-gamma [Actimmune]) may be beneficial. Previous studies using GM-CSF in combination with amphotericin B  have been encouraging, but significant side effects, such as the capillary leak syndrome, are possible limitations. The determination of monocyte and macrophage function and of circulating cytokine levels may identify patients likely to respond to this therapeutic modality . Nevertheless, there is a need for randomized, placebo-controlled trials to determine the impact of these factors on the mortality rate.
The use of granulocyte transfusions from donors stimulated with G-CSF may be another strategy for increasing the levels of circulating granulocytes until endogenous recovery from granulocytopenia occurs .
Opportunistic viral infections are a significant cause of morbidity and mortality in immunocompromised patients such as BMT recipients and patients with hematologic malignancies . The most common viruses isolated from these patients are the herpesviruses (especially cytomegalovirus [CMV], herpes simplex virus [HSV], and varicella zoster virus [VZV]. Their frequency is probably due to their ability to remain latent until they are reactivated when the patient is immunosuppressed. Infections by RNA respiratory viruses, such as respiratory syncytial virus (RSV) and influenza and parainfluenza viruses, usually occur in outbreaks and also are seen frequently . At present, it is important to diagnose these infections correctly, because treatment is available for some of them (Table 3).
|Cytomegalovirus||Ganciclovir (10 mg/kg/d IV) ± IV IgGª||Foscarnet (40-60 mg/kg IV q8h)|
|Herpes simplex virus||Acyclovir (5 mg/kg IV q8h)||Famciclovir (500 mg PO q8h)|
|Varicella zoster virus||Acyclovir (10 mg/kg IV q8h)||Famciclovir (500 mg PO q8h)|
|Influenza A||Amantadine^ (100 mg PO bid)||Rimantadine^ (100 mg PO bid)|
|Respiratory syncytial virus||Aerosolized ribavirin + IV IgG|
Cytomegalovirus is a common cause of death in allogeneic BMT patients, ranking second after graft-vs-host disease (GVHD). CMV may be the result of primary infection (from donor bone marrow graft or blood products to a seronegative patient) or the reactivation of a latent infection . The incidence of CMV infection is the same after autologous or allogeneic BMT; however, morbidity and mortality are lower in the autologous group . Most commonly, infection appears 4 to 10 weeks after transplantation. Mild forms of the illness may manifest as fever, hepatitis, leukopenia, and thrombocytopenia . Severe forms manifest as interstitial pneumonia (with a mortality rate of 80% to 90%) and gastroenteritis .
The diagnosis can be established from the clinical presentation and the detection of CMV antigen or CMV cultures from buffy coat or urine. The development of effective, rapid techniques that utilize CMV-specific monoclonal antibodies has made possible the earlier diagnosis of this disease. In addition, DNA amplification using the polymerase chain reaction has made viral detection highly sensitive and should be useful for clinical diagnosis . Occasionally, histopathologic diagnosis may be needed.
Treatment with acyclovir is not effective because the virus lacks thymidine kinase, an enzyme necessary for the activation of acyclovir . Ganciclovir and foscarnet are active in vitro and in vivo against CMV. The initial treatments consist of IV ganciclovir at a dosage of 10 mg/kg/d (usually for 3 weeks) followed by a maintenance dosage of 6 mg/kg/d 5 days per week (for an additional 6 to 7 weeks). Periodic blood cell counts should be measured, because the main toxicity of ganciclovir is hematologic.
In cases of CMV pneumonitis, CMV immunoglobulin G intravenous (CMV-IGIV) has been shown to improve survival , probably because it blocks T-cell-mediated destruction of lung tissue . To prevent CMV infection, seronegative allogeneic BMT recipients should receive seronegative blood products only. The prophylactic use of CMV-IGIV in BMT patients has decreased the incidence of CMV pneumonitis without significantly decreasing mortality . The prophylactic use of ganciclovir for patients who were seropositive before transplantation  or as early treatment (as soon as CMV is detected in throat, urine, or blood cultures ) has reduced CMV infection and improved survival.
Herpes Simplex Virus
More than 80% of BMT patients will have reactivation of latent HSV residing in the neuronal ganglia. The same situation is true for patients with leukemia, lymphoma, or solid tumors who receive intensive chemotherapy . This reactivation usually occurs within the first 3 weeks after transplantation or chemotherapy and is characterized by ulcerative oral lesions (in 85% of the cases) or genital lesions (in 15% of the cases).
In immunocompromised patients, the herpetic lesions may be larger and deeper or may have another atypical aspect . It is believed that several cases of chemotherapy-induced mucositis were actually due to HSV infection . Other possible presentations of HSV infection in immunocompromised patients are esophagitis, tracheitis, pneumonitis, and, rarely, encephalitis. When pneumonitis occurs, it may present as a local infiltrate (usually originating from aspiration of the virus from the upper airways) or as a diffuse interstitial infiltrate (from viremia) .
The diagnosis of HSV infection is based on viral culture of suspected lesions. Treatment with acyclovir (Zovirax) has been effective by reducing the viral shedding, enhancing the resolution of pain, and shortening the time to healing . The suggested dose is 5 mg/kg every 8 hours administered intravenously for a total of 7 days.
Alternatively, famciclovir (Famvir), a newly approved antiviral agent, has been shown to be effective against herpesviruses. It is the oral prodrug of penciclovir and has a considerably longer intracellular half-life than acyclovir. Side effects, which include headache, nausea, and diarrhea, are uncommon .
Valacyclovir, the oral prodrug of acyclovir, is currently under investigation. Its oral administration results in plasma concentrations three to five times greater than those achieved with a comparable dose of oral acyclovir, and the intervals between valacyclovir doses can be longer. Strains of acyclovir-resistant HSV may develop. In such cases, foscarnet (Foscavir) is the treatment of choice.
Prophylaxis with acyclovir prevents the reactivation of the virus in patients undergoing BMT or cytotoxic chemotherapy. If the oral intake is inconsistent, the IV route is preferred. Doses as low as 250 mg/m² have been effective .
Varicella Zoster Virus
VZV infection in cancer patients can present either as primary infection (chickenpox) or as reactivation (shingles). The latter infection can remain localized in a dermatomal distribution or can disseminate, causing extensive cutaneous and/or visceral involvement, which can prove fatal . When visceral involvement occurs, the lungs are affected more commonly, followed by the liver and the central nervous system . Patients with Hodgkin's disease or non-Hodgkin's lymphoma and patients undergoing BMT are at increased risk for VZV reactivation. Unlike HSV, VZV takes longer to reactivate (usually within the first 2 years).
The treatment of choice is acyclovir, 10 to 12 mg/kg every 8 hours for no fewer than 7 days. This treatment decreases the time to full crusting and prevents the dissemination of the disease ; however, it does not have any significant impact on postherpetic neuralgia. Uncomplicated cases may be treated with famciclovir, at a dose of 500 mg orally every 8 hours.
Prophylaxis with acyclovir effectively prevents VZV reactivation; however, upon discontinuation of the drug, the rate of reactivation increases again . VZV immunoglobulin has a role in the prevention of primary infection in the susceptible immunocompromised host . A live, attenuated vaccine is under investigation .
Adenovirus affects patients with cellular immune defects. It is not clear whether the majority of infections are primary or a reactivation of latent viral infection. Pneumonia and hepatitis are the most common infections. Hemorrhagic cystitis occasionally occurs and has been associated with specific serotypes of the virus. No specific treatment is available ; however, in some anecdotal case reports, IV ribavirin (Virazole) has shown some efficacy .
Respiratory RNA Viruses
Influenza virus is a known cause of annual epidemics of respiratory disease with significant morbidity and mortality, especially among cancer patients . Clinically, this virus presents as fever, cough, coryza, myalgias, fatigue, and headache. Primary influenza pneumonia or secondary bacterial pneumonia may develop, especially in the immunocompromised host .
Influenza A can be treated effectively with amantadine or rimantadine (Flumadine) during the early phases of disease. Measures should concentrate on prophylaxis; this can be accomplished with annual influenza vaccination for immunocompromised patients, their families, and hospital staff . The efficacy of the vaccine is 60% to 90% , but the rate may be lower in immunosuppressed patients. Chemoprophylaxis with amantadine (effective only for influenza A) should be administered for 2 weeks during nosocomial outbreaks when late immunization has been given.
Parainfluenza and RSV also can cause upper respiratory infection followed by severe viral pneumonia in susceptible hosts, such as BMT patients [65,66]. The diagnosis of parainfluenza can be difficult because the virus grows slowly in cell culture. The diagnosis of RSV can be made by culture or by detecting RSV antigen in respiratory specimens. Aerosolized ribavirin in association with IV immunoglobulins is effective in cases of RSV pneumonia . There is, however, no well-established antiviral treatment of parainfluenza pneumonia.
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