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TNF-a has variable effects on viral pathogens. In some instances, the presence of TNF-a interferes with viral pathology; in others it may be causative in pathogenesis [112]. Influenza is the most common serious infection likely to be contracted in patients receiving TNF-a inhibition. Administration of influenza vaccine seems to be safe [113].

At least six cases of varicella-zoster virus [114-116] have been described after first infusion of infliximab. Varicella-zoster virus usually occurs as a primary infection in childhood and has a lifetime reactivation of 10% to 15% as shingles, a painful neurocutaneous disorder during times of physiologic stress or immunosuppression that can lead to serious morbidity. The Spanish Registry found that herpes zoster was the second most common infection identified after TB, although these data did not reach statistical significance [87]. Screening for varicella-zoster virus should be done by confirming a history of childhood chickenpox; if uncertain, varicella-zoster virus serology should be considered with subsequent administration of varicella vaccine with negative history or serology. Varicella vaccine was newly approved by the FDA for adults after the vaccine was shown to decrease the incidence and severity of herpes zoster and postherpetic neuralgia [117]. Development of herpetic disease with TNF inhibition and possibly with abatacept warrants dosing of acyclovir as for immunosuppressed patients.

TNF-a has been shown to protect mice from infection with herpes simplex virus-1 and human monocytes infected with herpes simplex virus-1 secrete higher amounts of TNF and are less susceptible to herpes simplex virus-1 infection [112]. TNF-a is critical in both the primary and reactivating phases; inhibition allows free replication of herpes simplex virus-1 [118]. Patients receiving anti-TNF therapy and probably abatacept should be followed closely for recurrent lesions and offered pre-emptive treatment for herpes simplex virus infection.

Cytomegalovirus, also known as HHV-5, is ubiquitous approaching 100% seropositivity in early adulthood. Cytomegalovirus is usually latent without manifestation in the immunocompetent host. It can reactivate with severe immunosuppression as seen in HIV, marrow toxic chemotherapy, or organ transplantation. Its manifestations can be treacherous and fatal presenting as blindness-causing retinitis, pneumonitis, and painful destruction of the gastrointestinal tract. Cytomegalovirus having a predilection for the immunosuppressed state has caused concern about the risk of reactivation with the use of biologic agents.

Torre-Cisneros and colleagues [119] in a prospective study of 15 patients receiving infliximab who were cytomegalovirus positive or had latent infection were found to have no reactivation of cytomegalovirus during or 6 months after treatment of RA with infliximab. A case is described of disseminated cytomegalovirus in a woman treated with infliximab for Crohn's disease. She had initial improvement but subsequently developed fever, worsening diarrhea, and skin lesions and was found to have cytomegalovi-rus on biopsies. Cessation of infliximab resulted in improvement with authors recommending that cytomegalovirus infection be ruled out with apparent worsening of symptoms before fortification of biologic therapy [120].

A pilot trial for evaluating safety and efficacy of rituximab and alemtuzu-mab (CD 52 targeted humanized antibody) in 12 patients with lymphoid malignancy who had failed prior chemotherapy found no evidence of cyto-megalovirus reactivation during or 6 months after administration [121]. Faderl and colleagues [122] had a different outcome in the treatment of 48 patients, finding that 52% of patients developed infections of which cyto-megalovirus was prominent with viremia in 27% and 15% of patients with symptomatic viremia requiring treatment.

Epstein-Barr virus is an ubiquitous herpes virus to which most people have been exposed and retain a low level of circulating Epstein-Barr virus-positive B-cell population in healthy people. In the immunosuppressed, Epstein-Barr virus-positive cells can increase in titers with the most serious complications being development of lymphomas. It is too early to ascertain firm assertions regarding biologics' effects on Epstein-Barr virus activation. Reijasse and colleagues [123] conducted a pilot study that did not reveal an overall difference in Epstein-Barr virus serial viral loads between Epstein-Barr virus-positive Crohn's patients receiving infliximab and Epstein-Barr virus-positive healthy controls over an 18-month period. It was noted, however, that some of the Crohn's disease patients had transiently high viral loads compatible with increased risk of lymphoma advising that long-term outcome need be determined. Cezard and colleagues [124] describe adverse effects in a prospective study of severe pediatric Crohn's disease treated with infliximab. In all eight EBV positive patients, there was reactivation of Epstein-Barr virus with increase of viral load by 100- to 1000-fold as determined by polymerase chain reaction. All patients were EBV PCR negative prior to infliximab administration and became EBV PCR negative again 6 months after discontinuation of treatment, leading the authors to be concerned about development of lymphoma with retreatment. Rituximab has been shown to control Epstein-Barr virus viral load [125,126] and successfully treat Epstein-Barr virus-related lymphoma [127]. Further investigation is required to establish guidelines for monitoring reactivation with anti-TNF therapy and possibly abatacept.

TNF-a has been shown to have antiproliferative effects on strains of human papillomavirus known to mediate cervical cancer. Cervical carcinoma in HIV-positive women is AIDS defining regardless of CD4 counts or viral load because it is an expression of extreme immune suppression. In theory, anti-TNF agents and abatacept potentially allow proliferation of culprit human papillomavirus strains by interference of multiple TNF-a activities. TNF-a induces strong inhibition of transcription of oncogenes E6-E7 required for proliferation in human papillomavirus-16 cervical carcinoma [128,129]. Lysis of tumor cells that express E6 is dependent on TNF-a to stimulate macrophage activity and nitric oxide-mediated apoptosis [130]. Although case reports seem nonexistent, in these early days of new biologics and until time yields more information, a pap smear before biologic therapy and routine surveillance should be considered.

Parvovirus B19 is a single-stranded DNA virus, known as the viral exan-them in childhood called "fifth disease'' or ''slapped cheek syndrome.'' It is well known to cause a transient reactive arthritis in adulthood. Its most impressive manifestation is an association with a spectrum of hematologic aplasias. Two case reports suggest immunosuppression with rituximab in causal relation in the development of pure red cell aplasia associated with parvovirus B19 infection [131,132]. Both patients were being treated for lymphoid malignancies with CHOP in addition to rituximab and were without evidence of malignant invasion of bone marrow. The authors assert that aplasia with parvovirus B19 infection is not a known association of CHOP therapy; however, three cases were found possibly to contest this [133-135]. There was also a report of red cell aplasia during a large phase II trial with rituximab alone for treatment of relapsed indolent lymphoma for which cause was not disclosed [132,136]. Polymerase chain reaction for virus may be required for detection, because serology could be negative with first exposures [132].

JC virus is a double-stranded DNA virus and is ubiquitous in that sero-positivity tends to occur before 20 years old worldwide with a prevalence of 80% to 90% [137]. There has been no syndrome associated with primary infection nor has the mode of transmission been identified. Once contracted it seems that it lies dormant in the bone marrow and lymphoid tissues of individuals. Any manifestation of the JC virus is exceedingly rare unless the subject develops immunosuppression or granulomatous disease at which time there is potential for development of progressive multifocal leukoence-phalopathy. Progressive multifocal leukoencephalopathy is a rare, invariably fatal demyelinating disorder with increased prevalence since the introduction HIV. Progressive multifocal leukoencephalopathy may present with symptoms similar to those of stroke, seizure, or dementia. Berger and Houff [137] report "best evidence to date suggests that JC virus is not latent in the brain—to establish infection in the brain, it must traffic there,'' suggesting facility of transit by a predisposing circumstance.

Concern arose when natalizumab had been taken off the market in February 2005. Three patients had developed progressive multifocal leukoence-phalopathy during drug trials with data suggesting that patients receiving natalizumab may be at particular risk [138]. Later, Yousry and colleagues [139] quantified this associated risk to be 1 per 1000 with mean treatment time of 17.9 months (95% confidence interval).

These events prompted Roos and Oster [140] to argue for a high index of suspicion and evaluation for the JC virus with polymerase chain reaction of cerebrospinal fluid in all patients receiving immunomodulating therapy whose presentation suggests encephalopathy or demyelination, ring-enhancing lesions, or mass effect on imaging [141]. Their arguments were based on a review of literature that included the following salient points: Mohan and colleagues [142] reported in 2001 the development of demyelination in 18 cases of patients receiving etanercept and two receiving infliximab for RA as reported to the FDA AERS. The diagnosis of progressive multifocal leu-koencephalopathy is easily missed and likely to be underreported and underdiagnosed in patients receiving anti-TNF-a therapy [143].

Goldberg and colleagues [144] describe two patients who underwent au-tologous blood stem cell transplant and rescue and, after established immune reconstitution, received rituximab, who developed progressive multifocal leukoencephalopathy while in remission at 9 and 20 months after transplantation. Although these patients also underwent high-dose chemotherapy in addition to receiving rituximab, it is worth noting that only 10 cases of bone marrow transplant-associated progressive multifocal leukoen-cephalopathy had been documented before these two cases documented by Goldberg and colleagues [144], which suggests possible significance.

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