Bacterial and fungal pneumonias are common co-infections with CMV. 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.
Treatment of GI tract disease usually requires a longer duration of induction therapy weeks , followed by maintenance. There is no indication that IVIg adds to therapeutic outcomes.
CMV can become resistant to multiple antivirals, especially in the setting that predicts viral replication during low-dose drug exposure e. 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.
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. 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.
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.
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. Cellular immunotherapies are being developed. Antivirals do not have a documented role in management. 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. 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.
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.
Neuraminidase inhibitors e. The treatment dose is 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 which was associated with worse outcomes compared to seasonal influenza. 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. 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 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.
Similarly, anti-protein F antibody palivizumab , may be a therapeutic option, although it has not been evaluated for efficacy in BMT patients. Flynn, J. Goldman, R. Ramsay, J. Among patients undergoing allogeneic bone marrow transplantation over a five-year period through , cytomegalovirus CMV infection was a frequent and often lethal complication.
Recipient pretransplant serology was the most important predictor of posttransplant CMV infection. Among patients who developed CMV infection, the time to infection was identical in seronegative and seropositive patients median, 71 days post transplant.
Patients who developed CMV infections had also received more cellular blood products post transplant. These data suggest that CMV infection may occur through reactivation of latent virus in seropositive recipients or through exogenous exposure, possibly through transfused blood products, but the duration of immunoincompetence may be more critical than route of exposure in timing of clinically evident CMV infection.
Prophylaxis tailored to the likely infectious source and more effective GVHD prevention both may be critical in preventing CMV infection after bone marrow transplantation. Cytomegalovirus infection after bone marrow transplantation : An association with acute graft-v-host disease. N2 - Among patients undergoing allogeneic bone marrow transplantation over a five-year period through , cytomegalovirus CMV infection was a frequent and often lethal complication.
In prophylactic therapy, Gancyclovir, acyclovir, valacyclovir and forcarnet have been shown to be effective. When laboratory support in the form of availability of sensitive rapid molecular tests such as CMV DNA PCR is available, the pre-emptive strategy is preferable and most centres now prefer this approach[ 46 , 47 ].
Patients must be screened for viremia or antigenemia once a week from days [ 45 ]. Gancyclovir is most commonly used followed by foscarnet and cidofovir[ 48 , 49 ]. The therapy may be given for 2 wk or till the virus falls to below detection levels or up to d[ 34 ]. The genotype of the infecting CMV strain can be tested and Second line drugs must be considered[ 24 ].
Foscarnet is preferred in cases with myelosuppression or known GCV resistance but nephrotoxicity which may lead to acute renal failure or electrolyte abnormality is a major limiting factor[ 50 ]. Cidofovir is a third line agent for CMV, but again, myelotoxicity and nephrotoxicity are major side effects. Gastrointestinal CMV is generally treated with intravenous gancyclovir for several weeks; alternatively foscarnet may also be used[ 24 ].
However the supposed beneficial role of CMV specific immunoglobulin or pooled IVIG is still not clear from available studies[ 51 , 52 ]. There is a need to further standardize and evolve a consensus on the frequency and cut off values of viral load estimations used in pre-emptive therapy.
Maribavir in high dosage can be used for treatment of resistant cases[ 53 ]. Maribavir does not cause myelosuppression.
Immune augmentation by using transfer of donor derived CMV specific T-cells have shown promising response in refractory cases without significant toxicity[ 54 ]. The anti CMV effect of drugs like artisunate and sirolimus also need to be further explored[ 24 ]. Tests to detect antiviral resistance should be available more easily. Conflict-of-interest statement: The authors declare no conflicts of interest regarding this manuscript.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. Peer-review started: June 5, First decision: August 10, Article in press: November 17, National Center for Biotechnology Information , U. Journal List World J Transplant v. World J Transplant. Published online Dec Author information Article notes Copyright and License information Disclaimer.
Published by Baishideng Publishing Group Inc. All rights reserved. This article has been cited by other articles in PMC. Abstract Cytomegalovirus CMV infection is an important contributor to the morbidity and mortality associated with bone marrow transplantation BMT. Keywords: Cytomegalovirus, Infection, Bone marrow transplant. Pathogenesis CMV can ubiquitously infect any cell in human body. Clinical manifestations Infection with CMV is a major cause for morbidity and mortality in immunocompromised patients, particularly in transplant recipients[ 21 , 22 ].
Central nervous system infections Central nervous system CNS involvement is seen in patients with profound immunodeficiency disorder as in BMT or acquired immunodeficiency syndrome AIDS patients[ 31 ]. Miscellaneous disorders Cystitis, nephritis, myocarditis, pancreatitis can also be rarely seen in patients with CMV infection in BMT cases[ 37 ].
Diagnosis Several diagnostic methods are available for diagnostic surveillance of patients at risk of acquiring CMV infection. Treatment of CMV disease Gastrointestinal CMV is generally treated with intravenous gancyclovir for several weeks; alternatively foscarnet may also be used[ 24 ].
Future perspectives There is a need to further standardize and evolve a consensus on the frequency and cut off values of viral load estimations used in pre-emptive therapy. Footnotes Conflict-of-interest statement: The authors declare no conflicts of interest regarding this manuscript.
References 1. The human cytomegalovirus. Pharmacol Ther. Minton K. Viral immunity: How CMV bypasses immune memory. Nat Rev Immunol. Griffiths PD. Principles and Practice of Clinical Virology. London: John Wiley and Sons; Clinical aspects and management of cytomegalovirus infection. J Infect. Improving cytomegalovirus-specific T cell reconstitution after haploidentical stem cell transplantation.
J Immunol Res. Pre-transplant cytomegalovirus CMV serostatus remains the most important determinant of CMV reactivation after allogeneic hematopoietic stem cell transplantation in the era of surveillance and preemptive therapy.
Transpl Infect Dis. Zaia JA. Cytomegalovirus infections. Hematopoietic Cell Transplantation. Malden: Blackwell Science; Cytomegalovirus cell tropism. Curr Top Microbiol Immunol. Cytomegalovirus antigen within human arterial smooth muscle cells. High risk of death due to bacterial and fungal infection among cytomegalovirus CMV -seronegative recipients of stem cell transplants from seropositive donors: evidence for indirect effects of primary CMV infection.
J Infect Dis. Role of cytomegalovirus infection in allograft rejection: a review of possible mechanisms. Transpl Immunol.
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