Production of a low molecular weight eosinophil polymorphonuclear leukocyte chemotactic factor by anaplastic squamous cell carcinomas of human lung.

A peptide of approximately 300-400 daltons exhibiting in vitro chemotactic activity for human polymorphonuclear (PMN) leukocytes, with a preference for the eosinophil series, was isolated from extracts of anaplastic lung carcinomas of the large squamous cell type obtained from three patients with marked peripheral blood hypereosinophilia and eosinophilic infiltration of the tumors and surrounding normal pulmonary tissues. This chemotactic factor was termed ECF-LSC (eosinophil chemotactic factor of lung squamous cell carcinoma). ECF-LSC appeared in the urine of two of the patients in increasing quantities late in the course of their disease and was also elaborated by long-term cultures of dispersed tumor cells from the same two patients. Three anaplastic large cell bronchogenic carcinomas which were not associated with tumor tissue or peripheral blood eosinophilia, a bronchogenic adenocarcinoma from a patient with only peripheral eosinophilia, and a renal cell carcinoma metastatic to the lungs and associated with transient pleural tissue and fluid eosinophilia were all devoid of ECF-LSC. ECF-LSC from tumor tissue extracts, urine, and tumor cell culture medium was comparable to the mast cell-associated tetrapeptides of the eosinophil chemotactic factor of anaphylaxis (ECF-A) in size, but eluted from Dowex-1 at pH 5.0-3.5 in contrast to the more acidic ECF-A tetrapeptides which eluted at pH 3.2-2.2 ECF-LSC, like the tetrapeptides of ECF-A, had a secondary chemotactic activity for neutrophil PMN leukocytes, but not mononuclear leukocytes, and deactivated both eosinophil and neutrophil PMN leukocytes so that they would not respond to a subsequent in vitro chemotactic stimulus. Eosinophils from the two patients with urinary excretion of ECF-LSC and the highest concentrations in tumor extracts were hyporesponsive in vitro to homologous and heterologous chemotactic stimuli, suggesting that ECF-LSC had deactivated the eosinophils in vivo.

A murine model of myocardial microvascular thrombosis.

Disorders of hemostasis lead to vascular pathology. Endothelium-derived gene products play a critical role in the formation and degradation of fibrin. We sought to characterize the importance of these locally produced factors in the formation of fibrin in the cardiac macrovasculature and microvasculature. This study used mice with modifications of the thrombomodulin (TM) gene, the tissue-type plasminogen activator (tPA) gene, and the urokinase-type plasminogen activator (uPA) gene. The results revealed that tPA played the most important role in local regulation of fibrin deposition in the heart, with lesser contributions by TM and uPA (least significant). Moreover, a synergistic relationship in fibrin formation existed in mice with concomitant modifications of tPA and TM, resulting in myocardial necrosis and depressed cardiac function. The data were fit to a statistical model that may offer a foundation for examination of hemostasis-regulating gene interactions.

The circadian rhythm in photosynthesis in Acetabularia in the presence of actinomycin D, puromycin, and chloramphenicol.

Anucleate Acetabularia crenulata shows a circadian rhythm in photosynthesis. In this study, an oxygen electrode was employed to measure this photosynthetic rhythm in the presence and absence of the inhibitors, actinomycin D, chloramphenicol, and puromycin. High concentrations of the inhibitors were used: actinomycin D, 20-40 micrograms ml-1; puromycin, 30 and 100 micrograms ml-1; and chloramphenicol, 250 micrograms ml-1. The effectiveness of these inhibitors on protein synthesis was also measured under the same conditions used for the determination of rhythmicity. In spite of large effects of all three inhibitors on the incorporation of 14C leucine, no effect on the period or the phase of the photosynthetic rhythm was observed. The higher concentration of puromycin and chloramphenicol produced toxic effects which were expressed as a reduction in the amount of photosynthesis, but rhythmicity was still apparent. After 3 or 4 days' exposure to actinomycin, Acetabularia became resistant to its effect. Recovery was also observed in the ability to incorporate leucine. The implications of these results for theories of the basic oscillator responsible for circadian rhythmicity are discussed.

Systemic salmonellosis in patients with disseminated histoplasmosis. Case for 'macrophage blockade' caused by Histoplasma capsulatum.

Five patients are described with disseminated histoplasmosis and systemic salmonellosis. Four of these patients were also immunocompromised because of the acquired immunodeficiency syndrome in two patients and renal transplantation in another two patients. Histologic studies in two patients showed histiocytes that were heavily laden with Histoplasma capsulatum yeast-phase organisms. We postulate that diffuse parasitization of the reticuloendothelial system (RES) by Histoplasma organisms may cause "RES blockade," which then predisposes to systemic salmonellosis, as reported in certain other infections and in sickle cell anemia.

Dermatologic manifestations of infections in immunocompromised patients.

Thirty-one immunocompromised patients (22 renal allograft recipients, 5 patients receiving chronic corticosteroid therapy, and 4 patients undergoing chemotherapy for acute leukemia) with significant dermatologic infection, excluding typical cellulitis and herpesvirus infections, were retrospectively identified over a 12-year period. Of these 31 patients, 15 (48%) had infection restricted to their skin, 6 (19%) appeared to have primary cutaneous infection that spread hematogenously to other parts of the body, 2 (6%) had infections of adjoining nasal tissue that spread to contiguous skin, and 8 (26%) appeared to have disseminated systemic infection that spread to the skin. In six of the eight patients with apparent secondary skin involvement, the development of the cutaneous lesion was the first clinical indication of disseminated infection. Eleven immunocompromised patients (35%) with bacterial infection of the skin or subcutaneous tissue were identified. These patients could be divided into three categories: leukemic patients with bacteremic gram-negative infection metastasizing to the skin (3 cases), renal transplant recipients with recurrent staphylococcal infection on and around the elbow ("transplant elbow") or streptococcal sepsis from a site of cellulitis (5 cases), and immunocompromised patients with opportunistic bacterial infection due to Nocardia asteroides or atypical mycobacteria (3 cases). Seventeen immunocompromised patients (55%) with fungal infection of the skin or subcutaneous tissue were identified. These included 12 patients with opportunistic fungal infection (Cryptococcus neoformans, 4 cases; Aspergillus species, 3 cases; Paecilomyces, 2 cases; Rhizopus species, 2 cases; and Candida tropicalis, 1 case) and 5 patients with extensive, confluent cutaneous dermatophyte infections. One patient with protothecosis and two patients with extensive papillomavirus infection were identified. Of these latter two cases, one had his immunosuppression discontinued, with clearing of his extensive warts; the other had confluent warts of the face and neck that subsequently underwent malignant degeneration to squamous cell carcinoma while chronic immunosuppressive therapy was continued.(ABSTRACT TRUNCATED AT 400 WORDS)

Neurologic complications of bacterial endocarditis.

(1) Neurologic complications remain a significant problem in bacterial endocarditis. Of 218 patients with endocarditis, 84 (39%) had a neurologic complication and 58% of these 84 patients died. In contrast, the mortality rate was only 20% among those endocarditis patients without neurologic complications. (2) Of the neurologic complications, cerebral embolism is the most frequent and important. An embolic stroke occurred in 37 (17%) of our patients, with 30 of these patients dying. Emboli are important not only in terms of the direct morbidity and mortality they cause via cerebral infarction, but also because of their role in the causation of mycotic aneurysms, brain abscesses, and abnormal CSF formulae. (3) Cerebral emboli are particularly common in patients with mitral valve infection, and in patients with infection due to virulent organisms, particularly S. aureus and enteric gram-negative bacilli. (4) Mycotic aneurysms occur more frequently in the course of acute endocarditis rather than late in the course of subacute disease. Management of angiographically demonstrated mycotic aneurysms is dependent upon the presence or absence of hemorrhage, the anatomic location of the aneurysm, and the clinical course of the patient. Healing of mycotic aneurysms can occur during the course of effective antimicrobial therapy, thus obviating the need for neurosurgical intervention in all such patients. (5) Macroscopic brain abscess is a rare complication of bacterial endocarditis. Miliary microscopic abscesses are more common than larger abscesses, particularly in patients with acute disease and miliary infection in other organs of the body. (6) Focal seizures occur most commonly in endocarditis patients with acute embolic disease; generalized seizures are of diverse etiologies, with metabolic factors being most important. Penicillin neurotoxicity should be considered in patients with impaired renal function who are receiving high dose penicillin. (7) With the exception of hemorrhagic complications, lumbar puncture results tend to reflect the nature of the infecting organism rather than the nature of the neurologic complication. Endocarditis due to virulent organisms such as S. aureus is usually associated with a purulent CSF formula while nonvirulent organisms, such as viridans streptococci, susually have aseptic or normal CSF formulae.

Regional pharmacokinetics of orally administered PET tracers.

Positron emission tomography (PET) is currently the most useful imaging technique for noninvasive measurement of drug pharmacokinetics regionally in a variety of tissues. Over the past decade, PET measurements have provided many critical insights about the tissue distribution of several classes of drugs; neuroleptics, antimicrobials, antineoplastics, etc. PET measurements can be performed after any route of drug administration, intravenous, inhalation or oral, however, intravenously administered drugs have been the most extensively evaluated. Studies of orally administered drugs are clearly of great interest; however, formulation issues have precluded widespread applications in these areas. In this report, we discuss the unique problems associated with studying orally administered drugs and review the results of recent studies performed in our laboratory.

Clinical, microbiologic and therapeutic aspects of purulent pericarditis.

Twenty-six patients with purulent pericarditis were seen at the Massachusetts General Hospital between 1960 and 1974. The diagnosis was made in 18 of them during life, but only 6 survived, with an over-all mortality rate of 77 per cent. In eight patients, purulent pericarditis developed in the early postoperative period after thoracic surgery. In seven, purulent pericarditis was the result of contiguous spread of infection from a pleural, mediastinal or pulmonary focus in nonsurgical patients. In five patients, it was the result of direct spread to the pericardium from an intracardiac infection. In the remaining six patients, purulent pericarditis developed as the result of a systemic bactermia. Immunosuppressive therapy, extensive thermal burns, lymphoproliferative disease and other systemic processes affecting host resistance were present in at least half the patients. Staphylococcus aureus was the etiologic agent in the largest number of patients (8 of 26 in this report). However, in contrast to previous studies, in a significant number of the patients (five), purulent pericarditis was the result of fungal infection (in three patients subjected to thoracic surgery and in two immunosuppressed patients). This report confirms that purulent pericarditis is an acute disease with a fulminant course. The diagnosis is easily missed since classic signs of pericarditis (including chest pain, friction rub and diagnostic electrocardiographic abnormalities) may be absent. The echocardiogram shows considerable promise in allowing earlier diagnosis of the pericardial effusion which accompanies purulent pericarditis. Optimal therapy consists of prolonged antibiotic therapy and aggressive drainage of the pericardium. In this series, there were 6 survivors among the 11 patients (55 per cent) who received appropriate therapy.

New approaches to the treatment of urinary tract infection.

The term urinary tract infection encompasses a broad range of clinical entities, each with its own pathology and each requiring its own form of treatment. There are at least four different modes in which antimicrobial therapy may be prescribed for urinary tract infection: single-dose therapy aimed at patients with superficial mucosal infection; a conventional seven- to 14-day course of therapy; a prolonged four- to six-week course of therapy for patients with deep tissue infection; and low-dose prophylactic therapy. Increasingly, the response to single-dose therapy is being utilized to delineate the mode of therapy needed by a patient. Patients with underlying renal disease and/or structural abnormalities of the urinary tract are prone to the development of recurrent urinary tract infection, frequently with bacteria resistant to antimicrobial agents conventionally employed to treat the infection. There has been a steady increase, even among otherwise normal persons with urinary tract infection, in the level of antimicrobial resistance exhibited by bacterial uropathogens to the drugs commonly used to treat these infections. The quinolones in general, and ciprofloxacin in particular, appear to be very promising for the treatment of urinary tract infection. It will be important to evaluate the performance of this drug in the four different therapeutic modes and in patients with renal dysfunction or anatomic abnormalities of the urinary tract.

Infection in the renal transplant recipient.

The incidence of infection in the renal transplant patient is directly related to the net immunosuppressive effect achieved and the duration of time over which this therapy is administered. A second major factor in the causation of infections in this population is the nosocomial hazards to which these patients are exposed, ranging from invasive instrumentation to environmental contamination with Aspergillus species, Legionella pneumophila, Pseudomonas aeruginosa and other microbial pathogens. Careful surveillance is necessary to identify and eliminate such nosocomial sources of infection. The major types of infection observed can be categorized according to the time period post-transplant in which they occur: postsurgical bacterial infection in the first month after transplantation; opportunistic infection, with cytomegalovirus playing a major role, and transplant pyelonephritis in the period one to four months post-transplant; and a mixture of conventional and opportunistic infections in the last post-transplant period. Conventional infection in this late period occurs primarily in patients with good renal function who are receiving minimal immunosuppressive therapy; opportunistic infection occurs primarily in patients with poor renal function who are receiving higher levels of immunosuppression.

Bacteremic hemophilus influenzae type B cellulitis in the adult.

Described herein are three patients over the age of 50 years who had cellulitis of the neck and the upper portion of the chest, associated with Hemophilus influenzae type B bacteremia and respiratory tract infection--particularly that of the upper airway. Only one of the patients with cellulitis had the classic bluish-purple hue commonly seen in children affected with this syndrome. In the other two, the H. influenzae type B cellulitis could not be distinguished clinically from the more common group A streptococcal or staphylococcal cellulitis. Since the antibiotics employed in treating patients with infection due to the latter two organisms differ significantly from those used to treat patients with H. influenzae type B infection, the possibility of disease due to H. influenzae type B must be considered in any adult or child in whom cellulitis of the neck, chest and possibly face is associated with a respiratory tract infection, especially of the upper airway.

Pharmacokinetics of fleroxacin as studied by positron emission tomography and [18F]fleroxacin.

A new method of tracing the disposition of fleroxacin was tested in infected and noninfected animals in an effort to develop a technique that might be applicable in humans. [18F]fleroxacin was synthesized and shown to be identical physically, chemically, and in its antimicrobial activity to the commercially produced product. Tracer amounts of [18F]fleroxacin were coinjected with a pharmacologic dose of unlabeled drug (10 mg/kg) into normal mice, rats with focal thigh infection due to Escherichia coli, and normal and infected rabbits. The rats and mice were killed at fixed time intervals after injection, and the concentration of drug was determined by radioactive counting in a well-type counter; the rabbits were studied both by this method and by positron emission tomographic (PET) imaging. These studies validated the reliability of the new approach and suggested that it could be applied safely to humans. In all three animal species studied, delivery of [18F]fleroxacin to most tissues was rapid, with the notable exception of the brain. Accumulation of drug in infected thigh muscle was similar to that in normal muscle. The concentrations of drug reached in various tissues suggest that fleroxacin will be particularly useful in the treatment of gastrointestinal, urinary tract, hepatobiliary, and skeletal infections and that it shows promise for the treatment of lung and soft tissue infection. The minimal concentrations of drug delivered to the brain should decrease the occurrence of central nervous system toxicity with this particular fluoroquinolone.

The independent role of cytomegalovirus as a risk factor for invasive fungal disease in orthotopic liver transplant recipients. Boston Center for Liver Transplantation CMVIG-Study Group. Cytogam, MedImmune, Inc. Gaithersburg, Maryland.

PURPOSE: To assess impact of cytomegalovirus (CMV) donor-recipient serostatus, infection, or disease on development of invasive fungal infection in orthotopic liver transplant recipients. PATIENTS AND METHODS: An analysis of prospectively collected data in 146 liver transplant recipients (intention to treat cohort) from 4 tertiary care, university-affiliated transplant centers in Boston (Boston Center for Liver Transplantation). Patients were observed for 1 year after transplantation for the development of CMV infection, CMV disease, CMV pneumonia, as well as for the development of opportunistic fungal infections, graft survival, and mortality. Weekly cultures were taken of urine and throat and every other week of buffy coat for CMV for 2 months, then monthly for 6 months, at 1 year, and at the time of any clinical illness. Pre- and posttransplant variables including CMV-serostatus of donor and recipient, fungal isolation from sterile body sites, fungemia, bacteremia, antibiotic use, immunosuppression, treatment for rejection, and volumes of blood products were measured. RESULTS: Survival analysis demonstrated that 36% of patients with CMV disease developed invasive fungal disease within the first year post-transplant compared with 8% of those without CMV disease (P < 0.0001). One-year mortality in patients with invasive fungal disease was 15 of 22 (68%) compared with 23 of 124 (19%) in those without invasive fungal disease (P < 0.001). A multivariable, time-dependent analysis demonstrated that being a CMV-seronegative recipient of a CMV-seropositive donor organ (P < 0.001), having bacteremia (P = 0.001), UNOS (United Network for Organ Sharing) status 4 (need for life support measures) at transplant (P = 0.002), and volume of platelets (P = 0.002) were independently associated with invasive fungal disease. Restriction of cases of invasive fungal disease to those that occurred more than 2 weeks after transplant demonstrated an association with CMV disease (P = 0.003), bacteremia (P = 0.003), need for life support (P = 0.03), and volume of blood products transfused (P = 0.02). CONCLUSION: CMV disease or being a CMV-seronegative recipient of a CMV-seropositive donor organ is an important predictor for invasive fungal disease following orthotopic liver transplantation.

Hepatitis C virus and organ transplantation.

Hepatitis C virus (HCV) is both the leading cause of cirrhosis and hepatic failure leading to liver transplantation and a cause of chronic hepatitis in approximately 10% of all transplant recipients. Beginning 5-10 years or more posttransplant, HCV causes progressive liver disease in a significant fraction of infected individuals and contributes to an increased incidence of opportunistic infection and hepatocellular carcinoma. The existence of multiple genotypes of HCV with differing biologic behaviors and the generation of antigenic diversity of the virus (quasispecies) during the course of infection, limit the capacity of the immune system to generate protective immunity. Antiviral therapy with interferon-alpha is effective in only a minority of transplant patients, and since allografts from HCV infected donors are quite efficient in transmitting the virus, great attention is paid to the appropriate use of organs from HCV-positive donors. At present, these organs should be particularly targeted for patients in emergent need of lifesaving heart, liver, or lung transplants. Issues requiring further investigation include the impact of viral superinfection on HCV-infected recipients of organs from HCV-infected donors and the use of such organs in seronegative patients who are older, diabetic, or highly sensitized, for whom quality of life issues may outweigh the long-term impact of HCV infection.

BK virus in solid organ transplant recipients: an emerging syndrome.

BK virus is a human polyomavirus associated with a range of clinical presentations from asymptomatic viruria with pyuria to ureteral ulceration with ureteral stenosis in renal transplant patients or hemorrhagic cystitis in bone marrow transplant recipients. Infection of renal allografts has been associated with diminished graft function in some individuals. Fortunately, however, the majority of patients with BK virus infections are asymptomatic. The type, duration, and intensity of immunosuppression are major contributors to susceptibility to the activation of BK virus infection. Histopathology is required for the demonstration of renal parenchymal involvement; urine cytology and viral polymerase chain reaction methods are useful adjunctive diagnostic tools. Current, treatment of immunosuppressed patients with polyomavirus viruria is largely supportive and directed toward minimizing immunosuppression. Improved diagnostic tools and antiviral therapies are needed for polyomavirus infections.

Primary cytomegalovirus infection following cardiac transplantation in a murine model.

A murine cytomegalovirus (CMV) model was utilized to determine the source of primary CMV infection in cardiac transplantation. Hearts were taken from actively or latently infected BALB/C mice and then transplanted as primary, heterotopic isografts into CMV-negative BALB/C recipients. The transplantation of hearts from acutely infected donors into nonimmunosuppressed recipients resulted in asymptomatic primary infection as manifested by detectable virus in both donor and recipient hearts, liver, spleen, and salivary glands and by the development of anti-CMV antibody. When hearts from latently infected animals were transplanted into nonimmunosuppressed recipients, a transient primary infection occurred that was manifested by detectable virus in the spleen and salivary glands and the appearance of anti-CMV antibody. When recipient animals were immunosuppressed with cortisone acetate (125 mg/kg/day i.p.) and rabbit antimouse thymocyte globulin (0.2 ml i.p. twice weekly), after transplantation of hearts from acutely and latently infected mice, lethal primary CMV infection developed. High titers of virus were recovered in all organs tested in these animals, including both the donor and recipient hearts. We conclude that the heart is infected during the course of primary murine CMV infection, and that hearts from latently infected animals are a source of serious primary infection in immunosuppressed recipients. This experimental system should be a useful model relevant to human cardiac transplantation.

Salvage therapy with voriconazole for invasive fungal infections in patients failing or intolerant to standard antifungal therapy.

BACKGROUND: Invasive fungal infections (IFI), particularly those caused by Aspergillus and other angioinvasive molds, are associated with an excessive mortality despite therapy. METHODS: Voriconazole was prescribed on a compassionate basis to patients with IFI who were intolerant to or who had progressed despite standard therapy. Outcome was determined by protocol-based criteria as established by the consensus definitions (complete response [CR], partial response [PR], stable disease, failure, and intolerance). RESULTS: Forty-five patients were enrolled in a compassionate release program (29 [64%] because of failure of response to standard therapy), between 1998 and 2002. Of the 45 patients enrolled, 35 (78%) had invasive Aspergillus, 3 (7%) had Fusarium, and 2 (4%) had Scedosporium infections. Underlying illnesses were as follows: 13 (29%) solid-organ transplant (SOT), 11 (24%) BMT, and 7 (13%) hematologic malignancy. Site of infection was as follows: 26 (58%) pulmonary, 9 (20%) disseminated, 5 (11%) central nervous system (CNS), and 3 (7%) sinus. Overall response rates were as follows: 9 (20%) CR, 17 (38%) PR, 15 (33%) failure, and 4 (9%) intolerant. Seven of the eight (88%) patients with sinus or CNS disease demonstrated stabilization of the IFI. The median duration of voriconazole therapy was 79 days with 9 (20%) patients receiving over 1 year of therapy. Nine thousand one hundred twenty-eight days of therapy were given with only four serious adverse events in two cases considered possibly or probably drug related. CONCLUSIONS: In this population of severely immunocompromised patients with life-threatening IFI who have failed or were intolerant to standard antifungal therapy, voriconazole demonstrated substantial efficacy and an acceptable level of toxicity.

Successful toxoplasmosis prophylaxis after orthotopic cardiac transplantation with trimethoprim-sulfamethoxazole.

BACKGROUND: The efficacy of trimethoprim-sulfamethoxazole (TMP/SMX) in the prevention of toxoplasmosis after orthotopic cardiac transplantation has been the subject of some controversy, with many transplant groups preferring to use the combination of pyrimethamine and sulfadiazine. Although effective, this latter regimen does not offer equal protection against other pathogens, such as or. To assess the value of TMP/SMX, we reviewed the experience in our heart transplant patients, all of whom received TMP/SMX (160/800 mg) three times weekly for approximately 8 months after transplantation. METHODS: We report on 417 orthotopic cardiac transplants during a 17-year period. We have 100% one-year patient follow-up after transplantation. Data was collected on pretransplantation donor and recipient anti- serology, immunosuppression, allograft rejection, survival, yearly posttransplantation anti- serology, development of acute toxoplasmosis, and the occurrence of other infections. RESULTS: In this cohort, acute toxoplasmosis developed after transplantation in one case (0.2%). Among the highest risk patients (D+R-) who were treated for at least one episode of rejection, the risk of acute toxoplasmosis was 5% (1 of 22 patients). No change in survival was found between the different anti- IgG serogroups (D-R-, D-R+, D+R-, or D+R+). Anti- IgG seroconversion occurred in eight -seronegative recipients after transplantation; all patients, except the case already noted, were asymptomatic and required no specific anti- therapy. No cases of, or infections were identified. Five proven and two suspected cases of pneumonia were found (only 2 of these 7 patients were receiving TMP/SMX at the time of pneumonia diagnosis). CONCLUSIONS: These data demonstrate that TMP/SMX prophylaxis (160/800 mg) three times per week is effective prophylaxis after orthotopic cardiac transplantation and has prophylactic benefits against other posttransplantation opportunistic pathogens.

Effect of oral acyclovir or ganciclovir therapy after preemptive intravenous ganciclovir therapy to prevent cytomegalovirus disease in cytomegalovirus seropositive renal and liver transplant recipients receiving antilymphocyte antibody therapy.

BACKGROUND: Organ transplant recipients who are seropositive for cytomegalovirus (CMV) and who are treated with antilymphocyte antibody (ALA) therapy have a high rate of symptomatic CMV disease. The intravenous administration of ganciclovir therapy once daily during ALA therapy decreased the incidence from 24% to 10% in patients receiving ALA as an induction therapy and from 64% to 22% in those treated for rejection. The present study was undertaken to determine whether a more intensive and sustained antiviral regimen could be more effective. METHODS: From April 1995 to December 1997, all CMV seropositive renal and liver transplant recipients who received ALA therapy were treated with intravenously administered ganciclovir (5 mg/kg/day with dose adjusted for renal dysfunction) for the length of ALA therapy and then with orally administered acyclovir (400 mg three times/day) or ganciclovir (1 gm twice/day) for 3 to 4 months. The incidence of CMV viremia and of CMV disease was determined during the 6 months after completion of ALA therapy. RESULTS: Forty-one patients (35 renal and 6 liver transplant recipients) were studied. CMV disease occurred in 2 patients (4.9%), both of whom were treated for rejection; it occurred in 1 of 21 patients (4.8%) treated with orally administered acyclovir, and in 1 of 20 patients (5%) treated with orally administered ganciclovir. The only patient who developed CMV disease in the ganciclovir group had received only 26 days of oral antiviral therapy. No CMV disease was documented in the group of patients receiving ALA therapy as induction therapy. CMV viremia occurred in three patients in the acyclovir group (14.3%) and in one patient in the ganciclovir group (5%). Among renal transplant recipients only, 1 of 35 patients developed CMV disease (2.9%) and no case of CMV disease was documented in patients treated with orally administered ganciclovir. All six patients receiving two courses of ALA therapy each were free of CMV disease. Toxicity of the regimen was minimal, and antiviral resistance did not develop. CONCLUSIONS: Preemptive antiviral therapy with intravenously administered ganciclovir during ALA therapy and then orally administered ganciclovir for 3 to 4 months provides virtually complete protection against the excessive rate of CMV disease that occurs in CMV seropositive allograft recipients receiving ALA therapy.