Viral infections after bone marrow transplant

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

General comments

Viral infections are a major issue for bone marrow transplant (BMT) recipients. Important viral pathogens in this population include herpes simplex viruses (HSV) 1 and 2, varicella zoster virus (VZV), cytomegalovirus (CMV), human herpes 6 virus (HHV-6), influenza, parainfluenza, respiratory syncytial virus (RSV), rhinovirus, adenovirus, BK virus, and norovirus. There are many that are not discussed here, such as enteroviruses, HIV, hepatitis, and parvovirus, which are discussed in other chapters and essentially every organ system in the body can be impacted by viral infections. Moreover, 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.

Disease manifestations may occur due to reactivation of latent infections, such as with herpes viruses, which are often already present in the recipient before transplant, or as a consequence of de-novo acquisition after the transplant. Unlike in the general population, where clinical manifestations of infection generally range from asymptomatic carriage to mild to moderate symptoms, BMT recipients may develop much more severe disease. Identifying patients at risk for reactivation of latent viruses or acquisition of new ones is important, as active infection and diseases can potentially be prevented with pre-emptive monitoring or tailored prophylaxis during the most critical periods.

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Here, we’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 often acquired through the respiratory tract (e.g., Epstein-Barr virus [EBV] and cytomegalovirus [CMV]).

There are eight members in the human Herpesviridae family, including CMV, EBV, HSV1 and 2, VZV, and human herpesvirus 6, 7, and 8 (HHV6, 7, 8). Asymptomatic latent infection before transplant is common. Disease is usually from viral 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 and cutaneous disease, others invasive disease of multiple organ systems, and some have oncogenic properties. The more common are discussed below.

Herpes simplex viruses and varicella zoster virus

HSV1 and 2 are acquired via oral or genital routes, and remain dormant in local nerves. Viral shedding can occur even without clear mucosal disease. Reactivation with mucosal disease typically manifests as vesicles and ulcers. More severe presentations can include cranial nerve palsies, encephalitis, and recurrent meningitis. In severely immunosuppressed patients, disease can also 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 universally performed today.

People who have been infected with VZV (chicken pox) have life-long latency of the virus in dorsal root ganglia. Reactivation typically causes disease in a dermatomal distribution (shingles), but may also present with visceral involvement. In highly 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 evident skin disease. Lung and neurologic complications, including encephalitis and post-infectious vasculopathy also occur. When followed for 2 years after BMT, VZV disease can occur in up to 30-60% of allogeneic BMT recipients with pretransplant infection. Thus, prevention is a mainstay in management.

Prophylaxis

Following allogeneic bone marrow transplantation, prolonged courses of both acyclovir and valacyclovir reduce the incidence of VZV disease. Antiviral prophylaxis to prevent HSV and VZV is thus warranted in essentially all BMT recipients. A potential (and uncommon) exception is when both the donor and recipient are seronegative for HSV and VZV. Suitable agents are acyclovir 800 mg, twice daily, valacyclovir 500 mg, twice daily and famciclovir 250 mg, twice daily. Doses may require adjustment in patients with renal dysfunction. Ganciclovir (or valganciclovir) are also active against HSV and VZV, but much more toxic and hence not routinely used for these viruses unless already given for another indication (e.g., CMV).

Although there is some variation in recommendations from consensus panels, most institutions have adopted a longer-term prophylaxis strategy. Antiviral suppression through one year after allogeneic BMT decreases the frequency of HSV1 and 2 reactivation disease and VZV-related morbidity. It also appears to prevent emergence of acyclovir resistance. We recommend prophylaxis for at least 6-12 months after autologous transplant and for at least 12 months after allogeneic transplant. Beyond that, prophylaxis should be used during periods of neutropenia or severe mucositis, and perhaps in those with graft-versus-host disease (GVHD) and delayed T cell engraftment.

Additionally, immunization with 1 dose of the varicella (not zoster) vaccine should be given at ≥ 24 months after transplant for patients who are seronegative for varicella, providing that there is no GVHD or ongoing immunosuppression at the time.

Management

Herpes simplex viruses

When HSV disease is suspected, higher doses and/or parenteral therapy is required. For moderate to severe mucocutaneous infection use acyclovir 5 mg/kg IV every 8 hours or 800 mg 5 times/day; valacyclovir 1 gm PO, thrice daily; or famciclovir 250 mg PO, thrice daily. For disseminated and/or deep tissue (e.g., encephalitis) infection, use IV acyclovir at 10 mg/kg IV every 8 hours. Doses should be modified for children and in patients with renal impairment.

Length of treatment in mucocutaneous disease is usually 7-10 days, but must be individualized based on response to therapy. For more severe and invasive infections, duration of therapy is longer and highly variable. Establishing a definitive diagnosis, with culture, immunofluorescence, or nucleic acid testing 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 with extensive drug exposure. In such situations, foscarnet at 40 mg/kg every 8 hours (for individuals with normal function) may be an option, but resistance to that drug can also occur.

Varicella zoster virus

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. Treatment for dermatomal disease is with acyclovir 800 mg PO, 5 times daily or 10 mg/kg IV every 8 hours; valacyclovir 1 gm, thrice daily; or famciclovir 500 mg, thrice daily. In cases of multi-dermatomal, disseminated, or visceral VZV, the treatment is acyclovir 10 mg/kg every 8 hours. Doses should be modified for children and in patients with renal impairment. Higher dosing of acyclovir is the baseline therapy for both dermatomal and visceral disease.

Length of treatment in dermatomal disease is usually 7-10 days, but must be individualized based on response to therapy. For more severe infections, duration of therapy is longer and highly variable. 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.

Cytomegalovirus

CMV is a major cause of morbidity and mortality in BMT transplant recipients. The virus, which latently infects many different types of cells, including hematopoietic cells, epithelial cells, and endothelial cells, may already be present in the recipient or acquired at or subsequent to transplant. Disease can be caused by reactivation during periods of immunosuppression, especially late after allogeneic BMT with T cell dysfunction, or can be primarily acquired from the transplanted stem cells, via respiratory or sexual transmission, or with exposure to infected blood products. 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.

Knowledge of the serostatus of the donor and recipient enables development of prevention strategies that are pivotal to successful management. CMV seropositivity indicates latent infection AND suggests presence of host defenses that when functional can keep the virus in check. Conversely, CMV seronegative patients typically have neither latent virus nor effective anti-CMV host defenses. Most disease in allogeneic BMT recipients is progressed from viral reactivation; hence seropositive BMT recipients have the highest risk for infection and disease. Seropositive donor cells provide a level of protection against CMV that is especially important in seropositive recipients who are already latently infected with the virus and at risk for losing their innate protection during the transplantation process. This may be less of an issue in those receiving a reduced intensity conditioning regimen and are thus able to maintain some protective anti-CMV responses. The risk of primary infection in CMV negative recipients is great enough that they should receive stem cells from a seronegative donor when possible, and only receive CMV safe blood products.

The following caveats should be noted. Cord blood does not typically have CMV specific cells. Therefore, 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 (e.g., alemtuzumab), deplete CMV specific T cell responses, enhancing risks for reactivation and disease.

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. Effective prevention techniques have significantly reduced the burden of CMV disease in BMT recipients. When it does occur, disease involving the lungs and the gastrointestinal (GI) tract are the most common. Retinitis, hepatitis, and encephalitis occur, but at lower frequency.

Prevention

Allogeneic BMT recipients are at highest risk for reactivation of CMV during months 1-6 after transplantation and at times of GVHD severe enough to require corticosteroids.

While there are several prophylaxis options, none are ideal. Valganciclovir (900 mg daily) is effective as prophylaxis, but can cause considerable bone marrow suppression and is thus generally avoided prior to engraftment and during times of neutropenia. High-dose acyclovir (800 mg, 4 times daily) and valacyclovir (2 gm, 4 times daily) may be effective as CMV prophylaxis. However, as these are relatively weak anti-CMV agents, patients should be monitored for viral reactivation.

The mainstay of prevention is regular monitoring of blood CMV PCR, which should be done once weekly during high-risk periods and at least through day 100 after allogeneic BMT. The goal is to detect and pre-emptively treat incipient disease. High-intensity combined prophylaxis and screening methods may be needed in people with particularly high risks, for instance, with seropositive recipients of cord-blood. When viremia is discovered, antiviral therapy with oral valganciclovir (900 mg, twice daily) or IV ganciclovir (5 mg/kg, twice daily) is given for at least 2 weeks and until CMV is no longer detected in the blood. Decisions regarding whether valganciclovir is appropriate to use depend upon whether there are issues limiting oral absorption of the drug and/or the need to dose the drug precisely (such as in cases of high viral load or bone marrow toxicity), which is easier to do with IV ganciclovir. The dose of valganciclovir and ganciclovir may require adjustment based on renal function.

Organ disease

Lung disease is most frequently apparent as an interstitial pneumonitis, although radiographic presentation can be variable; symptoms are usually fever, non-productive cough, and shortness of breath. Patients with lung disease usually have CMV viremia (detected by PCR), 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 (5 mg/kg, twice daily), followed by maintenance therapy with either IV ganciclovir (5 mg/kg/day) or valganciclovir (900 mg daily). Doses may require adjustment with renal dysfunction. Most people supplement antivirals with IV immunoglobulin (Ig), based on results of observational studies.

Manifestations of GI tract disease can be variable, ranging from focal colonic ulcerations, to more extensive colitis and esophagitis. 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 endoscopy and biopsy. Treatment of GI tract disease usually requires a longer duration of induction therapy (3-4 weeks), followed by maintenance. There is no indication that IVIg adds to therapeutic outcomes.

Cytomegalovirus antiviral resistance

CMV can become resistant to multiple antivirals, especially in the setting that predicts viral replication during low-dose drug exposure (e.g., 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. The induction dose is 90 mg/kg every 12 hours in patients with normal renal function. Side effects include renal and electrolyte disturbances, the impact of which can be reduced with adequate hydration and careful attention to serum calcium, potassium, magnesium, and phosphorous levels. 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, letermovir, and brincidofivir; 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.

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 the potential for transmission from donor to recipient. 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. Persistently high viral load in the absence of attributable symptoms can be a clue for this entity.

Viral reactivation is common ranging from 30-90%, 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. Clinical associations include fevers, rash, and CNS syndromes. The latter include neurocognitive decline and amnesia, delirium, encephalitis,, and seizures. Typical MRI findings include hyperintense signals on T2 imaging of the medial temporal lobes, primarily affecting the hippocampus and amygdala. However, because both viral reactivation and CNS disease due to other etiologies are common in BMT patients and may occur simultaneously, a causal connection can be difficult to establish in individual patients. Suspected associations also include pneumonitis, graft dysfunction, and hepatitis, but these remain controversial.

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 pre-emptive treatment has been suggested in high-risk patients, although it has not been confirmed to alter outcomes.

Epstein-Barr virus

EBV, 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 pre-emptive treatment with rituximab 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, BMT patients, especially those with a large degree of cellular immunosuppression, have a relatively higher risk for progression from upper respiratory tract infection (URTI), to lower respiratory tract infection (LRTI), or pneumonitis. In that regard, lymphopenia is the major risk factor for lower tract disease.

There are many different viruses that cause disease, including rhinovirus, influenza, parainfluenza, adenovirus, coronaviruses, human metapneumovirus, and RSV. There are more that have been identified with the use of molecular technologies, but only a few are discussed here.

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 viruses, 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.

Lower tract disease presents additional risks for other infections, such as bacterial and fungal pneumonia, as well as airflow obstruction/bronchiolitis obliterans. An aggressive diagnostic approach (bronchoscopy) is usually indicated in people with confirmed URTI and signs of LRTI, and vigilance for the development of secondary bacterial and filamentous fungal infections is mandatory.

Influenza virus

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

Neuraminidase inhibitors (e.g., oseltamivir) appear effective in reducing progression to LRTI, and in reducing acquisition of disease in outbreak settings. The treatment dose is 75-150 mg BID. 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. The higher dose of oseltamivir therapy is a good idea in people with severe disease and/or who are severely immunosuppressed. Therapy should be continued for 10 days or longer depending on clinical symptoms. Inhaled zanamavir is another option.

Vaccines can be partially effective, but responses are dependent on timing after BMT and immunosuppression. One dose of inactivated influenza immunization should be administered annually starting 6 months (or 4 months if there is a community outbreak) after transplant. Live attenuated influenza vaccine is contraindicated in BMT.

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

Standard treatment of RSV LRTI in BMT has historically been aerosolized ribavirin by intermittent dosing (2 gm over 2 hours, thrice daily) or continuous (6 gm every 12-18 hours daily) for 7 days. Because of difficulties in administering the drug via the aerosol route due to its teratogenicity, and significant cost issues, oral ribavirin is increasingly used. However, the role of systemic ribavirin for pneumonia is unclear, although perhaps there is some benefit for URTI. No comparative studies have been performed to define the ‘best’ approach in an adequate sampling of subjects.

Intravenous immunoglobulin (IVIG) at 400-500 mg/kg every other day 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 portends 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. DAS181, an inhaled fusion protein that cleaves sialic acid receptors from respiratory epithelial cells is currently undergoing clinical testing and may be a promising option.

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, etc.,) 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 pre-emptive 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 their 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 (e.g., irradiation). The 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 cidofovir therapy. Other treatments, including leflunomide and quinolone antibiotics, have not been well-evaluated.

Norovirus

Norovirus can mimic or co-exist with GI tract GVHD, leading to misdiagnosis and potential transmission. Diagnosis can be accomplished by PCR testing of stool for the virus and should be considered in anyone with recalcitrant diarrheal illness. Treatment is largely supportive, but nitazoxanide 500 mg, twice daily may be effective.

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Pathophysiology

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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, Brand, R, Hoek, J, de la Camara, R, Cordonnier, C, Einsele, H. “Donor cytomegalovirus status influences the outcome of allogeneic stem cell transplant: a study by the European group for blood and marrow transplantation”. Clin Infect Dis.. vol. 59. 2014. pp. 473-81. (Analysis of nearly 50,000 BMT recipients demonstrating the important roles that pre-transplant recipient and donor CMV serostatus play in determining outcomes).

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.)

Waghmare, A, Englund, JA, Boeckh, M.. “How I treat respiratory viral infections in the setting of intensive chemotherapy or hematopoietic cell transplantation”. Blood. 2016. (Excellent review of treatment options for respiratory viral infections in BMT recipients.)

Boeckh, M, Nichols, WG, Chemaly, RF, Papanicolaou, GA, Wingard, JR, Xie, H. “Valganciclovir for the prevention of complications of late cytomegalovirus infection after allogeneic hematopoietic cell transplantation: a randomized trial”. Ann Intern Med.. vol. 162. 2015. pp. 1-10. (Prospective study demonstrating similar outcomes for two CMV prevention strategies: valganciclovir prophylaxis and CMV PCR-guided pre-emptive therapy.)

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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