HSV

Infections caused by HSV are the most common viral infections in patients with lymphoma and acute leukemia. These infections occur predominantly in patients with preexistent antibodies to HSV, indicating that most represent reactivation of endogenous latent infection. More than 80% of bone marrow transplant recipients will have reactivation of latent HSV residing in the neuronal ganglia. Lesions caused by HSV are found most often on the lips and oral mucosa. In patients receiving antineoplastic chemotherapy, these lesions tend to become large and painful, and severe mucositis with extensive ulceration of the oral mucosa is not uncommon. Secondary infection with bacteria or fungi may occur. Localized bleeding may be a complication in patients with severe chemotherapy-induced thrombocytopenia. Some patients develop chronic localized herpetic ulcers involving the nose, lips, or eyelids that begin as small papulovesicular lesions and gradually enlarge over several weeks. Herpetic lesions can extend from the oropharyngeal mucosa to involve the esophageal mucosa, producing symptoms that are indistinguishable from Candida esophagitis. Occasionally, esophagitis may occur without oropharyngeal lesions, and it may become necessary to perform invasive diagnostic procedures, such as endoscopy, and obtain a biopsy specimen in order to make an accurate diagnosis. Patients with herpetic esophagitis may also have lesions involving the larynx and trachea and occasionally may develop severe necrotizing tracheobronchitis. Localized HSV lesions may also be seen in other areas of the body, such as the genital and perianal areas, and may become quite destructive. Dissemination of HSV infection is uncommon and occurs most often in patients with Hodgkin disease. The liver, spleen, adrenal glands, kidneys, pancreas, lungs, brain, and gastrointestinal tract may be involved in disseminated infection. Acyclovir, famciclovir, and valaciclovir are effective for the treatment of these infections.^123–125 Because of the high frequency of mucocutaneous infections in acute leukemia patients undergoing induction chemotherapy and bone marrow transplant recipients who are seropositive, antiviral prophylaxis is indicated. Disseminated infection, encephalitis, and infection in immunocompromised patients generally require intravenous therapy with acyclovir (10 mg/kg q8h). Strains of HSV resistant to acyclovir may develop. In such cases, foscarnet is the treatment of choice.

VZV

Primary infection with VZV causes approximately 4 million cases of chicken pox in the United States each year.¹²⁶ VZV remains latent in the sensory ganglia for the lifetime of the host, and reactivates in 15% of persons to cause herpes zoster.¹²⁷

Varicella has been recognized as a potentially serious infection in children undergoing cancer chemotherapy. Because it is a highly contagious infection, it is especially hazardous, and epidemics have occurred in pediatric cancer facilities. Serious complications arise in approximately 5% of otherwise healthy children who develop varicella, but the fatality rate is less than 0.5%. Approximately 30% of children receiving cancer chemotherapy develop serious complications during varicella infection, and the fatality rate is around 7%. Most serious complications and deaths occur in children with hematologic neoplasms. The severity of infection is related to the extent of the underlying cancer and to antitumor therapy.

Characteristic manifestations of varicella include a generalized vesicular rash and fever. Lesions appear initially on the face and scalp and subsequently spread to the trunk and extremities. New lesions continue to appear as older lesions crust. Infection may be unduly prolonged in patients with cancer. The vesicles become hemorrhagic and necrotic in patients with thrombocytopenia. Approximately 10% of children develop a bacterial superinfection. The disease is occasionally rapidly progressive, and in a few patients, this can lead to circulatory collapse and death shortly after the appearance of the vesicles. Disseminated visceral infection may result in widespread pneumonia, and focal necrosis of the liver, pancreas, or adrenal glands. Fulminating encephalitis may develop occasionally. Dissemination generally develops within 1 week of the onset of skin lesions.

Herpes zoster occurs sporadically in the general adult population. Among cancer patients, it occurs most often in those with lymphoproliferative disorders. The risk for herpes zoster in HIV-infected individuals is increased about 20-fold. The infection is characterized by a unilateral vesicular rash in the distribution of one or two adjacent sensory dermatomes (Figure 160-9). The thoracic, cervical, and lumbar dermatomes are most commonly involved. In approximately 20% of patients with cancer, herpes zoster lesions arise initially at sites where the tumor is in close proximity to a nerve trunk. In an additional 20% of the patients, eruption first appears at sites of recent radiation therapy. Initially, the lesions appear to be erythematous and maculopapular in nature but swiftly evolve into a vesicular rash. Vesicles may coalesce to form larger, bulbous lesions. Localized herpes zoster usually causes no unique problems in the cancer patient. Occasionally, the lesions heal slowly with necrosis and scarring. In others, lesion formation may continue for 10 to 15 days, and crusting or scabbing of lesions may not occur until approximately 3 to 4 weeks into the course of the disease. Occasional patients develop a generalized varicelliform eruption, without localization, at the onset of the disease. The rash is accompanied by pain (zoster-associated pain) that often precedes the eruption by 2 to 3 days, and can last for several weeks or even months. Postherpetic neuralgia is zoster-associated pain that persists beyond 1 month.

Figure 160-9

Typical vesicular rash caused by varicella-zoster virus. Note the dermatomal distribution, and the hemorrhagic nature of lesions in this patient with thrombocytopenia. (Four-color version of figure on CD-RM)

Cutaneous dissemination of herpes zoster occurs in approximately 35% of cancer patients, as compared with only 4% of those without cancer. Therapy with adrenal corticosteroids, radiation, or antitumor agents facilitates dissemination. Localized skin lesions may precede cutaneous dissemination by 2 to 15 days. Lesions may appear in the mouth, pharynx, labia, or anus. Visceral dissemination occurs infrequently but then commonly involves the gastrointestinal tract, liver, adrenals, pancreas, lungs, and brain, resulting in hepatitis, pneumonitis, and meningoencephalitis. Muscular weakness, motor paralysis, and postherpetic neuralgia seem to be more common in cancer patients. Multiple episodes of herpes zoster are much more common in immunosuppressed individuals than in persons who are immunocompetent.

Laboratory confirmation of the diagnosis is not required for most cases of varicella. VZV can be recovered from the vesicular fluid for a few days after the onset of the eruption but is recovered infrequently from other sites. Cultures are positive 30% to 60% of the time. Detection of VZV antigens in skin scrapings using fluorescence microscopy, and detection of VZV DNA, in the cerebrospinal fluid or other tissues, using PCR, are more rapid and sensitive diagnostic techniques.

Therapy of VZV infection shortens viral shedding, accelerates healing of lesions and reduces the frequency of visceral disease.^128,129 Oral famciclovir and valaciclovir are more effective than acyclovir. Severe infections such as meningoencephalitis and pneumonitis require intravenous acyclovir therapy along with skilled supportive therapy. Significant mortality may occur despite these measures. Therapy with foscarnet or combination therapy with foscarnet and acyclovir should be considered for patients who fail to respond to acyclovir alone.¹³⁰

Zoster-associated pain represents a continuum that includes prodromal pain, acute phase pain, and chronic pain (commonly referred to as postherpetic neuralgia). All these appear to be more common in the elderly and in immunosuppressed patients. Although the role of adrenal corticosteroids to prevent this complication is controversial, one randomized study in patients older than age 50 years showed that acyclovir plus prednisone was more effective against zoster-associated pain than acyclovir alone.¹³¹

The administration of varicella-zoster immune globulin is useful for postexposure prophylaxis in high-risk individuals and can also ameliorate established infection. Varicella-zoster immune globulin must be given within 96 h of exposure to be effective. The OKA vaccination strain of varicella vaccine is now available for universal immunization and postexposure prophylaxis.^132,133 The vaccine is safe, immunogenic, and effective in leukemic children at risk for serious disease if chemotherapy is interrupted for 1 week before and after administration. Approximately 50% developed a mild rash, of whom 40% were treated with acyclovir.¹³⁴ A 1-week course of antiviral therapy following exposure may be useful for patients at risk.¹³⁵

CMV

Although CMV infections occur sporadically among cancer patients, especially among those with hematologic malignancies, they are a significant complication among BMT recipients. Like other herpes viruses, CMV remains latent in tissues after recovery from initial infection. Up to 80% of seropositive patients undergoing BMT reactivate latent infection and approximately 30% of seronegative recipients with seropositive donors acquire infection. The most common forms of infection in cancer patients are pneumonia and gastroenteritis, but other infections include esophagitis, myocarditis, hepatitis, encephalitis, and retinitis. Prior to the use of prophylaxis, most CMV infections occurred by day 60 after transplantation, but now it is diagnosed more often after day 100.

Early detection of CMV infection is critical to optimal management. The isolation of virus from body fluids or tissues indicates infection but not always symptomatic disease. Although, the shell vial technique provides a rapid culture diagnosis, noncultural methods are usually used for rapid detection of infection. The CMV pp65 antigenemia assay using infected white blood cells or serum is a reliable, rapid, and sensitive test that is cost-effective.^136–138 Real-time PCR for detection of CMV DNA in blood is an alternative that is also rapid and sensitive and is useful for diagnosing active disease and monitoring response to therapy.¹³⁹

The usual therapy for established CMV infection has been ganciclovir.¹⁴⁰ In combination with intravenous immunoglobulin, it has been shown to improve survival in transplant recipients with CMV pneumonia or gastroenteritis. The dose-limiting toxicity of ganciclovir is the development of neutropenia, which can increase the risk of bacterial and fungal superinfections. Resistance to ganciclovir may occur during therapy because of viral mutations. Foscarnet is an acceptable alternative that does not cause neutropenia but is associated with nephrotoxicity. It has also been used in combination with foscarnet. Cidofovir can also be used for treatment, but like foscarnet, causes nephrotoxicity. Unfortunately, the treatment of established infections such as CMV pneumonitis is not very satisfactory. Among patients with leukemia, the mortality rate among treated patients was approximately 60%.¹⁴¹

Primary CMV infection can be prevented in CMV negative BMT recipients by using bone marrow and screened blood products from donors who are CMV negative. Because of the high risk of CMV infection in BMT recipients who are seropositive or whose donors are seropositive it is important to institute measures to prevent CMV disease. Two strategies are currently used to prevent CMV infection in seropositive patients who are at risk for reactivation. One is the prophylactic administration of ganciclovir.¹³⁹ Although effective, prolonged ganciclovir administration often produces neutropenia. There is also evidence that prolonged ganciclovir prophylaxis inhibits the development of CMV-specific T-cell lymphocyte responses and promotes the occurrence of late CMV pneumonia.¹⁴² The other approach involves preemptive therapy for subclinical CMV infection, on the basis of positive CMV antigenemia assays in blood or detection of CMV in bronchoalveolar lavage fluid.^143,144 This strategy has the advantage that it targets patients with subclinical CMV infection. However, a small percentage of patients may present with CMV pneumonia without prior detection of the virus. Foscarnet can be used as an alternative for prophylaxis. Valganciclovir is an oral prodrug of ganciclovir that may prove to be useful for prophylaxis in some high-risk patients.

HHV-6

HHV-6 is being recognized as an important pathogen in organ transplant (including bone marrow) recipients. Serologic reactivation accompanied by specific manifestations, including fever, rash, pneumonitis, hepatitis, myelosuppression, and neurologic dysfunction, have been described in recipients of bone marrow, kidney, and liver transplants. Ganciclovir and foscarnet inhibit viral replication, and therapy with these agents may be useful in patients with severe infections.¹⁴⁵

EBV

Reactivation of EBV may occur after BMT or following chemotherapy with purine analogs such as fludarabine. EBV-transformed cells can cause a mononucleosis syndrome or clonal lymphoid malignancies. EBV infection may be responsible for Richter transformation or development of Hodgkin disease in patients with chronic lymphocytic leukemia.

Community Respiratory Viral Infections

During the last decade, it became apparent that community respiratory viruses can cause significant infection in leukemia patients receiving chemotherapy and in BMT recipients, accounting for approximately 30% of respiratory infections during the “flu” season. Although there are temporal and geographical variations, RSV accounts for approximately 35% to 50%, influenza 20% to 25%, and parainfluenza about 10% to 30% of infections. Rhinoviruses, picornaviruses, and adenoviruses have been detected less frequently. Strict infection control practices must be instituted to prevent the spread of these infections among patients, personnel, and visitors.

Hepatitis Viruses

Hepatitis B virus (HBV) infection is the most common cause of acute liver disease worldwide, and more than 300 million people have chronic infection with HBV.¹⁴⁸ Chronic HBV infection leads to progressive liver disease, cirrhosis, and hepatocellular cancer. Hepatitis C virus (HCV) has been estimated to infect 100 million persons worldwide and 4 million in the United States.¹⁴⁹ Eventually 10% to 15% of these individuals will develop cirrhosis (chronic HCV infection is the leading indication for liver transplantation), and some will develop hepatocellular carcinoma.¹⁵⁰ Recently, an association with HCV and non-Hodgkin lymphoma has been established.¹⁵¹ Many cancer patients develop elevation of transaminase levels indicating the presence of hepatitis, but it is often difficult to determine whether the disease is viral or drug induced. Although the current risk of transmission of HBV and HCV infection by the transfusion of screened blood is negligible, patients with acute leukemia and others who receive multiple transfusions may be at greater risk. The greatest threat to the safety of the blood supply are seronegative donors who donate blood during the infectious window period when they are undergoing seroconversion.¹⁵² However, the majority of HBV and HCV infections occur in individuals who use illegal drugs and/or engage in high-risk sexual behaviors.¹⁵² Drug-induced hepatitis is exceedingly common and a large number of agents commonly used in medicine can inflict liver damage.

Hepatitis can be a serious problem in cancer patients for various reasons. Patients with impaired host defense mechanisms are more likely to develop fulminant infections. The presence of hepatitis may result in substantial delays in the administration of antineoplastic therapy, and may further interfere with nutrition in a group of patients where nutritional status is already impaired. Several reports have focused on the phenomenon of reactivation of quiescent liver disease as a consequence of HBV following immunosuppressive or cytotoxic therapy.^153–155 The clinical picture is that of fulminant hepatic failure and some patients have required liver transplantation as a consequence. This syndrome has also been reported after withdrawal of low-dose methotrexate therapy, which has not been clearly established to be immunosuppressive.

Interferon-alpha (INF-α) is currently the only approved treatment for HBV infection.¹⁵⁶ Recent evidence indicates that the oral nucleoside analog lamivudine produces substantial histologic improvement in many patients with chronic hepatitis.¹⁵⁷ Long-term therapy with this drug may result in the emergence of resistant mutants. The combination of pegylated INF-α plus ribavirin produces sustained virologic responses in hepatitis C; approximately 50% in genotype 1 infections and 80% in other genotype infections.¹⁵⁸ Preexposure vaccination of persons at risk using recombinant hepatitis B vaccines affords protection against hepatitis B infection. Postexposure prophylaxis includes the administration of hepatitis B vaccine and hepatitis B immunoglobulin. Measures for preventing hepatitis C need to be developed.

Progressive Multifocal Leukoencephalopathy

Progressive multifocal leukoencephalopathy is a demyelinating disease of the brain caused by the JC virus that occurs infrequently among patients with chronic lymphocytic leukemia and Hodgkin disease. The disease results from activation of latent infection. Symptoms include visual disturbances, speech defects and mental deterioration leading to dementia and coma. The mortality rate is 80% at 1 year. Arabinosyl cytosine may cause transient improvement.