Changing Etiologies of Fever in Liver Transplantation
abstract & commentary
Synopsis: Cytomegalovirus and organ rejection are now uncommon causes of fever in adult liver transplant recipients in Pittsburgh. Patients with fever and otherwise unexplained leukopenia may have HHV-6 infection.
Source: Chang FY, et al. Fever in liver transplant recipients: Changing spectrum of etiologic agents. Clin Infect Dis 1998; 26:59-65.
Chang and colleagues in pittsburgh assessed the etiologies of fever in adult male liver transplant patients over a recent two-year period. During this time, immunosuppressive therapy in all patients was comprised of tacrolimus and low-dose prednisone, with rejection episodes treated with bolus methylprednisolone. None of the patients considered in this review received OKT3, which was reserved for steroid-resistant rejection. All patients received perioperative antibiotics for 24 hours, as well as prophylaxis against Pneumocystis carinii pneumonia, usually with trimethoprim-sulfamethoxazole. All patients received acyclovir orally for one month. Surveillance cytomegalovirus (CMV) buffy coat cultures were performed regularly, and a short course of ganciclovir was administered pre-emptively for positive cultures.
There were 45 episodes of fever and 25 episodes of documented infection without fever in 43 patients. Ten (22%) of the 45 episodes of fever were due to non-infectious causes, including two each due to malignancy and rejection. Other non-infectious causes of fever, occurring in one patient, included transfusion reaction and drug reaction.
Fever was due to infection in 35 (78%) of 45 episodes; 28 (80%) of the 35 infections were bacterial, and seven (20%) were viral. None of the febrile episodes was due to fungal infection. Of the 25 episodes of infection without fever, 15 (60%) were bacterial, six (24%) were viral, and seven (28%) were fungal. Thus, none of the seven fungal infections (2 each due to Aspergillus and Cryptococcus and 3 fungemias due to Candida albicans) were associated with fever.
A total of 10 patients had infection due to virus, including parvovirus B19 and varicella zoster virus in one each, cytomegalovirus in three, and five (50%) believed to be due to human herpesvirus-6 (HHV-6). In these five, all of whom were febrile, HHV-6 was detected in bone marrow in three and lung in one, while the fifth had viremia in the absence of other explanation for fever.
Twenty-six (58%) of the febrile episodes occurred within 12 weeks of transplantation and 29% more than one year after. Fever in the first two weeks was most often due to IV catheter-related bacteremia or to rejection. From two to four weeks post-transplantation, most infections were due to HHV-6 or to bacterial infection.
Eight (80%) of the 10 patients with non-infectious causes of fever and 19 (54%) of 35 with infectious causes had normal white blood cell counts at the time. Eight patients had leukopenia (WBC < 3000/mm3); four (50%) were believed to have HHV-6 infection. The WBC in these four ranged from 700/mm3 to 1800/mm3. Of five patients with leukopenia that could not be explained by chemotherapy or other causes, four (80%) had apparent HHV-6 infection.
Comment by Stan Deresinski, MD, FACP
The spectrum and relative frequency of etiologies of fever and infection in liver transplant patients has clearly changed. In contrast to the much higher rates previously reported, in the study reviewed here, CMV accounted for only 7% of febrile episodes. This decreased incidence of CMV infection is undoubtedly the consequence of the use of tacrolimus, a more conservative use of immunosuppressive therapy in general (none received OKT3), (possibly) pre-emptive therapy for CMV infection, and better CMV matching; only 9% of patients transplanted during this time were CMV seronegative and received an organ from a CMV seropositive donor.
Another change is the markedly decreased frequency with which rejection accounted for febrile episodes. In this series, only 4% of febrile episodes were due to rejection. Rejection still occurred, but it was less likely to be associated with fever. This change is the result of the changes in immunosuppressive therapy that have occurred.
HHV-6 is the cause of exanthem subitum (roseola) in infants. Infection of the few adults who escaped exposure during infancy most often results in a clinical illness resembling infectious mononucleosis.
Evidence is accumulating suggesting that HHV-6 may cause focal encephalitis in adults, presumably as the consequence of late reactivation of latent infection. This virus has also been reported to cause interstitial pneumonitis and hematopoietic suppression in bone marrow transplant recipients. The study reviewed here suggests that HHV-6 may be an important cause of febrile illness in liver transplant recipients and that a clue to its presence is the finding of otherwise unexplained leukopenia.
However, as with other infectious agents with life-long latency, the diagnosis of disease due to active HHV-6 infection is tricky in adults. For instance, HHV-6 DNA can commonly be detected by PCR in lung tissue of apparently normal adult lung (Cone RW, et al. J Clin Microbiol 1996;34:877-881). In this study, the evidence of HHV-6 infection in five of six patients consisted of detection of the virus in bone marrow or lung by immunohistochemical staining using a murine monoclonal antibody to protein 101 of HHV-6 Type A and structural protein gp82 of HHV-6 Type B; this assay is said to detect only productively infected cells and to not cross-react with other herpesviruses (Pitalia AK, et al. J Med Virol 1993;41:103-107). Nonetheless, it is important to maintain an element of skepticism until there is confirmation of findings such as these, as well as evidence that administration of drugs that have activity against this virus is associated with clinical resolution of the febrile illness in association with appropriate virological findings. While the provocative findings with regard to HHV-6 may represent the most important contribution of these investigators, the other intriguing finding was the fact that all seven patients with invasive fungal infection were afebrile. The reason for this finding escapes me.
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