Skin lesions are common in cancer patients, and the appearance of these lesions may permit the diagnosis of systemic bacterial or fungal infection. While cellulitis caused by skin organisms such as Streptococcus or Staphylococcus is common, neutropenic patients—i.e., those with <500 functional polymorphonuclear leukocytes (PMNs)/μL—and patients with impaired blood or lymphatic drainage may develop infections with unusual organisms. Innocent-looking macules or papules may be the first sign of bacterial or fungal sepsis in immunocompromised patients (Fig. 30-1). In the neutropenic host, a macule progresses rapidly to ecthyma gangrenosum (see Fig. 25e-35), a usually painless, round, necrotic lesion consisting of a central black or gray-black eschar with surrounding erythema. Ecthyma gangrenosum, which is located in nonpressure areas (as distinguished from necrotic lesions associated with lack of circulation), is often associated with Pseudomonas aeruginosa bacteremia, but may be caused by other bacteria.
A. Papules related to Escherichia coli bacteremia in a patient with acute lymphocytic leukemia. B. The same lesions on the following day.
Candidemia is also associated with a variety of skin conditions and commonly presents as a maculopapular rash. Punch biopsy of the skin may be the best method for diagnosis.
Cellulitis, an acute spreading inflammation of the skin, is most often caused by infection with group A Streptococcus or Staphylococcus aureus, virulent organisms normally found on the skin. Although cellulitis tends to be circumscribed in normal hosts, it may spread rapidly in neutropenic patients. A tiny break in the skin may lead to spreading cellulitis, which is characterized by pain and erythema; in the affected patients, signs of infection (e.g., purulence) are often lacking. What might be a furuncle in a normal host may require amputation because of uncontrolled infection in a patient presenting with leukemia. A dramatic response to an infection that might be trivial in a normal host can mark the first sign of leukemia. Fortunately, granulocytopenic patients are likely to be infected with certain types of organisms (Table 30-4); thus the selection of an antibiotic regimen is somewhat easier than it might otherwise be (see “Antibacterial Therapy,” below). It is essential to recognize cellulitis early and to treat it aggressively. Patients who are neutropenic or who have previously received antibiotics for other reasons may develop cellulitis with unusual organisms (e.g., Escherichia coli, Pseudomonas, or fungi). Early treatment, even of innocent-looking lesions, is essential to prevent necrosis and loss of tissue. Debridement to prevent spread may sometimes be necessary early in the course of disease, but it can often be performed after chemotherapy, when the PMN count increases.
TABLE 30-4Organisms Likely to Cause Infections in Granulocytopenic Patients ||Download (.pdf) TABLE 30-4 Organisms Likely to Cause Infections in Granulocytopenic Patients
|Gram-Positive Cocci |
|Staphylococcus epidermidis ||Staphylococcus aureus |
|Viridans Streptococcus ||Enterococcus faecalis |
|Streptococcus pneumoniae |
|Gram-Negative Bacilli |
|Escherichia coli ||Serratia spp. |
|Klebsiella spp. ||Acinetobacter spp.a |
|Pseudomonas aeruginosa ||Stenotrophomonas spp. |
|Enterobacter spp. ||Citrobacter spp. |
|Non-aeruginosa Pseudomonas spp.a |
|Gram-Positive Bacilli |
|Diphtheroids ||JK bacillusa |
|Candida spp. ||Mucor/Rhizopus |
|Aspergillus spp. |
Sweet syndrome, or febrile neutrophilic dermatosis, was originally described in women with elevated white blood cell (WBC) counts. The disease is characterized by the presence of leukocytes in the lower dermis, with edema of the papillary body. Ironically, this disease now is usually seen in neutropenic patients with cancer, most often in association with acute myeloid leukemia (AML) but also in association with a variety of other malignancies. Sweet syndrome usually presents as red or bluish-red papules or nodules that may coalesce and form sharply bordered plaques. The edema may suggest vesicles, but on palpation the lesions are solid, and vesicles probably never arise in this disease. The lesions are most common on the face, neck, and arms. On the legs, they may be confused with erythema nodosum. The development of lesions is often accompanied by high fevers and an elevated erythrocyte sedimentation rate. Both the lesions and the temperature elevation respond dramatically to glucocorticoid administration. Treatment begins with high doses of glucocorticoids (prednisone, 60 mg/d) followed by tapered doses over the next 2–3 weeks.
Data indicate that erythema multiforme with mucous membrane involvement is often associated with herpes simplex virus (HSV) infection and is distinct from Stevens-Johnson syndrome, which is associated with drugs and tends to have a more widespread distribution. Because cancer patients are both immunosuppressed (and therefore susceptible to herpes infections) and heavily treated with drugs (and therefore subject to Stevens-Johnson syndrome), both of these conditions are common in this population.
Cytokines, which are used as adjuvants or primary treatments for cancer, can themselves cause characteristic rashes, further complicating the differential diagnosis. This phenomenon is a particular problem in bone marrow transplant recipients, who, in addition to having the usual chemotherapy-, antibiotic-, and cytokine-induced rashes, are plagued by graft-versus-host disease.
Because IV catheters are commonly used in cancer chemotherapy and are prone to cause infection, they pose a major problem in the care of patients with cancer. Some catheter-associated infections can be treated with antibiotics, whereas in others the catheter must be removed (Table 30-5). If the patient has a “tunneled” catheter (which consists of an entrance site, a subcutaneous tunnel, and an exit site), a red streak over the subcutaneous part of the line (the tunnel) is grounds for immediate device removal. Failure to remove catheters under these circumstances may result in extensive cellulitis and tissue necrosis.
TABLE 30-5Approach to Catheter Infections in Immunocompromised Patients ||Download (.pdf) TABLE 30-5 Approach to Catheter Infections in Immunocompromised Patients
|Clinical Presentation or Isolated Pathogen ||Catheter Removal ||Antibiotics ||Comments |
|Evidence of Infection, Negative Blood Cultures |
|Exit-site erythema ||Not necessary if infection responds to treatment ||Usually, begin treatment for gram-positive cocci. ||Coagulase-negative staphylococci are most common. |
|Tunnel-site erythema ||Required ||Treat for gram-positive cocci pending culture results. ||Failure to remove the catheter may lead to necrosis of the involved area requiring skin grafts in the future. |
|Blood Culture–Positive Infections |
|Coagulase-negative staphylococci ||Line removal optimal but may be unnecessary if patient is clinically stable and responds to antibiotics ||Usually, start with vancomycin. Linezolid, quinupristin/dalfopristin, and daptomycin are alternative agents. ||If there are no contraindications to line removal, this course of action is optimal. If the line is removed, antibiotics may not be necessary. |
|Other gram-positive cocci (e.g., Staphylococcus aureus, Enterococcus); gram-positive rods (Bacillus, Corynebacterium spp.) ||Recommended ||Treat with antibiotics to which the organism is sensitive, with duration based on the clinical setting. ||The incidence of metastatic infections following S. aureus infection and the difficulty of treating enterococcal infection make line removal the recommended course of action. In addition, gram-positive rods do not respond readily to antibiotics alone. |
|Gram-negative bacteria ||Recommended ||Use an agent to which the organism is shown to be sensitive. ||Organisms like Stenotrophomonas, Pseudomonas, and Burkholderia are notoriously hard to treat, as are carbapenem-resistant organisms. |
|Fungi ||Recommended ||— ||Fungal infections of catheters are extremely difficult to treat. |
More common than tunnel infections are exit-site infections, often with erythema around the area where the line penetrates the skin. Most authorities recommend treatment (usually with vancomycin) for an exit-site infection caused by coagulase-negative Staphylococcus. Treatment of coagulase-positive staphylococcal infection is associated with a poorer outcome, and it is advisable to remove the catheter if possible. Similarly, most clinicians remove catheters associated with infections due to P. aeruginosa and Candida species, because such infections are difficult to treat and bloodstream infections with these organisms are likely to be deadly. Catheter infections caused by Burkholderia cepacia, Stenotrophomonas species, Agrobacterium species, Acinetobacter baumannii, Pseudomonas species other than aeruginosa, and carbapenem-resistant Enterobacteriaceae are likely to be very difficult to eradicate with antibiotics alone. Similarly, isolation of Bacillus, Corynebacterium, and Mycobacterium species should prompt removal of the catheter.
GASTROINTESTINAL TRACT–SPECIFIC SYNDROMES
Upper gastrointestinal tract disease
The oral cavity is rich in aerobic and anaerobic bacteria that normally live in a commensal relationship with the host. The antimetabolic effects of chemotherapy cause a breakdown of mucosal host defenses, leading to ulceration of the mouth and the potential for invasion by resident bacteria. Mouth ulcerations afflict most patients receiving cytotoxic chemotherapy and have been associated with viridans streptococcal bacteremia. Candida infections of the mouth are very common. Fluconazole is clearly effective in the treatment of both local infections (thrush) and systemic infections (esophagitis) due to Candida albicans. Other azoles (e.g., voriconazole) as well as echinocandins offer similar efficacy as well as activity against the fluconazole-resistant organisms that are associated with chronic fluconazole treatment.
Noma (cancrum oris), commonly seen in malnourished children, is a penetrating disease of the soft and hard tissues of the mouth and adjacent sites, with resulting necrosis and gangrene. It has a counterpart in immunocompromised patients and is thought to be due to invasion of the tissues by Bacteroides, Fusobacterium, and other normal inhabitants of the mouth. Noma is associated with debility, poor oral hygiene, and immunosuppression.
Viruses, particularly HSV, are a prominent cause of morbidity in immunocompromised patients, in whom they are associated with severe mucositis. The use of acyclovir, either prophylactically or therapeutically, is of value.
The differential diagnosis of esophagitis (usually presenting as substernal chest pain upon swallowing) includes herpes simplex and candidiasis, both of which are readily treatable.
Lower gastrointestinal tract disease
Hepatic candidiasis results from seeding of the liver (usually from a gastrointestinal source) in neutropenic patients. It is most common among patients being treated for AML and usually presents symptomatically around the time the neutropenia resolves. The characteristic picture is that of persistent fever unresponsive to antibiotics, abdominal pain and tenderness or nausea, and elevated serum levels of alkaline phosphatase in a patient with hematologic malignancy who has recently recovered from neutropenia. The diagnosis of this disease (which may present in an indolent manner and persist for several months) is based on the finding of yeasts or pseudohyphae in granulomatous lesions. Hepatic ultrasound or CT may reveal bull’s-eye lesions. MRI scans reveal small lesions not visible by other imaging modalities. The pathology (a granulomatous response) and the timing (with resolution of neutropenia and an elevation in granulocyte count) suggest that the host response to Candida is an important component of the manifestations of disease. In many cases, although organisms are visible, cultures of biopsied material may be negative. The designation hepatosplenic candidiasis or hepatic candidiasis is a misnomer because the disease often involves the kidneys and other tissues; the term chronic disseminated candidiasis may be more appropriate. Because of the risk of bleeding with liver biopsy, diagnosis is often based on imaging studies (MRI, CT). Treatment should be directed to the causative agent (usually C. albicans but sometimes Candida tropicalis or other less common Candida species).
Typhlitis (also referred to as necrotizing colitis, neutropenic colitis, necrotizing enteropathy, ileocecal syndrome, and cecitis) is a clinical syndrome of fever and right-lower-quadrant (or generalized abdominal) tenderness in an immunosuppressed host. This syndrome is classically seen in neutropenic patients after chemotherapy with cytotoxic drugs. It may be more common among children than among adults and appears to be much more common among patients with AML or ALL than among those with other types of cancer. Physical examination reveals right-lower-quadrant tenderness, with or without rebound tenderness. Associated diarrhea (often bloody) is common, and the diagnosis can be confirmed by the finding of a thickened cecal wall on CT, MRI, or ultrasonography. Plain films may reveal a right-lower-quadrant mass, but CT with contrast or MRI is a much more sensitive means of diagnosis. Although surgery is sometimes attempted to avoid perforation from ischemia, most cases resolve with medical therapy alone. The disease is sometimes associated with positive blood cultures (which usually yield aerobic gram-negative bacilli), and therapy is recommended for a broad spectrum of bacteria (particularly gram-negative bacilli, which are likely to be found in the bowel flora). Surgery is indicated in the case of perforation.
Clostridium difficile–Induced diarrhea
Patients with cancer are predisposed to the development of C. difficile diarrhea as a consequence of chemotherapy alone. Thus, they may test positive for C. difficile even without receiving antibiotics. Obviously, such patients are also subject to C. difficile–induced diarrhea as a result of antibiotic pressure. C. difficile should always be considered as a possible cause of diarrhea in cancer patients who have received either chemotherapy or antibiotics.
CENTRAL NERVOUS SYSTEM–SPECIFIC SYNDROMES
The presentation of meningitis in patients with lymphoma or CLL and in patients receiving chemotherapy (particularly with glucocorticoids) for solid tumors suggests a diagnosis of cryptococcal or listerial infection. As noted previously, splenectomized patients are susceptible to rapid, overwhelming infection with encapsulated bacteria (including S. pneumoniae, H. influenzae, and N. meningitidis). Similarly, patients who are antibody-deficient (e.g., those with CLL, those who have received intensive chemotherapy, or those who have undergone bone marrow transplantation) are likely to have infections caused by these bacteria. Other cancer patients, however, because of their defective cellular immunity, are likely to be infected with other pathogens (Table 30-3). Central nervous system (CNS) tuberculosis should be considered, especially in patients from countries where tuberculosis is highly prevalent in the population.
The spectrum of disease resulting from viral encephalitis is expanded in immunocompromised patients. A predisposition to infections with intracellular organisms similar to those encountered in patients with AIDS is seen in cancer patients receiving (1) high-dose cytotoxic chemotherapy, (2) chemotherapy affecting T cell function (e.g., fludarabine), or (3) antibodies that eliminate T cells (e.g., anti-CD3, alemtuzumab, anti-CD52) or cytokine activity (anti–tumor necrosis factor agents or interleukin 1 receptor antagonists). Infection with varicella-zoster virus (VZV) has been associated with encephalitis that may be caused by VZV-related vasculitis. Chronic viral infections may also be associated with dementia and encephalitic presentations. A diagnosis of progressive multifocal leukoencephalopathy should be considered when a patient who has received chemotherapy (rituximab in particular) presents with dementia (Table 30-6). Other abnormalities of the CNS that may be confused with infection include normal-pressure hydrocephalus and vasculitis resulting from CNS irradiation. It may be possible to differentiate these conditions by MRI.
TABLE 30-6Differential Diagnosis of Central Nervous System Infections in Patients With Cancer ||Download (.pdf) TABLE 30-6 Differential Diagnosis of Central Nervous System Infections in Patients With Cancer
| ||Underlying Predisposition |
|Findings on CT or MRI ||Prolonged Neutropenia ||Defects in Cellular Immunitya |
|Mass lesions ||Aspergillus, Nocardia, or Cryptococcus brain abscess ||Toxoplasmosis, Epstein-Barr virus lymphoma (rare) |
|Diffuse encephalitis ||Progressive multifocal leukoencephalopathy (JC virus) ||Infection with varicella-zoster virus, cytomegalovirus, herpes simplex virus, human herpesvirus type 6, JC virus, Listeria |
Mass lesions of the brain most often present as headache with or without fever or neurologic abnormalities. Infections associated with mass lesions may be caused by bacteria (particularly Nocardia), fungi (particularly Cryptococcus or Aspergillus), or parasites (Toxoplasma). Epstein-Barr virus (EBV)–associated lymphoma may also present as single—or sometimes multiple—mass lesions of the brain. A biopsy may be required for a definitive diagnosis.
Pneumonia in immunocompromised patients may be difficult to diagnose because conventional methods of diagnosis depend on the presence of neutrophils. Bacterial pneumonia in neutropenic patients may present without purulent sputum—or, in fact, without any sputum at all—and may not produce physical findings suggestive of chest consolidation (rales or egophony).
In granulocytopenic patients with persistent or recurrent fever, the chest x-ray pattern may help to localize an infection and thus to determine which investigative tests and procedures should be undertaken and which therapeutic options should be considered (Table 30-7). In this setting, a simple chest x-ray is a screening tool; because the impaired host response results in less evidence of consolidation or infiltration, high-resolution CT is recommended for the diagnosis of pulmonary infections. The difficulties encountered in the management of pulmonary infiltrates relate in part to the difficulties of performing diagnostic procedures on the patients involved. When platelet counts can be increased to adequate levels by transfusion, microscopic and microbiologic evaluation of the fluid obtained by endoscopic bronchial lavage is often diagnostic. Lavage fluid should be cultured for Mycoplasma, Chlamydia, Legionella, Nocardia, more common bacterial pathogens, fungi, and viruses. In addition, the possibility of Pneumocystis pneumonia should be considered, especially in patients with ALL or lymphoma who have not received prophylactic trimethoprim-sulfamethoxazole (TMP-SMX). The characteristics of the infiltrate may be helpful in decisions about further diagnostic and therapeutic maneuvers. Nodular infiltrates suggest fungal pneumonia (e.g., that caused by Aspergillus or Mucor). Such lesions may best be approached by visualized biopsy procedures. It is worth noting that while bacterial pneumonias classically present as lobar infiltrates in normal hosts, bacterial pneumonias in granulocytopenic hosts present with a paucity of signs, symptoms, or radiographic abnormalities; thus, the diagnosis is difficult.
TABLE 30-7Differential Diagnosis of Chest Infiltrates in Immunocompromised Patients ||Download (.pdf) TABLE 30-7 Differential Diagnosis of Chest Infiltrates in Immunocompromised Patients
| ||Cause of Pneumonia |
|Infiltrate ||Infectious ||Noninfectious |
|Localized ||Bacteria (including Legionella, mycobacteria) ||Local hemorrhage or embolism, tumor |
|Nodular ||Fungi (e.g., Aspergillus or Mucor), Nocardia ||Recurrent tumor |
|Diffuse ||Viruses (especially cytomegalovirus), Chlamydia, Pneumocystis, Toxoplasma gondii, mycobacteria ||Congestive heart failure, radiation pneumonitis, drug-induced lung injury, lymphangitic spread of cancer |
Aspergillus species can colonize the skin and respiratory tract or cause fatal systemic illness. Although this fungus may cause aspergillomas in a previously existing cavity or may produce allergic bronchopulmonary disease in some patients, the major problem posed by this genus in neutropenic patients is invasive disease, primarily due to Aspergillus fumigatus or Aspergillus flavus. The organisms enter the host following colonization of the respiratory tract, with subsequent invasion of blood vessels. The disease is likely to present as a thrombotic or embolic event because of this ability of the fungi to invade blood vessels. The risk of infection with Aspergillus correlates directly with the duration of neutropenia. In prolonged neutropenia, positive surveillance cultures for nasopharyngeal colonization with Aspergillus may predict the development of disease.
Patients with Aspergillus infection often present with pleuritic chest pain and fever, which are sometimes accompanied by cough. Hemoptysis may be an ominous sign. Chest x-rays may reveal new focal infiltrates or nodules. Chest CT may reveal a characteristic halo consisting of a mass-like infiltrate surrounded by an area of low attenuation. The presence of a “crescent sign” on chest x-ray or chest CT, in which the mass progresses to central cavitation, is characteristic of invasive Aspergillus infection but may develop as the lesions are resolving.
In addition to causing pulmonary disease, Aspergillus may invade through the nose or palate, with deep sinus penetration. The appearance of a discolored area in the nasal passages or on the hard palate should prompt a search for invasive Aspergillus. This situation is likely to require surgical debridement. Catheter infections with Aspergillus usually require both removal of the catheter and antifungal therapy.
Diffuse interstitial infiltrates suggest viral, parasitic, or Pneumocystis pneumonia. If the patient has a diffuse interstitial pattern on chest x-ray, it may be reasonable, while considering invasive diagnostic procedures, to institute empirical treatment for Pneumocystis with TMP-SMX and for Chlamydia, Mycoplasma, and Legionella with a quinolone or azithromycin. Noninvasive procedures, such as staining of induced sputum smears for Pneumocystis, serum cryptococcal antigen tests, and urine testing for Legionella antigen, may be helpful. Serum galactomannan and β-d-glucan tests may be of value in diagnosing Aspergillus infection, but their utility is limited by their lack of sensitivity and specificity. The presence of an elevated level of β-d-glucan in the serum of a patient being treated for cancer who is not receiving prophylaxis against Pneumocystis suggests the diagnosis of Pneumocystis pneumonia. Infections with viruses that cause only upper respiratory symptoms in immunocompetent hosts, such as respiratory syncytial virus (RSV), influenza viruses, and parainfluenza viruses, may be associated with fatal pneumonitis in immunocompromised hosts. CMV reactivation occurs in cancer patients receiving chemotherapy, but CMV pneumonia is most common among HSCT recipients. Polymerase chain reaction testing now allows rapid diagnosis of viral pneumonia, which can lead to treatment in some cases (e.g., influenza). Multiplex studies that can detect a wide array of viruses in the lung and upper respiratory tract are now available and will lead to specific diagnoses of viral pneumonias.
Bleomycin is the most common cause of chemotherapy-induced lung disease. Other causes include alkylating agents (such as cyclophosphamide, chlorambucil, and melphalan), nitrosoureas (carmustine [BCNU], lomustine [CCNU], and methyl-CCNU), busulfan, procarbazine, methotrexate, and hydroxyurea. Both infectious and noninfectious (drug- and/or radiation-induced) pneumonitis can cause fever and abnormalities on chest x-ray; thus, the differential diagnosis of an infiltrate in a patient receiving chemotherapy encompasses a broad range of conditions (Table 30-7). The treatment of radiation pneumonitis (which may respond dramatically to glucocorticoids) or drug-induced pneumonitis is different from that of infectious pneumonia, and a biopsy may be important in the diagnosis. Unfortunately, no definitive diagnosis can be made in ~30% of cases, even after bronchoscopy.
Open-lung biopsy is the gold standard of diagnostic techniques. Biopsy via a visualized thoracostomy can replace an open procedure in many cases. When a biopsy cannot be performed, empirical treatment can be undertaken; a quinolone or an erythromycin derivative (azithromycin) and TMP-SMX are used in the case of diffuse infiltrates, and an antifungal agent is administered in the case of nodular infiltrates. The risks should be weighed carefully in these cases. If inappropriate drugs are administered, empirical treatment may prove toxic or ineffective; either of these outcomes may be riskier than biopsy.
Patients with Hodgkin’s disease are prone to persistent infections by Salmonella, sometimes (and particularly often in elderly patients) affecting a vascular site. The use of IV catheters deliberately lodged in the right atrium is associated with a high incidence of bacterial endocarditis, presumably related to valve damage followed by bacteremia. Nonbacterial thrombotic endocarditis (marantic endocarditis) has been described in association with a variety of malignancies (most often solid tumors) and may follow bone marrow transplantation as well. The presentation of an embolic event with a new cardiac murmur suggests this diagnosis. Blood cultures are negative in this disease of unknown pathogenesis.
Infections of the endocrine system have been described in immunocompromised patients. Candida infection of the thyroid may be difficult to diagnose during the neutropenic period. It can be defined by indium-labeled WBC scans or gallium scans after neutrophil counts increase. CMV infection can cause adrenalitis with or without resulting adrenal insufficiency. The presentation of a sudden endocrine anomaly in an immunocompromised patient can be a sign of infection in the involved end organ.
Infection that is a consequence of vascular compromise, resulting in gangrene, can occur when a tumor restricts the blood supply to muscles, bones, or joints. The process of diagnosis and treatment of such infection is similar to that in normal hosts, with the following caveats:
In terms of diagnosis, a lack of physical findings resulting from a lack of granulocytes in the granulocytopenic patient should make the clinician more aggressive in obtaining tissue rather than more willing to rely on physical signs.
In terms of therapy, aggressive debridement of infected tissues may be required. However, it is usually difficult to operate on patients who have recently received chemotherapy, both because of a lack of platelets (which results in bleeding complications) and because of a lack of WBCs (which may lead to secondary infection). A blood culture positive for Clostridium perfringens—an organism commonly associated with gas gangrene—can have a number of meanings. Clostridium septicum bacteremia is associated with the presence of an underlying malignancy. Bloodstream infections with intestinal organisms such as Streptococcus bovis biotype 1 and C. perfringens may arise spontaneously from lower gastrointestinal lesions (tumor or polyps); alternatively, these lesions may be harbingers of invasive disease. The clinical setting must be considered in order to define the appropriate treatment for each case.
RENAL AND URETERAL INFECTIONS
Infections of the urinary tract are common among patients whose ureteral excretion is compromised (Table 30-1). Candida, which has a predilection for the kidney, can invade either from the bloodstream or in a retrograde manner (via the ureters or bladder) in immunocompromised patients. The presence of “fungus balls” or persistent candiduria suggests invasive disease. Persistent funguria (with Aspergillus as well as Candida) should prompt a search for a nidus of infection in the kidney.
Certain viruses are typically seen only in immunosuppressed patients. BK virus (polyomavirus hominis 1) has been documented in the urine of bone marrow transplant recipients and, like adenovirus, may be associated with hemorrhagic cystitis.