Oncology

Viral infections after bone marrow transplant

Viral infections after bone marrow transplant

What every physician needs to know about viral infections after bone marrow transplant:

General comments

We already appreciate that viral infections are a common cause of morbidity and mortality after bone marrow transplants (BMTs), and yet we seem to be constantly identifying new viruses as a cause of previously undiagnosed syndromes. This discussion only mentions certain of the most common viruses. There are many that are not discussed here, such as enteroviruses, HIV, hepatitis, and parvovirus, which are discussed in other chapters.

Some viruses may be characterized by life-long latency; hence many disease manifestations occur due to reactivation, rather than newly acquired infection. This is important, as reactivation diseases can potentially be prevented with preemptive monitoring or tailored prophylaxis.

Here, I've broken the discussion down into herpes viruses, which are classically characterized by prolonged latency and "reactivated" after BMT, and viruses that are typically acquired via the respiratory tract. However, these categories are not exclusive, as some herpes viruses are typically acquired through the respiratory tract (for example, Epstein-Barr virus [EBV], cytomegalovirus [CMV]).

Herpes viruses

There are eight members in the human Herpesviridae family, including CMV, EBV, herpes simplex viruses 1 and 2 (HSV1 and 2), varicella zoster virus (VZV), and human herpesvirus 6,7, and 8 (HHV6, 7, 8). Infection in the BMT recipient is common, and disease is usually the result of reactivation during prolonged periods of immunosuppression, especially that associated with quantitative and qualitative defects in T cells. Some of these viruses cause relatively uncomplicated mucosal disease, others invasive disease of multiple organ systems, and some of oncogenic properties. Some of the more common are discussed below.

Herpes simplex viruses

HSV1 and 2 are acquired via oral or genital mucosa, and remain dormant in local nerves. Reactivation causes mucosal disease most frequently, although more severe manifestations can occur, including cranial nerve palsies, encephalitis, as well as recurrent meningitis. Viral shedding can occur without clear mucosal reactivation, and in severely immunosuppressed patients, disease can involve other organs. For example, HSV-associated lung disease can occur, especially in people who have airway instrumentation at the time of oral reactivation.

Donor-immunity to HSV is an important predictor of the frequency of mucosal and visceral HSV disease in allogeneic BMT recipients, especially in seropositive recipients. Donor seronegative/recipient seropositive discordance predicts frequent complications, suggesting that routine HSV serostatus testing may be useful to guide prevention strategies, although it is not frequently performed today.

Herpes simplex virus: management

Acyclovir prophylaxis is warranted in people who have a history of HSV reactivation, or in people who are known to be seropositive. This should extend at least through the early period after BMT, and in other periods of neutropenia or severe mucositis, and perhaps longer in people who have graft-versus-host disease (GVHD), delayed T cell engraftment, and in those who are seropositive for VZV. Long-term acyclovir suppression (through one year after allogeneic BMT) decreases VZV-related morbidity. It also decreases the frequency of reactivation of HSV1 and 2 disease, and appears to prevent emergence of acyclovir resistance.

Acyclovir (or equivalent dosing of valacyclovir) should be administered with suspected HSV disease. Establishing a definitive diagnosis, with culture or immunofluorescence is necessary in the absence of improvement, as multiple conditions can mimic mucosal HSV disease. Keep in mind that acyclovir resistance occurs, especially in people who have received the drug during the past. Foscarnet resistance also occurs.

Varicella zoster virus

People who have been infected with VZV (chicken pox) have life-long latency of the virus in dorsal root ganglia. Reactivation periodically can cause disease in a dermatomal distribution (shingles), or visceral involvement. In severely immunosuppressed patients, the classic severe visceral syndrome that can be easily missed involves the abdomen; hepatic VZV can cause abdominal pain and massive transaminitis with rapid organ necrosis, even without clear skin disease. Lung and neurologic complications, including encephalitis and post-infectious vasculopathy also occur. When followed for 2 years after BMT, VZV disease occurs in approximately 30 to 60% of allogeneic BMT recipients with pretransplant infection. Thus, prevention is a mainstay in management.

Varicella zoster virus: management

Following allogeneic bone marrow transplantation, prolonged courses of both acyclovir or valacyclovir reduce the incidence of VZV disease. Although there is some variation in recommendations from consensus panels, most institutions have adopted a longer term prophylaxis strategy, based on the results of these studies.

Inactivated vaccines are routinely used in BMT recipients, but there is controversy over the safety of the live attentuated vaccines. The latter has been reported to be effective and possibly safe, but prospective studies have not yet been performed in a variety of immunosuppressed conditions.

Dermatomal disease is usually clinically diagnosed; other tests, including viral culture and polymerase chain reaction (PCR), can be employed with lack of therapeutic response and in suspected visceral disease. Higher dosing of acyclovir is the baseline therapy for both dermatomal and visceral disease. Severity dictates duration of therapy. Although VZV immune globulin was previously used as an adjunct for severe disseminated disease, it is no longer available in the United States of America.

CMV

Human CMV is a beta herpesvirus, and it latently infects many different types of cells, including hematopoietic cells, epithelial cells, and endothelial cells. Hence, transmission is relatively easy after organ transplant or BMT. CD8 and CD4 T cell immunity is particularly important in controlling viral reactivation and disease, although other innate immune mechanisms (for example, natural killer [NK] function and toll-like receptor [TLR] polymorphisms have been shown to predict risk for complications.

Disease can be caused by reactivation during periods of immunosuppression, especially late after allogeneic BMT with T cell dysfunction, or can be primarily acquired, by stem cells, respiratory or sexual transmission, or exposure to infected blood products. Most disease in allogeneic BMT recipients is progressed from viral reactivation; hence seropositive BMT recipients have the highest risk for infection and disease. Seropositivity of donor cells impact kinetics of immune reconstitution and reactivation. Knowledge of the serostatus of the donor and recipient enables development of prevention strategies that are pivotal to successful management. Seronegative recipients should receive stem cells from a seronegative donor when possible, and only receive CMV safe blood products.

Risks for disease are contingent on seropositivity of the graft, as well as graft source; for instance, cord blood does not typically have CMV specific cells, and seropositive recipients of cord blood have particularly high risks for disease when prevention is not effectively administered. Predictably, T cell depletion, GVHD and therapy, as well as specific monoclonal therapies (for example, alemtuzumab), deplete CMV specific T cell responses, enhancing risks for reactivation and disease.

CMV: management

Viral reactivation itself can cause an infection syndrome, which may be accompanied by fever and other systemic symptoms. Progression from infection to organ disease results in people who are particularly immunosuppressed. In the BMT population, diseases involving the lungs and the gastrointestinal (GI) tract are the most common. Retinitis, hepatitis, and encephalitis occur, but at lower frequency.

  • Prevention

High dose acyclovir (and valacyclovir) prophylaxis effectively reduces reactivation, and perhaps disease, although patients should be monitored for viral reactivation. Ganciclovir effectively prevents reactivation and reduces risks for disease compared to placebo, but the costs are toxicities; cytopenias occur in up to 30% of people who receive intravenous (IV) ganciclovir prophylaxis. Results of preliminary studies suggest that valganciclovir may be a prophylaxis option, but the strategy has not yet been widely tested in BMT recipients.

More centers have moved towards preemptive strategies given toxicities of prophylaxis and availability of screening methods, especially PCR. Monitoring through day 100 after allogeneic BMT, with application of ganciclovir to preempt development of disease upon findings of viremia is effective. High-intensity combined prophylaxis and screening methods may be needed in people with particularly high risks, for instance in seropositive recipients of cord-blood.

  • Organ disease

Lung disease is most frequently apparent as an interstitial pneumonitis, although radiographic presentation can be variable; symptoms are usually fever, nonproductive cough, and shortness of breath. Patients with lung disease usually have CMV reactivation in the blood (by PCR or pp65 antigenemia [Ag]), although diagnosis should be supported with bronchoalveolar lavage (BAL), both to confirm CMV involvement in the lung, and to assure that there are no concurrent infections that require other therapies. Bacterial and fungal pneumonias are common co-infections with CMV. Treatment of lung disease requires a 2 week induction period of ganciclovir, followed by maintenance therapy with either IV ganciclovir or valganciclovir. Most people supplement antivirals with IV immunoglobulin (Ig), based on results of observational studies.

GI tract disease can be variable, ranging from focal colonic ulcerations, to more extensive colitis. Disease usually presents as diarrhea, fever, abdominal pain, or more vague symptoms (sweats, nausea). These can mimic GI tract GVHD, and peripheral testing is less reliable (one can have GI tract CMV disease with a negative blood PCR); for this reason, diagnosis should be supported with colonoscope with biopsy. Treatment of GI tract disease usually requires a longer duration of induction therapy (3 to 4 weeks), followed by maintenance. There is no indication that IVIg adds to therapeutic outcomes.

  • CMV antiviral resistance

CMV can become resistant to multiple antivirals, especially in the setting that predicts viral replication during low dose drug exposure (for example, severely cellular suppressed patients receiving inadequate doses of ganciclovir). Viral load increases on therapy during the first 2 weeks usually due to immune suppression; if the viral load is increasing beyond this time period, especially in people with prior drug exposure, drug resistance should be considered.

Ganciclovir resistance is usually due to mutations in the UL97 gene. In this setting, foscarnet is the second drug of choice. Mutation in the UL54 gene can also confer foscarnet resistance as well; in these patients, cidofovir can be used. There is some cross resistance with some UL54 mutations. There are other drugs under study, including maribavir (under evaluation now); reports of activity using other "off-target" drugs (leflunomide, and artesunate) also exist, but clinical utility is unclear. Sometimes people use combinations of drugs; treatment of drug resistant disease can be complicated and should involve consultation with experts.

Human herpes virus 6

HHV6 is a beta herpesvirus that typically infects people young in age (less than 2 years), causing a self-limited fever syndrome. Latency is life-long, and reactivation is common after BMT, especially that caused by the virion type B. Some people have been noted to have chromosomal integration of the virus, with horizontal transmission occurring. This state confuses diagnosis of HHV6 related disease, as these people can have very high viral loads by PCR, and positive findings by cellular staining.

There has been quite a lot of work done in the last decade to describe clinical syndromes caused by HHV6, with some controversy. Pneumonitis and hepatitis have been reported. More definitive evidence shows that HHV6 causes central nervous system (CNS) syndromes, including neurocognitive decline, as well as fever, and rash. Viral reactivation is common after BMT, ranging from 30 to 90%, and dependent on the graft cell source, with high risks notable in recipients of cord blood, human leukocyte antigen (HLA) mismatched grafts, GVHD, and with T cell depletion.

Human herpes virus 6: management

Diagnosis is usually suggested with molecular testing (PCR). Keep in mind that high level positive PCRs, repeatedly, suggests potential chromosomal integration and is not necessarily predictive of HHV6 related disease.

Antiviral treatment is similar to that of CMV, ganciclovir, foscarnet, and cidofovir have been used with success, although there are few data to indicate the best approach. Screening with preemptive treatment has been suggested in high-risk patients, although not confirmed to alter outcomes.

EBV

Epstein-Barr virus, the etiologic agent for classic mononucleosis, causes post-transplant lymphoproliferative diseases (PTLD), which are particularly common in settings of prolonged T cell depletion or delayed engraftment.

Screening for EBV reactivation may allow for preemptive treatment with Rituxan and/or reduced immunosuppression, when applicable. Cellular immunotherapies are being developed. Antivirals do not have a documented role in management.

Respiratory viruses

Infection with respiratory viruses in BMT recipients mimics the seasonal distribution of that seen in the general population. However, these patients, especially those with a large degree of cellular immunosuppression, have a relatively higher risk for progression from upper respiratory infection (URI), to lower tract infection (LRI), or pneumonitis.

There are many different viruses that cause disease, and more that have been identified with use of molecular technologies, but only a few are discussed here.

Lymphopenia is the major risk factor for lower tract disease. Lower tract disease presents additional risks for other infections, such as bacterial and fungal pneumonia, as well as airflow obstruction/bronchiolitis obliterans. For these reasons, an aggressive diagnostic approach (bronchoscopy) is usually indicated in people with confirmed URI and signs of LRI.

Keep in mind that there have been a lot of improvements in diagnostic methods during the last decade; as a result, some of the reported epidemiologic literature that relied on culture and antigen based diagnoses alone, may not adequately reflect the entire spectrum of respiratory virus diseases. Some, such as human metapneumovirus, have been noted to be the cause of idiopathic pneumonitis, when examined retrospectively using molecular assays. These observations support the use of multiplexed molecular testing in BMT patients.

Influenza virus

BMT recipients have high risks for influenza lower tract disease, occurring in up to 20% of people with confirmed URI. Unlike other viruses, receipt of steroids may not portend towards risk for progression. Also, the clinical syndrome that is classic in non-immunosuppressed (for example, myalgias), is not as common in BMT patients.

Neuraminidase inhibitors (for example, oseltamivir) appear effective in reducing progression to LRI, and in reducing acquisition of disease in outbreak settings. However, viral shedding is prolonged in BMT patients, and in this setting, development of oseltamivir resistance has been observed. This was particularly common with the pandemic H1N1 strain in 2009, which was associated with worse outcomes compared to seasonal influenza. Higher dose oseltamivir therapy is a good idea in people with severe disease, who are severely immunosuppressed.

Vaccines can be partially effective, but responses are dependent on timing after BMT and immunosuppression.

Respiratory syncytial virus

Respiratory syncytial virus (RSV) is particularly common during fall-winter outbreaks, and in BMT patients, disease can commonly progress to involve the lower respiratory tract, with typically poor outcomes (up to 80% mortality has been reported). Documented URI usually preceeds LRI, but it doesn't have to be present; lymphopenia and age predict progression.

Pulmonary co-pathogens, and progression towards bronchiolitis obliterans syndrome are particularly common, likely due to extensive airway epithelial injury. Bronchoscopy with tailored therapy is a very good idea.

Treatment of RSV URI is controversial, and is not routinely employed in the absence of lower respiratory tract disease, largely due to limitations in safety of standard effective therapies. However, there are small studies that suggest that the approach may be useful in higher-risk patients.

Current standard treatment of LRI typically involves aerosolized ribavirin (intermittent short duration or continuous), which was associated with better outcomes than historic controls in observational studies. Systemic ribavirin did not appear effective for pneumonia, although perhaps with some benefit for URI. No comparative studies have been performed to define 'best' approach in an adequate sampling of subjects.

Intravenous immunoglobulin (IVIg) is frequently used for severe disease, but its role has not been well studied. Similarly, anti-protein F antibody (palivizumab), may be a therapeutic option, although it has not been evaluated for efficacy in BMT patients.

Parainfluenza viruses

Parainfluenza virus types 1 to 4 cause disease year round, primarily though limited to the upper tract in this population. If disease does involve the lungs, co-pathogens are common, and receipt of corticosteroids portend a poor prognosis. There are no clear antiviral therapies that have been documented in clinical trials; decreased steroid based immunosuppression (when possible), IVIg, and aerosolized ribavirin have been suggested, but not evaluated.

Adenoviruses

There are over 50 different serotypes of adenoviruses, all of which cause disease in immunocompromised and suppressed hosts. The virus becomes latent in adenoidal tissues, hence, infection can be either reactivated or acute after BMT.

T cell deficiency and clinical variables that predict it (GVHD, HLA mismatch, etcetera) are the primary risk factors of disease. Adenoviral disease is particularly problematic in younger people, where dissemination is more common.

Multiple organs can be involved, including the lungs, liver, GI tract, skin, kidneys, and central nervous system. Adenovirus is also a common cause of hemorrhagic cystitis. Clinical presentation of disease can thus be variable, but keep in mind that this virus is a frequent mimic of GVHD itself. Fever, rash, diarrhea, and hepatitis misdiagnosed clinically as GVHD is a classic presentation of disseminated adenovirus disease after allogeneic BMT.

Weekly blood monitoring by PCR can pick up adenovirus, and some have suggested potential utility in preemptive approaches in particularly high risk patients, although it's not routinely employed in most BMT centers.

Treatment of adenovirus disease usually relies on cidofovir, based on case series. Although other antivirals appear to have activity (ganciclovir), treatment outcomes don't support its use.

Other notable viruses: BK polyomavirus and norovirus

  • BK polyomavirus

BK polyomavirus is a frequent cause of hemorrhagic cystitis in BMT recipients. Infection is typically acquired early in life, and the virus establishes latency primarily in the uroepithelium. Some degree of pathogenesis likely involves alloreactivity, so risks include GVHD and bladder insults (for example, irradiation). Virus is typically found in high copies in the urine and can be found in blood. Nephritis, a more common manifestation in kidney transplant recipients, is less common after BMT, but progressive renal dysfunction can occur due to obstruction (clots and epithelial necrosis) and treatments. The current therapeutic approach involves supportive care (hydration, bladder drainage), and cidofivir therapy. Other treatments, including leflunomide and quinolone antibiotics have not been well evaluated.

  • Norovirus

Recently, it was noted that infectious diarrhea, particularly norovirus, can mimic GI tract GVHD, leading to misdiagnosis and potential transmission. This is a difficult diagnosis to establish, requiring microscopy that is not offered by clinical laboratories. This diagnosis should be considered in anyone with recalcitrant diarrhea despite GVHD therapy; diagnosis and treatment should be pursued with infectious diseases consultation.

What features of the presentation will guide me toward possible causes and next treatment steps:

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What laboratory studies should you order to help make the diagnosis and how should you interpret the results?

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What conditions can underlie viral infections after bone marrow transplant?

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When do you need to get more aggressive tests?

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What imaging studies (if any) will be helpful?

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What therapies should you initiate immediately and under what circumstances - even if root cause is unidentified?

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What other therapies are helpful for reducing complications?

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What should you tell the patient and family about prognosis?

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"What if" scenarios

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Pathophysiology

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What other clinical manifestations may help me to diagnose viral infections after bone marrow transplant?

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What other laboratory studies may be ordered?

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What’s the evidence?

Erard, V, Wald, A, Corey, L, Leisenring, WM, Boeckh, M. "Use of long-term suppressive acyclovir after hematopoietic stem cell transplantation: impact on HSV disease and drug-resistant HSV-disease". J Infect Dis.. vol. 196. 2007. pp. 266-70.

[A well done study that illustrates important therapeutic issues.]

Ljungman, P, Hakki, M, Boeckh, M. "Cytomegalovirus in hematopoietic stem cell transplant recipients". Infect Dis Clin N Am.. vol. 24. 2010. pp. 319-37.

[A very complete and informative review.]

Zerr, DM, Fann, JR, Breiger, D. "HHV-6 reactivation and its effect on delirium and cognitive functioning in hematopoietic cell transplantation recipients". Blood. vol. 117. 2011. pp. 5243-49.

[A nicely performed prospective study that outlines the potential role of HHV6 in cognitive functioning.]

Boeckh, M. "The challenge of respiratory virus infections in hematopoietic cell transplant recipients". Brit J Haematol.. vol. 143. 2008. pp. 455-67.

[This is a thorough and well written summary.]

Schwartz, S, Vergoulidou, M, Schreier, E. "Norovirus gastroenteritis causes severe and lethal complications after chemotherapy and hematopoietic stem cell transplantation". Blood.. vol. 117. 2011. pp. 5850-6.

[This is a well-done study that outlines the potential of norovirus to masquerade as GVHD and other causes of diarrhea.]
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