PMCCPMCCPMCC

Search tips
Search criteria 

Advanced

 
Logo of ajbrLink to Publisher's site
 
Am J Blood Res. 2012; 2(4): 203–218.
Published online Nov 25, 2012.
PMCID: PMC3512176
Management of respiratory viral infections in hematopoietic cell transplant recipients
Dimpy P Shah,1,2 Shashank S Ghantoji,1,2 Victor E Mulanovich,1 Ella J Ariza-heredia,1 and Roy F Chemaly1,2
1Department of Infectious Diseases, Infection Control, and Employee Health, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
2The University of Texas School of Public Health, Houston, TX, USA
Address correspondence to: Dr. Roy F Chemaly, Department of Infectious Diseases, Infection Control, and Employee Health, Box 402, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030-4009. Phone: 713-7451116; Fax: 713-7456839; E-mail: rfchemaly/at/mdanderson.org
Received October 3, 2012; Accepted October 22, 2012.
Advances in stem cell transplantation procedures and the overall improvement in the clinical management of hematopoietic cell transplant (HCT) recipients over the past 2 decades have led to an increase in survival duration, in part owing to better strategies for prevention and treatment of post-transplant complications, including opportunistic infections. However, post-HCT infections remain a concern for HCT recipients, particularly infections caused by community respiratory viruses (CRVs), which can lead to significant morbidity and mortality. These viruses can potentially cause lower respiratory tract illness, which is associated with a higher mortality rate among HCT recipients. Clinical management of CRV infections in HCT recipients includes supportive care and antiviral therapy, especially in high-risk individuals, when available. Directed antiviral therapy is only available for influenza infections, where successful use of neuraminidase inhibitors (oseltamivir or zanamivir) and/or M2 inhibitors (amantadine or rimantadine) has been reported. Data on the successful use of ribavirin, with or without immunomodulators, for respiratory syncytial virus infections in HCT recipients has emerged over the past 2 decades but is still controversial at best because of a lack of randomized controlled trials. Because of the lack of directed antiviral therapy for most of these viruses, prevention should be emphasized for healthcare workers, patients, family, and friends and should include the promotion of the licensed inactivated influenza vaccine for HCT recipients, when indicated. In this review, we discuss the clinical management of respiratory viruses in this special patient population, focusing on commercially available antivirals, adjuvant therapy, and novel drugs under investigation, as well as on available means for prevention.
Keywords: RSV, influenza, parainfluenza, adenovirus, rhinovirus, metapneumovirus, HCT, transplant, cancer, immunocompromised host, antiviral therapy, infection prevention
Over the past 2 decades, advances in stem cell transplantation procedures and improvements in the clinical management of hematopoietic cell transplant (HCT) recipients, including better strategies for the prevention and treatment of post-transplant complications such as opportunistic infections, have led to an increase in survival duration [1]. HCT recipients are, however, still particularly susceptible to community respiratory viruses (CRVs) owing to a decreased host immune response, mainly because of a shortage of T cell lymphocytes [2]. CRVs, including respiratory syncytial virus (RSV), influenza virus, parainfluenza virus (PIV), human adenovirus (HAdV), human metapneumovirus (HMPV), human rhinovirus (HRhV), and human coronavirus (HCoV), have been reported to cause infections in this population at incidences between 1% and 30%, as shown in Figure 1 [3-7]. Other newly discovered viruses such as human bocavirus (HBoV) are emerging as potential causes of respiratory infections, but data on their impact in this population are lacking. All of these CRVs can potentially cause lower respiratory tract illnesses (LRTI) (rates of LRTI range from 5% to 50%), which could be associated with high mortality rates (10% to 50%) in HCT recipients [3-8]. As demonstrated in Figure 1, HAdV, HRhV, and HCoV have equally higher incidences in HCT recipients, whereas LRTI rates are higher for RSV, influenza, PIV, HAdV, and HMPV. Other late complications, such as bronchiolitis obliterans and organizing pneumonia, have been associated with some of these viral infections (i.e., RSV, PIV, and HMPV) [8,9], but the direct relationship needs to be better elucidated.
Figure 1
Figure 1
Incidence of respiratory viral infections and associated LRTI and mortality in HSCT recipients. Data obtained from [3,5,6,21]. *CRV indicates common respiratory viral infections; HSCT, hematopoietic stem cell transplant; LRTI, lower respiratory tract (more ...)
HCT recipients with CRV infections may present with various combinations of upper respiratory tract infection (URTI) symptoms such as rhinorrhea, nasal or sinus congestion, cough, low-grade fever, headache, otitis media, wheezing, and sore throat. Some patients may present with LRTI, with symptoms including dyspnea and hypoxemia and radiologic findings that include new or changing bilateral interstitial infiltrates. These signs and symptoms are suggestive of viral etiology, but laboratory confirmation is needed for a definitive diagnosis. Viral culture is the gold standard for diagnosing CRVs, but the time required for a culture to become positive is a limiting factor, especially in immunocompromised patients, where prompt institution of treatment is of utmost importance [10,11]. Direct immunofluorescence antigen testing is a rapid and inexpensive alternative, but it has low sensitivity (50% to 93%) [12-17]. More sensitive and specific modalities include molecular assays (e.g., multiplex polymerase chain reaction [PCR]) that test for multiple different viruses [18-20], and real-time PCR is becoming the most preferred method for diagnosing viral infections.
The management of CRV infections in HCT recipients includes supportive care and, when available, antiviral therapy, especially in individuals at high risk of developing LRTI. Some evidence of successful antiviral therapy has been reported with ribavirin for RSV, oseltamivir, zanamivir, and/or M2 inhibitors for influenza, and cidofovir for HAdV. There are also some anecdotal reports of PIV and HMPV infections being successfully treated with a combination of ribavirin and intravenous immunoglobulins (IVIGs). However, none of these regimens have been tested in randomized controlled trials to determine their efficacy in HCT recipients and, therefore, are not licensed by the US Food and Drug Administration (FDA) for virus-specific therapy in these patients.
With the high morbidity and mortality rates associated with CRV infections and the lack of directed antiviral therapy for most of these infections, prevention remains the mainstay for reducing their incidence and controlling transmission in HCT recipients. A licensed vaccine is only available for the influenza virus, and its use should be encouraged in all HCT recipients, when indicated, as well as in healthcare workers and family members. Infection control measures should be emphasized for healthcare workers and patients alike and should focus on basic precautions such as frequent hand washing and the use of protective equipment such as face masks, gowns, and gloves.
In this review, we discuss the available data behind the use of antiviral therapy, adjuvant therapy, and novel investigational drugs, as well as available means for prevention, in each respiratory virus with a significant incidence in HCT recipients.
This paramyxovirus (RNA virus) affects 2-17% of HCT recipients on a seasonal basis, with the highest incidence between the fall and spring [16,21-25]. Factors reported to be associated with the acquisition of RSV infection include male sex, allogeneic transplantation, cytomegalovirus seropositivity, and pre-engraftment status [25-27]. URTI is the most common presentation and may progress to LRTI in 17% to 84% of patients [5,21,22,27-32]. Risk factors associated with progression to LRTI include older age, myeloablative regimen, lymphopenia, mismatched or unrelated donor transplant, graft-versus-host disease (GVHD), and pre-engraftment status or early post-transplantation period [5,21,22,24-26,29,33]. RSV-LRTI in HCT recipients increases the likelihood of a fatal outcome; therefore, prompt diagnosis and early intervention at URTI stage may be indicated in patients at risk of LRTI [21].
Treatment
Aerosolized ribavirin is the only drug that has been approved by the FDA for the treatment of high-risk infants and young children hospitalized with RSV-LRTI [34]. In our recent systematic review on this subject, we reported that ribavirin-based therapy had variable success rates for preventing RSV-associated morbidity or mortality in high-risk HCT recipients [21]. In that review, we examined published studies to determine the efficacy of various routes of ribavirin administration (oral, intravenous, and aerosol), with or without immunomodulators (palivizumab and IVIGs), as therapy for RSV infections in adult HCT recipients. Based mostly on retrospective data, we found that patients treated with ribavirin with or without an immunomodulator had better outcomes than those not treated (16% vs. 45% rate of progression to LRTI and 35% vs. 70% mortality rate) [21]. In a recently published randomized clinical trial in HSCT recipients with RSV-URTI comparing two dose schedules of aerosolized ribavirin (continuous vs. intermittent), both of them were identified to be effective in preventing RSV-LRTI [35]. Time of administration may play an important role in the success of ribavirin-based therapy, with those treated at URTI stage having more favorable outcomes than those treated at LRTI stage, irrespective of the regimen [21].
An investigational monoclonal antibody, motavizumab, was compared with palivizumab for RSV prophylaxis in in vitro experiments, in a cotton rat model, and in phase III trials in preterm infants which showed comparative efficacy for these two drugs [36-38]. However, the FDA did not approve motavizumab in a recent filing, in part because the drug caused some non-fatal hypersensitivity adverse events, which may have been more severe in the sick child population where it is indicated than in healthy children [39]. ALN-RSV01 (Alnylam Pharmaceuticals, Cambridge, MA) interferes with viral replication and has shown some promising results in two randomized clinical trials. When used for prophylaxis, it reduced the occurrence of RSV infection by 44% in healthy individuals [40]. In lung transplant recipients, ALN-RSV01 decreased the incidence or the progression of bronchiolitis obliterans when used as therapy for RSV infection (6.3% vs. 50% in treated vs. non-treated groups, respectively) [41]. Whether this drug will be tested in phase III trials, and specifically in HCT recipients, is not known.
Prevention
No vaccine is yet available for RSV. Passive immunoprophylaxis for high-risk HCT recipients with RSV-IVIG was tested in a small study, which failed to determine its efficacy [42]. On the other hand, the use of palivizumab for prophylaxis in young children undergoing HCT was suggested by the 2009 international HCT guidelines [43]. It was also successful in controlling an outbreak of nosocomial transmission of RSV in a HCT unit and is well tolerated in this patient population [44,45]. However, the high cost of these drugs combined with a lack of clear evidence of efficacy in this patient population precludes their wide-scale acceptance. Infection control measures to prevent new infections and subsequent transmission remain the best approach for decreasing the burden of RSV in HCT recipients. Overall awareness among healthcare personnel and caregivers about the possible deleterious outcomes of RSV infections in HCT recipients and the importance of their early detection may have a major impact on the incidence of RSV infections and subsequent complications. More specifically, adherence to contact and respiratory droplet isolation, along with hand hygiene, will help reduce RSV infections in HCT recipients.
This orthomyxovirus causes seasonal outbreaks in HCT recipients, especially during the winter months. It has 2 types of glycoproteins (hemagglutinins [H1, H2, and H3] and neuraminidases [N1 and N2]), which undergo antigenic drifts and shifts that cause epidemics and pandemics, respectively. Patients may develop various combinations of constitutional symptoms (e.g., fatigue, malaise, myalgia) and URTI symptoms (e.g., rhinorrhea, cough, sore throat), thus presenting with the typical ‘flu-like’ illness, or may present with minimal respiratory symptoms and/or fever. The incidence rate of influenza infection in HCT recipients ranges from 1.3% to 2.6% [3,6]; however, this rate can vary depending on the dominant strain of influenza virus during a particular season. Progression to LRTI is particularly common in immunocompromised hosts such as HCT recipients [46,47]. The incidence rates of LRTI can range from 7% to 35%, and the associated risk factors for this outcome include lymphocytopenia and recent transplant [3,6]. Mortality rates following LRTI can range from 15% to 28% [6]. Influenza infection is suspected in patients with “flu-like” symptoms during community outbreaks; however, prompt confirmation by immunofluorescence assays, enzyme immunoassays, cultures, or PCR-based assays is needed, especially in immunocompromised patients, as early initiation of antiviral therapy may positively affect outcome [10,11].
Treatment
The two main classes of anti-influenza drugs are neuraminidase inhibitors (e.g., oseltamivir and zanamivir) and M2 inhibitors (e.g., amantadine and rimantadine). Prompt initiation of therapy, preferably within 24-48 hours of onset of symptoms, is essential to prevent complications in patients with cancer, including HCT recipients [10,11]. Nausea and vomiting are the most common side effects of oseltamivir, whereas central nervous system toxicities have been reported more frequently with amantadine [3].
Recommendations for the treatment of influenza infections have changed over the past few years to address the changes in the susceptibility patterns of different strains of influenza virus each season (Table 1). While its resistance to oseltamivir has increased, seasonal H1N1 has remained susceptible to zanamivir and M2 inhibitors [48-50] (http://www.cdc.gov./h1n1flu/immunosuppression/index.htm; http://www.who.int/csr/resources/publications/swineflu/h1n1_use_antivirals_20090820/en/index.html.), whereas the rece-nt pandemic 2009/H1N1 strain was only susceptible to oseltamivir and zanamivir. In a retrospective study comparing seasonal influenza with pandemic 2009/H1N1 in children with cancer, early initiation of antiviral therapy was critical in preventing LRTI and death from both strain [11].
Table 1
Table 1
Antiviral susceptibility patterns for various strains of human influenza virusa,b,c
Intravenous formulations of neuraminidase inhibitors such as peramivir and zanamivir are still being evaluated in phase III clinical trials [51-54]. This intravenous route may be advantageous for patients with graft versus host disease (GVHD) of the gastrointestinal tract, because of possible decreased absorption and less bioavailability of oral drugs, or for those with LRTI or lung injury, where the inhalation route of the drugs may not be appropriate. DAS181 is a new investigational antiviral drug that acts by removing from the respiratory epithelial cell surface the sialic acid residues that are essential for viral entry and infection [55,56]. This drug is undergoing phase II trials after promising results were seen against oseltamivir- and zanamivir-resistant strains in vitro and in mouse models [57-60]. Favipravir (T-705), another drug under investigation that inhibits viral replication by targeting viral-specific RNA-dependent RNA polymerase, is currently undergoing phase II trials [61-64]. Finally, the longacting neuraminidase inhibitor laninamivir had efficacy comparable to that of oseltamivir for the treatment of influenza infection in a large double-blind, randomized, non-inferiority clinical trial [65]. It may also be effective against oseltamivir-resistant influenza strains and is currently available in Japan [66,67]. Adjunctive therapy for influenza infections has yielded conflicting results. For example, corticosteroid therapy, possibly owing to its anti-inflammatory properties, has been shown to decrease the rates of LRTI; however, it has also been observed to prolong viral shedding [10,47,68].
Prevention
Intramuscular inactivated influenza virus vaccine is recommended annually for immunocompromised patients such as HCT recipients who are able to mount an immunologic response to the vaccine and for healthcare personnel, close family members, and friends [69]. HCT recipients may not, however, have the desired immune response to the influenza vaccine; which can be up to 50% lower than that observed in the general population [70-72]. Therefore, the Advisory Committee on Immunization Practices recommended daily chemoprophylaxis with an effective antiviral drug for immunocompromised individuals during community outbreaks [69]. Furthermore, the updated guidelines of the American Society of Bone Marrow Transplantation recommended annual inactivated influenza vaccination before the beginning of the influenza season and before transplantation or 4 to 6 months following transplantation [43]. The vaccine should be administered prior to the onset of the influenza season to avoid new infections and related complications. The main two contraindications for influenza vaccine are febrile illness and severe allergy to eggs [73]. Additionally, in cases of community or nosocomial outbreaks, prophylaxis and preemptive treatment with a strain-specific antiviral agent should be administered to all HCT recipients within 24 months of transplantation and to those who have GVHD and/or are taking immunosuppressive therapy [43]. The efficacy of oseltamivir prophylaxis (75 mg/day) in reducing the incidence of influenza infections during the peak of the season was reported by a randomized, double-blind, placebo-controlled trial in immunocompromised patients [74]. On the other hand, some studies have shown that oseltamivir prophylaxis may occasionally lead to the selection of resistant influenza strains, as during the 2009/H1N1 pandemic [75-77]. Last, but not the least, infection control practices should be strictly observed to prevent new infections and reduce transmission during community and nosocomial outbreaks.
PIV is an enveloped, single-stranded, RNA paramyxovirus comprising four antigens sharing serotypes. PIV infects 2.5% to 7.1% of HCT recipients, with the highest incidence observed during the summer season [4,26,78-80]. PIV type 3 is responsible for up to 90% of these infections, with URTI being the most common presentation following an incubation period of 1 to 4 days. The main risk factors reported in the literature for acquiring PIV in HCT recipients are a transplant from an unrelated donor [26] and CD4 lymphopenia in T-cell-depleted patients [81]. PIV is clinically indistinguishable from other CRVs encountered in immunocompromised patients; therefore, laboratory confirmation is important. Modalities used to diagnose PIV include rapid antigen testing, enzyme immunoassays, real-time PCR, and viral cultures [14,82-84]. One of the most common complications following PIV-URTI is progression to LRTI, which occurs at a rate of 20% to 39% in HCT recipients, with an associated mortality rate of up to 30% [4,80]. The associated risk factors for progression to LRTI include neutropenia, lymphopenia, systemic corticosteroid use, high APACHE II score at presentation, and pulmonary co-infections [79,81]. Furthermore, subsequent late airflow obstruction may be associated with PIV-URTI as well as PIV-LRTI [9].
Treatment
Ribavirin use for the treatment of PIV infections has shown promising results in animal models and children with severe combined immunodeficiency [85,86]. However, ribavirin therapy, with or without IVIG, has had conflicting results in PIV-infected HCT recipients in the absence of randomized clinical trials [4,8,79,80,87]. Mainly in large case series, ribavirin had no effect on viral shedding, duration of symptoms, length of hospital stay, progression to PIV-LRTI, or mortality associated with these infections in HCT recipients [4,79,80]. Many novel drugs, such as DAS-181 (a recombinant sialidase protein) and BCX2798 (a hemagglutinin-neuraminidase inhibitor), are being evaluated for the treatment of PIV infections [88-90]. However, no PIV-specific antiviral therapy is commercially available, and clinical management of HCT recipients relies on supportive care. The impact of IVIG on overall outcome still needs to be determined.
Prevention
In the absence of an effective therapy or vaccine, infection control measures are the mainstay for preventing the spread of PIV in HCT recipients. Contact isolation, hand hygiene, and wearing masks and gloves, along with universal precautions, should be emphasized for healthcare personnel, family members, and visitors, as 17% to 22% of these infections may be acquired in the healthcare setting [4,79].
Occurring throughout the year, HAdV belongs to the Adenoviridae family of DNA viruses with 6 subgroups and 51 known serotypes. It may infect up to 3% of HCT recipients overall, but has a higher incidence in allogeneic (6%) and pediatric (24-32%) HCT recipients [6,16,91-94]. Since T lymphocytes are crucial for building an immune response against HAdV infections, HCT recipients are most susceptible to these infections during post-transplant T cell suppression [95]. Consequently, risk factors unique to HCT recipients that may lead to acquiring adenoviral infections are GVHD, transplant from an unrelated donor, total body irradiation, presence and severity of T-cell depletion, recent transplantation, and T cell suppression following transplantation [95-99]. The clinical presentation may be similar to other respiratory viruses; however, any organ system can be affected and disseminated disease can occur without involvement of the respiratory system. The mortality rate in HCT recipients can be high (15-28%), especially in those with disseminated disease following DNAemia or LRTI [94,95,100,101].
Many diagnostic tests are available for HAdV detection, including enzyme immunoassays, immunofluorescence assays, PCR assays, and viral cultures [12,13]. Additionally, quantitative viral loads were shown to predict clinical response and prognosis, with high titers (more than 1 x 106 DNA copies/mL) correlating with increased risk of death [102,103].
Treatment
A lack of randomized controlled trials makes it difficult to ascertain the efficacy of available antiviral drugs for the treatment of HAdV infections, especially in HCT recipients. Cidofovir, a monophosphate nucleoside analogue of cytosine, appears to be the most effective agent in vitro against HAdV [104-106], and no HAdV strains have been shown to be clinically resistant to this drug [107]. In a recent review of the management of HAdV in HCT recipients, Lindemans et al recommended that vigilant monitoring using PCR assays in combination with preemptive cidofovir therapy may be the best strategy currently available to “bridge the severely immunocompromised period” following HCT [106]. Preemptive treatment with cidofovir, before dissemination of HAdV or endorgan disease, may be of prime importance, given the high mortality rates associated with these conditions [108]. However, the main limiting factor in cidofovir use is its associated side effects, mainly the high incidence of nephrotoxicity, including increased serum creatinine levels (up to 25% of cases), proteinuria following renal proximal tubule dysfunction (50% of cases), and, rarely, Fanconi syndrome (1% of cases) [105,109,110].
CMX001, a lipid conjugate of cidofovir, is an oral investigational drug with activity against HAdV in animal models [111] and in humans [112] and without untoward nephrotoxic effects. A few immunocompromised patients with adenoviral infections have been successfully treated with CMX001, without any serious adverse events reported [113,114]. Currently, oral CMX001is undergoing study in a phase II trial for the treatment of HAdV infections in HCT recipients.
Other drugs used for the treatment of HAdV diseases include ribavirin (oral or aerosolized) and ganciclovir; however, the data derived are mostly from uncontrolled studies, and the results are conflicting. Therefore, these drugs are not routinely recommended for the treatment of adenoviral diseases [97,115-118]. Immunotherapy with specific and non-specific T cells given exogenously has also been tried in several small studies with favorable outcomes [119-122].
Prevention
After production of adenovirus vaccine was stopped in 1996 because of a lack of funding, a new live oral vaccine against adenovirus types 4 and 7 was approved by the FDA in March 2011 for new military recruits entering basic training or military personnel who may be at higher risk for infection (http://www.cdc.gov/vaccines/pubs/vis/downloads/vis-adenovirus.pdf). For haploidentical stem cell transplant or cord blood transplant recipients, weekly PCR surveillance and pre-emptive therapy with cidofovir may be used to decrease the risk of disseminated disease [95,104]. As mentioned above, maintaining T cell function by using a reduced-intensity conditioning regimen and exogenous immunotherapy may be a good strategy to prevent reactivation of latent adenoviral infection and disseminated disease in HCT recipients [120-124]. Overall, general safety precautions, along with infection control measures, are recommended to decrease its horizontal transmission.
Commonly known to cause “the common cold” in the general population, these non-enveloped RNA picornaviruses may cause severe infections in immunocompromised hosts such as HCT recipients [125-127]. Although they occur throughout the year, fall and spring are the peak seasons for these infections, with the highest incidence in children, who also act as reservoirs for this virus. Self-inoculation and respiratory droplets are the common modes of transmission [128]. An incidence rate of 32% was reported in HCT recipients [125], and rates of progression to LRTI and mortality could be as high as 55% and 33%, respectively [6,125,126]. The prognosis largely depends upon the severity of immunosuppression.
Treatment
Currently, no specific antiviral therapy is available, and treatment is mainly supportive with antihistamines, decongestants, and non-steroidal anti-inflammatory drugs [3]. Many novel drugs, such as pleconaril, BTA-798, and inhaled interferon-β 1a (SNG001), are being tested in the general patient population with rhinovirus infections; however, their role in HCT recipients is uncertain [129,130].
Prevention
A vaccine for human rhinovirus seems implausible at the moment because of the sheer number of strains causing infections [128,131], and general infection control practices are recommended for controlling its horizontal transmission.
Human coronavirus (NL63 and HK)
HCoV is commonly encountered in the fall and spring seasons and may cause respiratory illnesses every 2-4 years. The clinical presentation is very similar to rhinovirus infections, and a definitive diagnosis can be made using PCR-based methods. Generally a self-limiting disease, this infection can progress to LRTI in HCT recipients [132]. Data are limited on the morbidity and mortality of these infections in immunocompromised hosts; however, a higher incidence rate was reported when compared to immunocompetent hosts (8.8% vs. 4-5%, respectively) [8]. Neither specific antiviral therapy nor a vaccine is available for HCoV, and supportive care with general infection control practices is recommended.
Human metapneumovirus
This newly discovered negative sense RNA paramyxovirus [133], which is genetically very similar to RSV, is reported to infect about 5-9% of HCT recipients [27,134]. The rate of progression to LRTI can range from 21% to 40%, and the mortality rate increases with the onset of LRTI (33-40%) [6] . High fatality rates (80%) in HCT recipients with positive bronchoalveolar lavages for HMPV and the potential for the virus to cause bronchiolitis obliterans, based on histological assessment, have been reported [135]. With clinically indistinguishable presentation compared to other respiratory viruses and unreliable growth of diagnostic cultures, this infection is best diagnosed using PCR-based assays or direct antigen detection. No drugs are currently licensed to treat HMPV infection, and the only drug shown to be active against this virus is ribavirin; however, there is a dearth of knowledge about this virus and its treatment [136,137]. A recent retrospective study examined the efficacy of ribavirin combined with IVIG in HCT recipients with HMPV-LRTI. No difference in mortality rates was observed between treated (n = 13) and untreated (n = 10) patients [138]. There is no vaccine available for HMPV, and general infection control practices are recommended for controlling its transmission.
Human bocavirus
A seemingly common virus affecting children worldwide, the impact of HBoV in HCT recipients is unclear [139]. A recent survey of 51 children with acute lymphoblastic leukemia identified HBoV in 5.6% of nasal swabs [140]. No drugs or vaccine is currently available for HBoV.
Despite overall advances in clinical management, respiratory viruses still remain a source of concern for HCT recipients because of the significant morbidity and mortality associated with these infections and the lack of directed antiviral therapy for most of these viruses. Randomized clinical trials are needed to determine the efficacy of novel antiviral agents, and future research should focus on developing potent vaccines to prevent outbreaks and epidemics in the community. Prevention of CRVs should be emphasized for healthcare workers and patients alike, with a focus on general safety precautions (Table 2).
Table 2
Table 2
Infection control guidelines at various levels of intervention
Acknowledgements
We thank Dawn Chalaire, Department of Scientific Publications, The University of Texas MD Anderson Cancer Center, for editorial support.
Financial support
This research was supported in part by the National Institutes of Health through MD Anderson’s Cancer Center Support Grant CA016672.
Conflict of interest statement
Authors have no conflicts of interest to declare.
1. Gooley TA, Chien JW, Pergam SA, Hingorani S, Sorror ML, Boeckh M, Martin PJ, Sandmaier BM, Marr KA, Appelbaum FR, Storb R, Mc-Donald GB. Reduced mortality after allogeneic hematopoietic-cell transplantation. N Engl J Med. 2010;363:2091–2101. [PMC free article] [PubMed]
2. Duncan MD, Wilkes DS. Transplant-related immunosuppression: A review of immunosuppression and pulmonary infections. Proceedings of the American Thoracic Society. 2005;2:449–455. [PMC free article] [PubMed]
3. Chemaly RF, Rathod DB, Couch R. Respiratory Viruses. In: Safdar A, editor. Principles and Practice of Cancer Infectious Diseases. USA: Humana Press; 2011. p. 371.
4. Chemaly RF, Hanmod SS, Rathod DB, Ghantoji SS, Jiang Y, Doshi A, Vigil K, Adachi JA, Khoury AM, Tarrand J, Hosing C, Champlin R. The characteristics and outcomes of parainfluenza virus infections in 200 patients with leukemia or recipients of hematopoietic stem cell transplantation. Blood. 2012;119:2738–2745. [PubMed]
5. Chemaly RF, Ghosh S, Bodey GP, Rohatgi N, Safdar A, Keating MJ, Champlin RE, Aguilera EA, Tarrand JJ, Raad II. Respiratory viral infections in adults with hematologic malignancies and humanstem cell transplantation recipients: A retrospective study at a major cancer center. Medicine (Baltimore) 2006;85:278–287. [PubMed]
6. Renaud C, Campbell AP. Changing epidemiology of respiratory viral infections in hematopoietic cell transplant recipients and solid organ transplant recipients. Current Opinion in Infectious Diseases. 2011;24:333–343. [PMC free article] [PubMed]
7. Whimbey E, Englund JA, Couch RB. Community respiratory virus infections in immunocompromised patients with cancer. The American Journal of Medicine. 1997;102:10–18. discussion 25-16. [PubMed]
8. Boeckh M. The challenge of respiratory virus infections in hematopoietic cell transplant recipients. Br J Haematol. 2008;143:455–467. [PMC free article] [PubMed]
9. Erard V, Chien JW, Kim HW, Nichols WG, Flowers ME, Martin PJ, Corey L, Boeckh M. Airflow decline after myeloablative allogeneic hematopoietic cell transplantation: The role of community respiratory viruses. J Infect Dis. 2006;193:1619–1625. [PubMed]
10. Choi SM, Boudreault AA, Xie H, Englund JA, Corey L, Boeckh M. Differences in clinical outcomes following 2009 influenza A/H1N1 and seasonal influenza among hematopoietic cell transplant recipients. Blood. 2011;117:5050–6. [PubMed]
11. Shah DP, El Taoum KK, Shah JN, Vigil KJ, Adachi JA, Granwehr BP, Tarrand JJ, Raad II, Chemaly RF. Characteristics and outcomes of pandemic 2009/H1N1 versus seasonal influenza in children with cancer. Pediatr Infect Dis J. 2012;31:373–378. [PubMed]
12. Raboni SM, Siqueira MM, Portes SR, Pasquini R. Comparison of PCR, enzyme immunoassay and conventional culture for adenovirus detection in bone marrow transplant patients with hemorrhagic cystitis. Journal of clinical virology: the official publication of the Pan American Society for Clinical Virology. 2003;27:270–275. [PubMed]
13. Raty R, Kleemola M, Melen K, Stenvik M, Julkunen I. Efficacy of PCR and other diagnostic methods for the detection of respiratory adenoviral infections. J Med Virol. 1999;59:66–72. [PubMed]
14. Ray CG, Minnich LL. Efficiency of immunofluorescence for rapid detection of common respiratory viruses. J Clin Microbiol. 1987;25:355–357. [PMC free article] [PubMed]
15. Raanani P, Gafter-Gvili A, Paul M, Ben-Bassat I, Leibovici L, Shpilberg O. Immunoglobulin prophylaxis in hematopoietic stem cell transplantation: Systematic review and meta-analysis. J. Clin. Oncol. 2009;27:770–781. [PubMed]
16. Raboni SM, Nogueira MB, Tsuchiya LRV, Takahashi GA, Pereira LA, Pasquini R, Siqueira MM. Respiratory Tract Viral Infections in Bone Marrow Transplant Patients. Transplantation. 2003;76:142–146. [PubMed]
17. Ohm-Smith MJ, Nassos PS, Haller BL. Evaluation of the Binax NOW, BD Directigen, and BD Directigen EZ assays for detection of respiratory syncytial virus. J Clin Microbiol. 2004;42:2996–2999. [PMC free article] [PubMed]
18. Krunic N, Yager TD, Himsworth D, Merante F, Yaghoubian S, Janeczko R. xTAG™ RVP assay: analytical and clinical performance. J Clin Virol. 2007;40:S39–S46. [PubMed]
19. Balada-Llasat JM, LaRue H, Kelly C, Rigali L, Pancholi P. Evaluation of commercial Res-Plex II v2.0, MultiCode ®-PLx, and xTAG ® respiratory viral panels for the diagnosis of respiratory viral infections in adults. J Clin Virol. 2011;50:42–45. [PubMed]
20. Rand KH, Rampersaud H, Houck HJ. Comparison of two multiplex methods for detection of respiratory viruses: Filmarray RP and xTAG RVP. J Clin Microbiol. 2011;49:2449–2453. [PMC free article] [PubMed]
21. Shah JN, Chemaly RF. Management of RSV infections in adult recipients of hematopoietic stem cell transplantation. Blood. 2011;117:2755–2763. [PubMed]
22. Whimbey E, Champlin RE, Couch RB, Englund JA, Goodrich JM, Raad I, Przepiorka D, Lewis VA, Mirza N, Yousuf H, Tarrand JJ, Bodey GP. Community respiratory virus infections among hospitalized adult bone marrow transplant recipients. Clin Infect Dis. 1996;22:778–782. [PubMed]
23. Khanna N, Widmer AF, Decker M, Steffen I, Halter J, Heim D, Weisser M, Gratwohl A, Fluckiger U, Hirsch HH. Respiratory syncytial virus infection in patients with hematological diseases: Single-center study and review of the literature. Clin Infect Dis. 2008;46:402–412. [PubMed]
24. Martino R, Porras RP, Rabella N, Williams JV, Rámila E, Margall N, Labeaga R, Crowe JE Jr, Coll P, Sierra J. Prospective study of the incidence, clinical features, and outcome of symptomatic upper and lower respiratory tract infections by respiratory viruses is adult recipients of hematopoietic stem cell transplants for hematologic malignancies. Biol Blood Marrow Transplant. 2005;11:781–796. [PMC free article] [PubMed]
25. Schiffer JT, Kirby K, Sandmaier B, Storb R, Corey L, Boeckh M. Timing and severity of community acquired respiratory virus infections after myeloablative versus non-myeloablative hematopoietic stem cell transplantation. Haematologica. 2009;94:1101–1108. [PubMed]
26. Nichols WG, Gooley T, Boeckh M. Community-acquired respiratory syncytial virus and parainfluenza virus infections after hematopoietic stem cell transplantation: The Fred Hutchinson Cancer Research Center experience. Biol Blood Marrow Transplant. 2001;7:11S–15S. [PubMed]
27. Peck AJ, Englund JA, Kuypers J, Guthrie KA, Corey L, Morrow R, Hackman RC, Cent A, Boeckh M. Respiratory virus infection among hematopoietic cell transplant recipients: Evidence for asymptomatic parainfluenza virus infection. Blood. 2007;110:1681–1688. [PubMed]
28. Englund JA, Sullivan CJ, Jordan MC, Dehner LP, Vercellotti GM, Balfour HH Jr. Respiratory syncytial virus infection in immunocompromised adults. Ann Intern Med. 1988;109:203–208. [PubMed]
29. Ljungman P. Respiratory virus infections in stem cell transplant patients: The European experience. Biol Blood Marrow Transplant. 2001;7:5S–7S. [PubMed]
30. Boeckh M, Berrey MM, Bowden RA, Crawford SW, Balsley J, Corey L. Phase 1 evaluation of the respiratory syncytial virus-specific monoclonal antibody palivizumab in recipients of hematopoietic stem cell transplants. J Infect Dis. 2001;184:350–354. [PubMed]
31. Boeckh M, Englund J, Li Y, Miller C, Cross A, Fernandez H, Kuypers J, Kim M, Gnann J, Whitley R. Randomized controlled multicenter trial of aerosolized ribavirin for respiratory syncytial virus upper respiratory tract infection in hematopoietic cell transplant recipients. Clin Infect Dis. 2007;44:245–249. [PubMed]
32. Avetisyan G, Mattsson J, Sparrelid E, Ljungman P. Respiratory syncytial virus infection in recipients of allogeneic stem-cell transplantation: A retrospective study of the incidence, clinical features, and outcome. Transplantation. 2009;88:1222–1226. [PubMed]
33. Ghosh S, Champlin RE, Englund J, Giralt SA, Rolston K, Raad I, Jacobson K, Neumann J, Ippoliti C, Mallik S, Whimbey E. Respiratory syncytial virus upper respiratory tract illnesses in adult blood and marrow transplant recipients: Combination therapy with aerosolized ribavirin and intravenous immunoglobulin. Bone Marrow Transplant. 2000;25:751–755. [PubMed]
34. Ribavirin aerosol approved for severe cases of RSV in infants and young children. FDA Drug Bull. 1986;16:7. [PubMed]
35. Chemaly RF, Torres HA, Munsell MF, Shah DP, Rathod DB, Bodey GP, Hosing C, Saifan C, Raad II, Champlin RE. An Adaptive Randomized Trial of an Intermittent Dosing Schedule of Aerosolized Ribavirin in Patients With Cancer and Respiratory Syncytial Virus Infection. J Infect Dis. 2012;206:1367–71. [PMC free article] [PubMed]
36. Mejías A, Chávez-Bueno S, Ríos AM, Aten MF, Raynor B, Peromingo E, Soni P, Olsen KD, Kiener PA, Gómez AM, Jafri HS, Ramilo O. Comparative effects of two neutralizing anti-respiratory syncytial virus (RSV) monoclonal antibodies in the RSV murine model: Time versus Potency. Antimicrob Agents Chemother. 2005;49:4700–4707. [PMC free article] [PubMed]
37. Carbonell-Estrany X, Simões EAF, Dagan R, Hall CB, Harris B, Hultquist M, Connor EM, Losonsky GA. Motavizumab for prophylaxis of respiratory syncytial virus in high-risk children: A noninferiority trial. Pediatrics. 2010;125:e35–e51. [PubMed]
38. Welliver RC. Pharmacotherapy of respiratory syncytial virus infection. Respiratory/Musculoskeletal. 2010;10:289–293. [PubMed]
39. Center for Drug E and Research. Motavizumab (RezieldTM) FDA. 2010:1.
40. DeVincenzo J, Lambkin-Williams R, Wilkinson T, Cehelsky J, Nochur S, Walsh E, Meyers R, Gollob J, Vaishnaw A. A randomized, double-blind, placebo-controlled study of an RNAi-based therapy directed against respiratory syncytial virus. Proc Natl Acad Sci U S A. 2010;107:8800–8805. [PubMed]
41. Zamora MR, Budev M, Rolfe M, Gottlieb J, Humar A, DeVincenzo J, Vaishnaw A, Cehelsky J, Albert G, Nochur S, Gollob JA, Glanville AR. RNA interference therapy in lung transplant patients infected with respiratory syncytial virus. Am J Respir Crit Care Med. 2011;183:531–538. [PubMed]
42. Cortez K, Murphy BR, Almeida KN, Beeler J, Levandowski RA, Gill VJ, Childs RW, Barrett AJ, Smolskis M, Bennett JE. Immune-globulin prophylaxis of respiratory syncytial virus infection in patients undergoing stem-cell transplantation. J Infect Dis. 2002;186:834–838. [PubMed]
43. Tomblyn M, Chiller T, Einsele H, Gress R, Sepkowitz K, Storek J, Wingard JR, Young JAH, Boeckh MA. Guidelines for Preventing Infectious Complications among Hematopoietic Cell Transplantation Recipients: A Global Perspective. Biol Blood Marrow Transplant. 2009;15:1143–1238. [PMC free article] [PubMed]
44. Kassis C, Champlin RE, Hachem RY, Hosing C, Tarrand JJ, Perego CA, Neumann JL, Raad II, Chemaly RF. Detection and control of a nosocomial respiratory syncytial virus outbreak in a stem cell transplantation unit: The role of palivizumab. Biol Blood Marrow Transplant. 2010;16:1265–1271. [PubMed]
45. Georgescu G, Chemaly RF. Palivizumab: where to from here? Expert Opinion on Biological Therapy. 2009;9:139–147. [PubMed]
46. Chemaly RF, Torres HA, Aguilera EA, Mattiuzzi G, Cabanillas M, Kantarjian H, Gonzalez V, Safdar A, Raad II. Neuraminidase inhibitors improve outcome of patients with leukemia and influenza: an observational study. Clin Infect Dis. 2007;44:964–967. [PubMed]
47. Nichols WG, Guthrie KA, Corey L, Boeckh M. Influenza infections after hematopoietic stem cell transplantation: Risk factors, mortality, and the effect of antiviral therapy. Clin Infect Dis. 2004;39:1300–1306. [PubMed]
48. Ong AK, Hayden FG. John F. Enders lecture 2006: antivirals for influenza. The Journal of infectious diseases. 2007;196:181–190. [PubMed]
49. Sheu TG, Deyde VM, Okomo-Adhiambo M, Garten RJ, Xu X, Bright RA, Butler EN, Wallis TR, Klimov AI, Gubareva LV. Surveillance for neuraminidase inhibitor resistance among human influenza A and B viruses circulating worldwide from 2004 to 2008. Antimicrob Agents Chemother. 2008;52:3284–3292. [PMC free article] [PubMed]
50. Okomo-Adhiambo M, Nguyen HT, Sleeman K, Sheu TG, Deyde VM, Garten RJ, Xu X, Shaw MW, Klimov AI, Gubareva LV. Host cell selection of influenza neuraminidase variants: implications for drug resistance monitoring in A(H1N1) viruses. Antiviral Res. 2010;85:381–388. [PubMed]
51. Gaur AH, Bagga B, Barman S, Hayden R, Lamptey A, Hoffman JM, Bhojwani D, Flynn PM, Tuomanen E, Webby R. Intravenous zanamivir for oseltamivir-resistant 2009 H1N1 influenza. N Engl J Med. 2010;362:88–89. [PubMed]
52. Calfee DP, Peng AW, Hussey EK, Lobo M, Hayden FG. Safety and efficacy of once daily intranasal zanamivir in preventing experimental human influenza A infection. Antiviral Therapy. 1999;4:143–149. [PubMed]
53. Birnkrant D, Cox E. The emergency use authorization of peramivir for treatment of 2009 H1N1 influenza. N Engl J Med. 2009;361:2204–2207. [PubMed]
54. Härter G, Zimmermann O, Maier L, Schubert A, Martens T, Kern P, Wöhrla J. Intravenous zanamivir for patients with pneumonitis due to pandemic (H1N1) 2009 influenza virus. Clin Infect Dis. 2010;50:1249–1251. [PubMed]
55. Malakhov MP, Aschenbrenner LM, Smee DF, Wandersee MK, Sidwell RW, Gubareva LV, Mishin VP, Hayden FG, Kim DH, Ing A, Campbell ER, Yu M, Fang F. Sialidase fusion protein as a novel broad-spectrum inhibitor of influenza virus infection. Antimicrob Agents Chemother. 2006;50:1470–1479. [PMC free article] [PubMed]
56. Nichols WG, Peck Campbell AJ, Boeckh M. Respiratory viruses other than influenza virus: Impact and therapeutic advances. Clin Microbiol Rev. 2008;21:274–290. [PMC free article] [PubMed]
57. Triana-Baltzer GB, Gubareva LV, Klimov AI, Wurtman DF, Moss RB, Hedlund M, Larson JL, Belshe RB, Fang F. Inhibition of neuraminidase inhibitor-resistant influenza virus by DAS181, a novel sialidase fusion protein. PLoS ONE. 2009;4:e7838. [PMC free article] [PubMed]
58. Triana-Baltzer GB, Gubareva LV, Nicholls JM, Pearce MB, Mishin VP, Belser JA, Chen LM, Chan RWY, Chan MCW, Hedlund M, Larson JL, Moss RB, Katz JM, Tumpey TM, Fang F. Novel pandemic influenza A(H1N1) viruses are potently inhibited by DAS181, a sialidase fusion protein. PLoS ONE. 2009;4:e7788. [PMC free article] [PubMed]
59. Triana-Baltzer GB, Babizki M, Chan MCW, Wong ACN, Aschenbrenner LM, Campbell ER, Li QX, Chan RWY, Peiris JSM, Nicholls JM, Fang F. DAS181, a sialidase fusion protein, protects human airway epithelium against influenza virus infection: An in vitro pharmacodynamic analysis. J Antimicrob Chemother. 2010;65:275–284. [PMC free article] [PubMed]
60. Triana-Baltzer GB, Sanders RL, Hedlund M, Jensen KA, Aschenbrenner LM, Larson JL, Fang F. Phenotypic and genotypic characterization of influenza virus mutants selected with the sialidase fusion protein DAS181. J Antimicrob Chemother. 2011;66:15–28. [PMC free article] [PubMed]
61. Furuta Y, Takahashi K, Kuno-Maekawa M, Sangawa H, Uehara S, Kozaki K, Nomura N, Egawa H, Shiraki K. Mechanism of action of T-705 against influenza virus. Antimicrob Agents Chemother. 2005;49:981–986. [PMC free article] [PubMed]
62. Furuta Y, Takahashi K, Fukuda Y, Kuno M, Kamiyama T, Kozaki K, Nomura N, Egawa H, Minami S, Watanabe Y, Narita H, Shiraki K. In vitro and in vivo activities of anti-influenza virus compound T-705. Antimicrob Agents Chemother. 2002;46:977–981. [PMC free article] [PubMed]
63. Sidwell RW, Barnard DL, Day CW, Smee DF, Bailey KW, Wong MH, Morrey JD, Furuta Y. Efficacy of orally administered T-705 on lethal avian influenza a (H5N1) virus infections in mice. Antimicrob Agents Chemother. 2007;51:845–851. [PMC free article] [PubMed]
64. Sleeman K, Mishin VP, Deyde VM, Furuta Y, Klimov AI, Gubareva LV. In vitro antiviral activity of favipiravir (T-705) against drug-resistant influenza and 2009 A(H1N1) viruses. Antimicrob Agents Chemother. 2010;54:2517–2524. [PMC free article] [PubMed]
65. Watanabe A, Chang SC, Kim MJ, Chu DWS, Ohashi Y. Long-acting neuraminidase inhibitor laninamivir octanoate versus oseltamivir for treatment of influenza: A double-blind, randomized, noninferiority clinical trial. Clin Infect Dis. 2010;51:1167–1175. [PubMed]
66. Gubareva LV, Trujillo AA, Okomo-Adhiambo M, Mishin VP, Deyde VM, Sleeman K, Nguyen HT, Sheu TG, Garten RJ, Shaw MW, Fry AM, Klimov AI. Comprehensive assessment of 2009 pandemic influenza A (H1N1) virus drug susceptibility in vitro. Antiviral Therapy. 2010;15:1151–1159. [PubMed]
67. Yamashita M. Laninamivir and its prodrug, CS-8958: Long-acting neuraminidase inhibitors for the treatment of influenza. Antivr Chem Chemother. 2010;21:71–84. [PubMed]
68. Boudreault AA, Xie H, Leisenring W, Englund J, Corey L, Boeckh M. Impact of corticosteroid treatment and antiviral therapy on clinical outcomes in hematopoietic cell transplant patients infected with influenza virus. Biol Blood Marrow Transplant. 2011;17:979–986. [PubMed]
69. Fiore AE, Shay DK, Broder K, Iskander JK, Uyeki TM, Mootrey G, Bresee JS, Cox NJ. Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2008. MMWR Recommendations & Reports. 2008;57:1–60. [PubMed]
70. Ljungman P, Avetisyan G. Influenza vaccination in hematopoietic SCT recipients. Bone Marrow Transplant. 2008;42:637–641. [PubMed]
71. Pauksen K, Linde A, Hammarström V, Sjölin J, Carneskog J, Jonsson G, Öberga G, Engelmann H, Ljungman P. Granulocyte-macrophage colony-stimulating factor as immunomodulating factor together with influenza vaccination in stem cell transplant patients. Clin Infect Dis. 2000;30:342–348. [PubMed]
72. Kunisaki KM, Janoff EN. Influenza in immunosuppressed populations: a review of infection frequency, morbidity, mortality, and vaccine responses. The Lancet Infectious Diseases. 2009;9:493–504. [PMC free article] [PubMed]
73. Influenza vaccine 2011-2012. The Medical letter on drugs and therapeutics. 2011;53:81–83. [PubMed]
74. Ison MG, Szakaly P, Shapira MY, Kriván G, Nist A, Dutkowski R. Oseltamivir prophylaxis significantly reduces the incidence of seasonal influenza infection in immunocompromized patients. 11th International Symposium Respiratory Viral Infections. 2009
75. Baz M, Abed Y, Papenburg J, Bouhy X, Hamelin MÈ, Boivin G. Emergence of oseltamivir-resistant pandemic H1N1 virus during prophylaxis. N Engl J Med. 2009;361:2296–2297. [PubMed]
76. Renaud C, Boudreault AA, Kuypers J, Lofy KH, Corey L, Boeckh MJ, Englund JA. H275Y mutant pandemic (H1N1) 2009 virus in immunocompromised patients. Emerg Infect Dis. 2011;17:653–660. [PMC free article] [PubMed]
77. Graitcer SB, Gubareva L, Kamimoto L, Doshi S, Vandermeer M, Louie J, Waters C, Moore Z, Sleeman K, Okomo-Adhiambo M, Marshall SA, George KS, Pan CY, Laplante JM, Klimov A, Fry AM. Characteristics of patients with oseltamivir-resistant pandemic (H1N1) 2009, United States. Emerg Infect Dis. 2011;17:255–257. [PMC free article] [PubMed]
78. Lewis VA, Champlin R, Englund J, Couch R, Goodrich JM, Rolston K, Przepiorka D, Mirza NQ, Yousuf HM, Luna M, Bodey GP, Whimbey E. Respiratory disease due to parainfluenza virus in adult bone marrow transplant recipients. Clinical infectious diseases: an official publication of the Infectious Diseases Society of America. 1996;23:1033–1037. [PubMed]
79. Nichols WG, Corey L, Gooley T, Davis C, Boeckh M. Parainfluenza virus infections after hematopoietic stem cell transplantation: risk factors, response to antiviral therapy, and effect on transplant outcome. Blood. 2001;98:573–578. [PubMed]
80. Wendt CH, Weisdorf DJ, Jordan MC, Balfour HH Jr, Hertz MI. Parainfluenza virus respiratory infection after bone marrow transplantation. The New England journal of medicine. 1992;326:921–926. [PubMed]
81. Chakrabarti S, Avivi I, Mackinnon S, Ward K, Kottaridis PD, Osman H, Waldmann H, Hale G, Fegan CD, Yong K, Goldstone AH, Linch DC, Milligan DW. Respiratory virus infections in transplant recipients after reduced-intensity conditioning with Campath-1H: High incidence but low mortality. Br J Haematol. 2002;119:1125–1132. [PubMed]
82. Osiowy C. Direct detection of respiratory syncytial virus, parainfluenza virus, and adenovirus in clinical respiratory specimens by a multiplex reverse transcription-PCR assay. J Clin Microbiol. 1998;36:3149–3154. [PMC free article] [PubMed]
83. Frank AL, Couch RB, Griffis CA, Baxter BD. Comparison of different tissue cultures for isolation and quantitation of influenza and parainfluenza viruses. J Clin Microbiol. 1979;10:32–36. [PMC free article] [PubMed]
84. Fan J, Henrickson KJ, Savatski LL. Rapid simultaneous diagnosis of infections with respiratory syncytial viruses A and B, influenza viruses A and B, and human parainfluenza virus types 1, 2, and 3 by multiplex quantitative reverse transcription-polymerase chain reaction-enzyme hybridization assay (Hexaplex) Clinical infectious diseases: an official publication of the Infectious Diseases Society of America. 1998;26:1397–1402. [PubMed]
85. Gilbert BE, Knight V. Biochemistry and clinical applications of ribavirin. Antimicrob Agents Chemother. 1986;30:201–205. [PMC free article] [PubMed]
86. McIntosh K, Kurachek SC, Cairns LM, Burns JC, Goodspeed B. Treatment of respiratory viral infection in an immunodeficient infant with ribavirin aerosol. Am J Dis Child. 1984;138:305–308. [PubMed]
87. Shima T, Yoshimoto G, Nonami A, Yoshida S, Kamezaki K, Iwasaki H, Takenaka K, Miyamoto T, Harada N, Teshima T, Akashi K, Nagafuji K. Successful treatment of parainfluenza virus 3 pneumonia with oral ribavirin and methylprednisolone in a bone marrow transplant recipient. Int J Hematol. 2008;88:336–340. [PubMed]
88. Alymova IV, Watanabe M, Boyd KL, Chand P, Babu YS, Portner A. Efficacy of the novel parainfluenza virus haemagglutinin-neuraminidase inhibitor BCX 2798 in mice - Further evaluation. Antiviral Therapy. 2009;14:891–898. [PMC free article] [PubMed]
89. Alymova IV, Taylor G, Takimoto T, Lin TH, Chand P, Babu YS, Li C, Xiong X, Portner A. Efficacy of Novel Hemagglutinin-Neuraminidase Inhibitors BCX 2798 and BCX 2855 against Human Parainfluenza Viruses In Vitro and In Vivo. Antimicrob Agents Chemother. 2004;48:1495–1502. [PMC free article] [PubMed]
90. Chen YB, Driscoll J, McAfee SL. Treatment of parainfluenza 3 infection with DAS181 in a patient after allogeneic stem cell transplantation. American Society of Blood and Marrow Transplantation (ASBMT) Annual Meeting. 2012 [PubMed]
91. Anderson EJ, Guzman-Cottrill JA, Kletzel M, Thormann K, Sullivan C, Zheng X, Katz BZ. High-risk adenovirus-infected pediatric allogeneic hematopoietic progenitor cell transplant recipients and preemptive cidofovir therapy. Pediatr Transplant. 2008;12:219–227. [PubMed]
92. Verdeguer A, De Heredia CD, González M, Martínez AM, Fernández-Navarro JM, Pérez-Hurtado JM, Badell I, Gómez P, González ME, Muñoz A, Díaz MA. Observational prospective study of viral infections in children undergoing allogeneic hematopoietic cell transplantation: A 3-year GETMON experience. Bone Marrow Transplant. 2011;46:119–124. [PubMed]
93. Öhrmalm L, Lindblom A, Omar H, Norbeck O, Gustafson I, Lewensohn-Fuchs I, Johansson JE, Brune M, Ljungman P, Broliden K. Evaluation of a surveillance strategy for early detection of adenovirus by PCR of peripheral blood in hematopoietic SCT recipients: Incidence and outcome. Bone Marrow Transplant. 2011;46:267–272. [PubMed]
94. La Rosa AM, Champlin RE, Mirza N, Gajewski J, Giralt S, Rolston KV, Raad I, Jacobson K, Kontoyiannis D, Elting L, Whimbey E. Adenovirus infections in adult recipients of blood and marrow transplants. Clinical infectious diseases: an official publication of the Infectious Diseases Society of America. 2001;32:871–876. [PubMed]
95. Lion T, Baumgartinger R, Watzinger F, Matthes-Martin S, Suda M, Preuner S, Futterknecht B, Lawitschka A, Peters C, Pötschger U, Gadner H. Molecular monitoring of adenovirus in peripheral blood after allogeneic bone marrow transplantation permits early diagnosis of disseminated disease. Blood. 2003;102:1114–1120. [PubMed]
96. Flomenberg P, Babbitt J, Drobyski WR, Ash RC, Carrigan DR, Sedmak GV, McAuliffe T, Camitta B, Horowitz MM, Bunin N, Casper JT. Increasing incidence of adenovirus disease in bone marrow transplant recipients. J Infect Dis. 1994;169:775–781. [PubMed]
97. Bruno B, Gooley T, Hackman RC, Davis C, Corey L, Boeckh M. Adenovirus infection in hematopoietic stem cell transplantation: Effect of ganciclovir and impact on survival. Biol Blood Marrow Transplant. 2003;9:341–352. [PubMed]
98. Baldwin A, Kingman H, Darville M, Foot ABM, Grier D, Cornish JM, Goulden N, Oakhill A, Pamphilon DH, Steward CG, Marks DI. Outcome and clinical course of 100 patients with adenovirus infection following bone marrow transplantation. Bone Marrow Transplant. 2000;26:1333–1338. [PubMed]
99. Gray GC, McCarthy T, Lebeck MG, Schnurr DP, Russell KL, Kajon AE, Landry ML, Leland DS, Storch GA, Ginocchio CC, Robinson CC, Demmler GJ, Saubolle MA, Kehl SC, Selvarangan R, Miller MB, Chappell JD, Zerr DM, Kiska DL, Halstead DC, Capuano AW, Setterquist SF, Chorazy ML, Dawson JD, Erdman DD. Genotype prevalence and risk factors for severe clinical adenovirus infection, United States 2004-2006. Clinical infectious diseases: an official publication of the Infectious Diseases Society of America. 2007;45:1120–1131. [PMC free article] [PubMed]
100. Omar H, Yun Z, Lewensohn-Fuchs I, Pérez-Bercoff L, Örvell C, Engström L, Vuong GK, Ljungman P. Poor outcome of adenovirus infections in adult hematopoietic stem cell transplant patients with sustained adenovirus viremia. Transplant Infectious Disease. 2010;12:465–469. [PubMed]
101. Gustafson I, Lindblom A, Yun Z, Omar H, Engstrom L, Lewensohn-Fuchs I, Ljungman P, Broliden K. Quantification of adenovirus DNA in unrelated donor hematopoietic stem cell transplant recipients. J Clin Virol. 2008;43:79–85. [PubMed]
102. Lankester AC, Heemskerk B, Claas ECJ, Schilham MW, Beersma MFC, Bredius RGM, Van Tol MJD, Kroes ACM. Effect of ribavirin on the plasma viral DNA load in patients with disseminating adenovirus infection. Clin Infect Dis. 2004;38:1521–1525. [PubMed]
103. Leruez-Ville M, Minard V, Lacaille F, Buzyn A, Abachin E, Blanche S, Freymuth F, Rouzioux C. Real-time blood plasma polymerase chain reaction for management of disseminated adenovirus infection. Clinical infectious diseases: an official publication of the Infectious Diseases Society of America. 2004;38:45–52. [PubMed]
104. Yusuf U, Hale GA, Carr J, Gu Z, Benaim E, Woodard P, Kasow KA, Horwitz EM, Leung W, Srivastava DK, Handgretinger R, Hayden RT. Cidofovir for the treatment of adenoviral infection in pediatric hematopoietic stem cell transplant patients. Transplantation. 2006;81:1398–1404. [PubMed]
105. Bhadri VA, Lee-Horn L, Shaw PJ. Safety and tolerability of cidofovir in high-risk pediatric patients: Short communication. Transplant Infectious Disease. 2009;11:373–379. [PubMed]
106. Lindemans CA, Leen AM, Boelens JJ. How I treat adenovirus in hematopoietic stem cell transplant recipients. Blood. 2010;116:5476–5485. [PubMed]
107. Morfin F, Dupuis-Girod S, Frobert E, Mundweiler S, Carrington D, Sedlacek P, Bierings M, Cetkovsky P, Kroes ACM, van Tol MJD, Thouvenot D. Differential susceptibility of adenovirus clinical isolates to cidofovir and ribavirin is not related to species alone. Antiviral Therapy. 2009;14:55–61. [PubMed]
108. Symeonidis N, Jakubowski A, Pierre-Louis S, Jaffe D, Pamer E, Sepkowitz K, O’Reilly RJ, Papanicolaou GA. Invasive adenoviral infections in T-cell-depleted allogeneic hematopoietic stem cell transplantation: High mortality in the era of cidofovir. Transplant Infectious Disease. 2007;9:108–113. [PubMed]
109. Ljungman P, Deliliers GL, Platzbecker U, Matthes-Martin S, Bacigalupo A, Einsele H, Ullmann J, Musso M, Trenschel R, Ribaud P, Bornhäuser M, Cesaro S, Crooks B, Dekker A, Gratecos N, Klingebiel T, Tagliaferri E, Ullmann AJ, Wacker P, Cordonnier C. Cidofovir for cytomegalovirus infection and disease in allogeneic stem cell transplant recipients. Blood. 2001;97:388–392. [PubMed]
110. Izzedine H, Launay-Vacher V, Deray G. Antiviral drug-induced nephrotoxicity. Am J Kidney Dis. 2005;45:804–817. [PubMed]
111. Toth K, Spencer JF, Dhar D, Sagartz JE, Buller RML, Painter GR, Wold WSM. Hexadecyloxypropyl-cidofovir, CMX001, prevents adenovirus-induced mortality in a permissive, immunosuppressed animal model. Proc Natl Acad Sci U S A. 2008;105:7293–7297. [PubMed]
112. Trost LC, Tippin TK, Anderson MT, Painter WP. Compromised renal function does not affect the pharmacokinetics of CMX001 in patients with severe doublestranded DNA virus infections. 50th Interscience Conference on Antimicrobial Agents and Chemotherapy. 2010
113. Florescu DF, Rigdon S, Pergam SA. Experience with CMX001, a novel antiviral drug, for adenovirus infections in immunocompromised patients. 48th Annual Meeting of Infectious Diseases Society of America. 2010
114. Paolino K, Sande J, Perez E, Loechelt B, Jantausch B, Painter W, Anderson M, Tippin T, Lanier ER, Fry T, DeBiasi RL. Eradication of disseminated adenovirus infection in a pediatric hematopoietic stem cell transplantation recipient using the novel antiviral agent CMX001. J Clin Virol. 2011;50:167–170. [PubMed]
115. Liles WC, Cushing H, Holt S, Bryan C, Hackman RC. Severe adenoviral nephritis following bone marrow transplantation: Successful treatment with intravenous ribavirin. Bone Marrow Transplant. 1993;12:409–412. [PubMed]
116. Chakrabarti S, Collingham KE, Fegan CD, Milligan DW. Fulminant adenovirus hepatitis following unrelated bone marrow transplantation: Failure of intravenous ribavirin therapy. Bone Marrow Transplant. 1999;23:1209–1211. [PubMed]
117. Bordigoni P, Carret AS, Venard V, Witz F, Faou AL. Treatment of adenovirus infections in patients undergoing allogeneic hematopoietic stem cell transplantation. Clin Infect Dis. 2001;32:1290–1297. [PubMed]
118. Gavin PJ, Katz BZ. Intravenous ribavirin treatment for severe adenovirus disease in immunocompromised children. Pediatrics. 2002;110:e9. [PubMed]
119. Chakrabarti S, Collingham KE, Marshall T, Holder K, Gentle T, Hale G, Fegan CD, Milligan DW. Respiratory virus infections in adult T cell-depleted transplant recipients: The role of cellular immunity. Transplantation. 2001;72:1460–1463. [PubMed]
120. Regn S, Raffegerst S, Chen X, Schendel D, Kolb HJ, Roskrow M. Ex vivo generation of cytotoxic T lymphocytes specific for one or two distinct viruses for the prophylaxis of patients receiving an allogeneic bone marrow transplant. Bone Marrow Transplant. 2001;27:53–64. [PubMed]
121. Feuchtinger T, Matthes-Martin S, Richard C, Lion T, Fuhrer M, Hamprecht K, Handgretinger R, Peters C, Schuster FR, Beck R, Schumm M, Lotfi R, Jahn G, Lang P. Safe adoptive transfer of virus-specific T-cell immunity for the treatment of systemic adenovirus infection after allogeneic stem cell transplantation. Br J Haematol. 2006;134:64–76. [PubMed]
122. Leen AM, Myers GD, Sili U, Huls MH, Weiss H, Leung KS, Carrum G, Krance RA, Chang CC, Molldrem JJ, Gee AP, Brenner MK, Heslop HE, Rooney CM, Bollard CM. Monoculture-derived T lymphocytes specific for multiple viruses expand and produce clinically relevant effects in immunocompromised individuals. Nat Med. 2006;12:1160–1166. [PubMed]
123. Zandvliet ML, Falkenburg JHF, van Liempt EV, Veltrop-Duits LA, Lankester AC, Kalpoe JS, Kester MGD, van der Steen DM, van Tol MJ, Willemze R, Guchelaar HJ, Schilham MW, Meij P. Combined cd8 + and cd4 + adenovirus hexon-specific T cells associated with viral clearance after stem cell transplantation as treatment for adenovirus infection. Haematologica. 2010;95:1943–1951. [PubMed]
124. Chakrabarti S, Collingham KE, Fegan CD, Pillay D, Milligan DW. Adenovirus infections following haematopoietic cell transplantation: Is there a role for adoptive immunotherapy? Bone Marrow Transplant. 2000;26:305–307. [PubMed]
125. Ghosh S, Champlin R, Couch R, Englund J, Raad I, Malik S, Luna M, Whimbey E. Rhinovirus infections in myelosuppressed adult blood and marrow transplant recipients. Clin Infect Dis. 1999;29:528–532. [PubMed]
126. Hassan IA, Chopra R, Swindell R, Mutton KJ. Respiratory viral infections after bone marrow/peripheral stem-cell transplantation: The Christie hospital experience. Bone Marrow Transplant. 2003;32:73–77. [PubMed]
127. Camps Serra M, Cervera C, Pumarola T, Moreno A, Perello R, Torres A, Jimenez de Anta MT, Marcos MA. Virological diagnosis in community-acquired pneumonia in immunocompromised patients. The European respiratory journal: official journal of the European Society for Clinical Respiratory Physiology. 2008;31:618–624. [PubMed]
128. Winther B, Gwaltney JM Jr, Mygind N, Hendley JO. Viral-induced rhinitis. Am J Rhinol. 1998;12:17–20. [PubMed]
129. Hayden FG, Herrington DT, Coats TL, Kim K, Cooper EC, Villano SA, Liu S, Hudson S, Pevear DC, Collett M, McKinlay M, Pleconaril Respiratory Infection Study G. Efficacy and safety of oral pleconaril for treatment of colds due to picornaviruses in adults: Results of 2 double-blind, randomized, placebo-controlled trials. Clin Infect Dis. 2003;36:1523–1532. [PubMed]
130. Renaud C, Englund JA. Antiviral therapy of respiratory viruses in haematopoietic stem cell transplant recipients. Antiviral Therapy. 2012;17:175–191. [PubMed]
131. Heymann PW, Platts-Mills TA, Johnston SL. Role of viral infections, atopy and antiviral immunity in the etiology of wheezing exacerbations among children and young adults. The Pediatric infectious disease journal. 2005;24:S217–222. discussion S220-211. [PubMed]
132. Folz RJ, Elkordy MA. Coronavirus pneumonia following autologous bone marrow transplantation for breast cancer. Chest. 1999;115:901–905. [PubMed]
133. Van Den Hoogen BG, De Jong JC, Groen J, Kuiken T, De Groot R, Fouchier RAM, Osterhaus ADME. A newly discovered human pneumovirus isolated from young children with respiratory tract disease. Nat Med. 2001;7:719–724. [PubMed]
134. Williams JV, Martino R, Rabella N, Otegui M, Parody R, Heck JM, Crowe JE Jr. A prospective study comparing human metapneumovirus with other respiratory viruses in adults with hematologic malignancies and respiratory tract infections. The Journal of infectious diseases. 2005;192:1061–1065. [PMC free article] [PubMed]
135. Englund JA, Boeckh M, Kuypers J, Nichols WG, Hackman RC, Morrow RA, Fredricks DN, Corey L. Brief communication: Fatal human metapneumovirus infection in stem-cell transplant recipients. Ann Intern Med. 2006;144:344–349. [PubMed]
136. Wyde PR, Chetty SN, Jewell AM, Boivin G, Piedra PA. Comparison of the inhibition of human metapneumovirus and respiratory syncytial virus by ribavirin and immune serum globulin in vitro. Antiviral Res. 2003;60:51–59. [PubMed]
137. Hamelin MÈ, Prince GA, Boivin G. Effect of ribavirin and glucocorticoid treatment in a mouse model of human metapneumovirus infection. Antimicrob Agents Chemother. 2006;50:774–777. [PMC free article] [PubMed]
138. Renaud C, Sampoleo R, Xie H. Human metapneumovirus lower respiratory tract infections in hematopoietic stem cell transplant (HCT) recipients have a high mortality rate. 27th Annual Clinical Virology Symposium. 2011
139. Schenk T, Strahm B, Kontny U, Hufnagel M, Neumann-Haefelin D, Falcone V. Disseminated bocavirus infection after stem cell transplant [2] Emerg Infect Dis. 2007;13:1425–1427. [PMC free article] [PubMed]
140. Koskenvuo M, Mottonen M, Waris M, Allander T, Salmi TT, Ruuskanen O. Human bocavirus in children with acute lymphoblastic leukemia. Eur J Pediatr. 2008;167:1011–1015. [PubMed]
Articles from American Journal of Blood Research are provided here courtesy of
e-Century Publishing Corporation