Data adopted from references: (Echavarria, 2006; Hierholzer, 1992; Kaneko et al., 2009; Wadell et al., 1980; Walsh et al., 2010; and from National Center for Biotechnology Information database (http://www.ncbi.nlm.nih.gov);

† according to Ebner et al. (2005) serotype 50 was reclassified into species D and serotype 51 into species B;

\* firstly described in year 2009, (proposal) (Kaneko et al., 2006);

ND- not determined, FL-fiber length, HA- hemaglutination;

Table 1. Adenovirus classification and general features.

#### **3. Virus transmission in stem cell recipients**

The most common source of adenoviral infection after haematopoietic stem cell transplantation is reactivation of a latent virus persisting in lymphocytes of peripheral blood, in adenoids, intestines and kidneys through low-grade replication. AdV1, AdV2 and AdV5 (C) are the most common serotypes remaining latent after primary exposure in the childhood (Lee et al., 2010; Malekshahi et al., 2010). They also play the significant role in development of AdV infections after SCT, therefore confirming the role of virus reactivation during an early post-transplant period. The next source of AdV infection in stem cell recipients might be the virus transmission from the positive donor to the negative recipient.

Adenoviral Infection – Common Complication Following Hematopoietic Stem Cell Transplantation 537

penetration into the host cell, transport of viral DNA to cell nucleus and transcription/translation of the "early genes" such as E1A, E1B, E2, E3, E4. The products of the early genes act as regulatory factors. They change cell functions to facilitate further replication of the virus and transactivate other early transcription units. Second phase of AdV replication leads to transcription and translation of the "late genes" (L1-L5) encoding mainly structural proteins of the virion shell. Assembly and maturation of AdV particles take place in the nuclei of infected cells. The whole process usually takes only 4-6 hours (Greber et al. 1997, Gonçalves & de Vries, 2006; Matthews & Russell, 1998; Russell, 2000).

Fig. 1. AdV infection cycle. An interaction between penton base and α,β integrins induces internalization of viral particle into the host cell. Intra-endosomal mechanisms lead to disintegration of virion shell. Viral DNA is transported into the cell nucleus providing material for DNA replication. The early phase of replication includes expression of the "early genes" (E1-E4) acting as regulatory factors and facilitating virus replication. Second phase of AdV replication leads to expression of L1-L4 encoding mainly structural proteins

Adenoviral infection and active virus replication in the host cell can exert three different cytopathological effects. In most cases AdV infection leads to cell lysis. AdV genome contains at least four different coding regions (E1a, E4ORF4, E4ORF6/7 i ADP, which products can induce cell death and lysis (Braithwaite & Russell, 2001). Alternatively, after acute phase of the infection, the virus might remain in latent phase. Human adenoviruses, especially AdV1, AdV2, AdV5 from species C, possess the ability to prolonged persistence in adenoids, intestines, renal parenchyma and lymphocytes in peripheral blood with

determining virus assembly and maturation.

There are many reports confirming more than 4-fold increased risk of primary adenoviral infections in HSCT recipients grafted from previously infected (seropositive) donors in comparison to uninfected donors (Runde et al., 2001; Walls et al., 2003).

Adenoviruses can spread directly through respiratory droplets hence upper respiratory tract infections occur very often. They are able to replicate in the environment of the gastrointestinal tract due to their resistance to low pH of a stomach and proteolytic enzymes in gastrointestinal secretions, thus allowing the virus to achieve a high viral load in the gut. Because viral loads in stool samples of infected patients achieve the highest levels in comparison to other clinical materials, it can be suggested that fecal-oral transmission is the most common route of infection spread (Baldwin et al., 2000; Chakrabarti et al., 2002; Hale et al., 1999; Howard et al., 1999; Jeulin et al., 2011; Lion et al., 2010; Rutala et al, 2006).

There are also some reports suggesting possible virus spread via unsterile instruments and medical equipment, direct staff-to-patient transmission or inadequate air conditioning in the post-transplantation ward. Adenoviruses are strongly resistant to chemical or physical agents and adverse pH conditions and are able to remain infectious for a long period outside of the body, but this route of infection can be prevented by disinfection procedures in transplantation units (Artieda et al., 2010; Gerber et al., 2001; Gray, 2006; Leruez-Ville et al., 2006; Lessa et al., 2007; Romero et al., 2010).

#### **4. Pathomechanism and clinical manifestations of adenoviral infections**

Individual serotypes of *Adenoviridae* family show varied tissue tropism. They infect postmitotic cells of even highly differentiated tissues such as skeletal muscles, lungs, brain and heart muscle (Russell, 2009; Zhang & Bergelson, 2005). The infection cycle is divided into two stages involving virus adsorption and internalization (Figure 1). Attachment to the host cell receptor and virus entry occurs via the fibre protein and penton base. Majority of adenoviruses (mainly those from species A, C, D, E and F) use the coxackie-adenovirus receptor (CAR) which is a member of the immunoglobulin family and is situated on a surface of most human tissues such as heart muscle, brain, liver, pancreas, intestines, lungs and kidneys (Dechecchi et al, 2001; Raschperger et al., 2006; Russell, 2000, 2009; Rux et al., 2003; Zhang & Bergelson, 2005). In human cells lacking CAR receptor, other cell molecules are used for virus attachment. For example, AdV2 and AdV5 are able to bind the α-domain of MHC class I (*Major Histocompatibility Complex Class I)* molecule or heparan sulfate glycosaminoglycans (HS GAG). Additionally, these serotypes are capable to recognize and interact with vascular cell adhesion molecule-1 (VCAM-1) which is situated on atherosclerotic lesions of vascular endothelium. More rarely, α(2-3)- sialic acid, sBAR and sB2AR and CD46, CD80, CD86 are used (mainly serotypes: 3, 7, 8, 11, 14, 16, 19, 21, 37, 34 , 35 and 50) (Benko et al., 2000; Burmeister et al., 2004; Chu et al., 2001; Sharma et al., 2009; Wang et al, 2007; Zhang & Bergelson, 2005). Virus binding to the cell receptor and interaction between penton base and integrins on the target cell induce internalization of the viral particle into the host cell by clathrin-coated vesicles and endosomes. Several proteins and intra-endosomal mechanisms lead to disintegration of virus particle and subsequently to viral core release. Viral DNA is transported to the cell nucleus by microtubule-mediated transport and undergoes DNA transcription and replication (Cusack, 2005; Kelkar et al., 2004; Russell, 2000). Replication process is divided into an early and late phase. Sometimes, an intermediate phase is also marked out. The early phase (6-8 hours) includes virus

There are many reports confirming more than 4-fold increased risk of primary adenoviral infections in HSCT recipients grafted from previously infected (seropositive) donors in

Adenoviruses can spread directly through respiratory droplets hence upper respiratory tract infections occur very often. They are able to replicate in the environment of the gastrointestinal tract due to their resistance to low pH of a stomach and proteolytic enzymes in gastrointestinal secretions, thus allowing the virus to achieve a high viral load in the gut. Because viral loads in stool samples of infected patients achieve the highest levels in comparison to other clinical materials, it can be suggested that fecal-oral transmission is the most common route of infection spread (Baldwin et al., 2000; Chakrabarti et al., 2002; Hale et

There are also some reports suggesting possible virus spread via unsterile instruments and medical equipment, direct staff-to-patient transmission or inadequate air conditioning in the post-transplantation ward. Adenoviruses are strongly resistant to chemical or physical agents and adverse pH conditions and are able to remain infectious for a long period outside of the body, but this route of infection can be prevented by disinfection procedures in transplantation units (Artieda et al., 2010; Gerber et al., 2001; Gray, 2006; Leruez-Ville et

al., 1999; Howard et al., 1999; Jeulin et al., 2011; Lion et al., 2010; Rutala et al, 2006).

**4. Pathomechanism and clinical manifestations of adenoviral infections** 

Individual serotypes of *Adenoviridae* family show varied tissue tropism. They infect postmitotic cells of even highly differentiated tissues such as skeletal muscles, lungs, brain and heart muscle (Russell, 2009; Zhang & Bergelson, 2005). The infection cycle is divided into two stages involving virus adsorption and internalization (Figure 1). Attachment to the host cell receptor and virus entry occurs via the fibre protein and penton base. Majority of adenoviruses (mainly those from species A, C, D, E and F) use the coxackie-adenovirus receptor (CAR) which is a member of the immunoglobulin family and is situated on a surface of most human tissues such as heart muscle, brain, liver, pancreas, intestines, lungs and kidneys (Dechecchi et al, 2001; Raschperger et al., 2006; Russell, 2000, 2009; Rux et al., 2003; Zhang & Bergelson, 2005). In human cells lacking CAR receptor, other cell molecules are used for virus attachment. For example, AdV2 and AdV5 are able to bind the α-domain of MHC class I (*Major Histocompatibility Complex Class I)* molecule or heparan sulfate glycosaminoglycans (HS GAG). Additionally, these serotypes are capable to recognize and interact with vascular cell adhesion molecule-1 (VCAM-1) which is situated on atherosclerotic lesions of vascular endothelium. More rarely, α(2-3)- sialic acid, sBAR and sB2AR and CD46, CD80, CD86 are used (mainly serotypes: 3, 7, 8, 11, 14, 16, 19, 21, 37, 34 , 35 and 50) (Benko et al., 2000; Burmeister et al., 2004; Chu et al., 2001; Sharma et al., 2009; Wang et al, 2007; Zhang & Bergelson, 2005). Virus binding to the cell receptor and interaction between penton base and integrins on the target cell induce internalization of the viral particle into the host cell by clathrin-coated vesicles and endosomes. Several proteins and intra-endosomal mechanisms lead to disintegration of virus particle and subsequently to viral core release. Viral DNA is transported to the cell nucleus by microtubule-mediated transport and undergoes DNA transcription and replication (Cusack, 2005; Kelkar et al., 2004; Russell, 2000). Replication process is divided into an early and late phase. Sometimes, an intermediate phase is also marked out. The early phase (6-8 hours) includes virus

comparison to uninfected donors (Runde et al., 2001; Walls et al., 2003).

al., 2006; Lessa et al., 2007; Romero et al., 2010).

penetration into the host cell, transport of viral DNA to cell nucleus and transcription/translation of the "early genes" such as E1A, E1B, E2, E3, E4. The products of the early genes act as regulatory factors. They change cell functions to facilitate further replication of the virus and transactivate other early transcription units. Second phase of AdV replication leads to transcription and translation of the "late genes" (L1-L5) encoding mainly structural proteins of the virion shell. Assembly and maturation of AdV particles take place in the nuclei of infected cells. The whole process usually takes only 4-6 hours (Greber et al. 1997, Gonçalves & de Vries, 2006; Matthews & Russell, 1998; Russell, 2000).

Fig. 1. AdV infection cycle. An interaction between penton base and α,β integrins induces internalization of viral particle into the host cell. Intra-endosomal mechanisms lead to disintegration of virion shell. Viral DNA is transported into the cell nucleus providing material for DNA replication. The early phase of replication includes expression of the "early genes" (E1-E4) acting as regulatory factors and facilitating virus replication. Second phase of AdV replication leads to expression of L1-L4 encoding mainly structural proteins determining virus assembly and maturation.

Adenoviral infection and active virus replication in the host cell can exert three different cytopathological effects. In most cases AdV infection leads to cell lysis. AdV genome contains at least four different coding regions (E1a, E4ORF4, E4ORF6/7 i ADP, which products can induce cell death and lysis (Braithwaite & Russell, 2001). Alternatively, after acute phase of the infection, the virus might remain in latent phase. Human adenoviruses, especially AdV1, AdV2, AdV5 from species C, possess the ability to prolonged persistence in adenoids, intestines, renal parenchyma and lymphocytes in peripheral blood with

Adenoviral Infection – Common Complication Following Hematopoietic Stem Cell Transplantation 539

adenoviral infection within short time (Ephros et al., 2009; Heim et al., 2003; Lion et al., 2003;

Acute follicular conjunctivitis and keratoconjunctivitis 1, 3, 4, 5, 7, 8, 9, 11, 16, 19, 26, 27,

30, 37, 53, 54

**Clinical symptoms Involved serotypes** 

Acute hemorrhagic cystitis (HC) 3, 7, 11, 21, 34, 35

Exudative pharyngitis 1, 2, 3, 5, 7

Hepatitis, appendicitis 1, 2, 3, 5, 7 Intussusception 1, 2, 5 Meningitis, encephalitis 2, 3, 7, 12, 32

Nephritis and kidney damage 11, 14, 34, 35

Pharyngitis 1, 2, 3, 5, 7 Pharyngoconjunctival fever (PCF) 3, 4, 7, 14

Prolonged diarrhea 40, 41, 52 Ulcerative changes in the female genital organs, cervicitis 19, 37

Myocarditis 7, 21

Pertussis−like syndrome 5

**5. Anti-viral response and viral immunoavoidance** 

Acute respiratory disease 1, 2, 3, 4, 5, 6, 7, 14, 21, 30

Gastroenteritis 1, 2, 12, 16, 18, 31, 40, 41, 52

Pneumonia 1, 2, 3, 4, 7, 11, 14, 21, 30, 34, 35

Urethritis 1, 3, 4, 7, 14, 16, 19, 34, 35, 37, 50 Table 2. Clinical manifestations of adenoviral infection in stem cell transplant recipients

Virus penetration into human organism induces both specific and non-specific response to infection. Firstly, virus by binding with the cell receptors activates congenital mechanisms of anti-viral defense. An induction of the inflammatory response stimulates interferon production by both immunocompetent and non-immunocompetent cells. Macrophages, natural killers (NK cells) and complement proteins are also involved in anti-adenovirus defense indirectly by killing infected cells or due to production of cytokins such as Il-1, Il-6 and TNF-α. Additionally, Smith et al. (2008) confirmed the role of the epithelial defensins which coat the capsid vertex of adenoviral particle and inhibit virus uncoating in cytoplasm of infected cell (Smith & Nemerow, 2008). Another way of virus elimination from the organism is induction of pro-apoptotic mechanisms in infected cells due to e.g. p53, TNFα and Bax proteins (Randall & Goodbourn, 2008; Russell, 2000, 2009; Smith & Nemerow, 2008). Very important role in viral clearance is played by acquired immunity mechanisms. The cellular response is limited to CD3+ cells activation (both helper and cytotoxic lymphocytes) which also produce TNFα and INFɣ. Activation of CD8+ cells due to presentation of hexon determinants in MHC I complex leads to eradication of infected cells by means of cell perforation and lyses. This mechanism prevents virus replication and further spread of viral particles. The humoral response is focused on production of

Walls et al., 2005).

(summary table).

periodic shedding of virus in feaces and respiratory secretions (Akiyama et al., 2001; Braithwaite & Russell, 2001; Echavarri´a, 2008; Watzinger et al., 2004). The third possible outcome of adenoviral infection is an oncogenic transformation of infected cells, that is observed in animal models (Russell, 2009).

Primary adenoviral infections affect predominantly pediatric population with more than 50% of children infected before the age of five (Cooper et al., 2003). Children are often infected with adenovirus types 1, 2, 3, 4, 5, 7 and 30 which are the most common causes of tonsillopharyngitis and pneumonia (Carballal et al., 2002; Faden et al., 2005). These antigenic types are also the most frequent in recipients of SCT indicating virus reactivation or droplets transmission as most reliable routes of virus spread. AdV infections in immunocompetent humans are usually asymptomatic, localized and tend to be self-limited. They are restricted to the respiratory system, genitourinary and gastrointestinal tract infections, occasionally affecting conjunctiva and cornea. Recipients of HSCT and other imunocompromised patients present much broader spectrum of clinical manifestations. According to different studies, the estimated rate of AdV infection after HSCT ranges from 3–47% (Akiyama et al., 2001; Arnberg et al., 2002; Ebner et al., 2005; Howard et al, 1999; Lauer et al., 2004; Mahr & Gooding, 1999; Rutala et al., 2006; Stone et al., 2003; Walls et al, 2003; Watcharananan et al, 2010; Watzinger et al., 2004;) with mortality reaching up to 80% in patients with disseminated disease (Akiyama et al., 2001; Kaneko et al., 2009; Russell, 2000; Walls et al., 2003; Watzinger et al., 2004). The wide range in reported AdV incidence can results from different diagnostic methods, variety of body sites analyzed as well as demographic differences and lack of strict criteria for defining adenovirus infection or disease. AdV infections in immunocompromised patients tend to be invasive. The most common are infections of AdVs from subgroup C, followed by A, B and D. They cause exudative pharyngitis, acute respiratory disease epidemics, febrile laryngitis, conjunctivitis, keratoconjunctivitis, necrotizing enterocolitis, pharyngeal−conjunctival fever and hemorrhagic cystitis. Less frequent are testitis, nephritis, arthritis, myocarditis and pericarditis. Infections of the gastrointestinal tract are especially frequent in young children and include gastroenteritis, mesenteric lymphadenitis, intussusception, hepatitis, and appendicitis (Table 2) (Akiyama et al., 2001; Arnberg et al., 2002; Benko, 2000; Chakrabarti et al., 2000; Chmielewicz et al., 2005; Ebner et al., 2005; Echavarria, 2009; Ephros et al., 2009; Howard et al., 1999; Ison, 2006; Jones et al., 2007; Kaneko et al., 2009; Lim et al., 2005; Mori et al., 2003; Robin et al., 2007; Runde et al., 2001; Venard et al., 2000; Walsh et al, 2009). Most adenoviral infections in patients following HSCT occur during an early posttransplantation period, within 2-3 months (Ephros et al., 2009; Lion et al., 2010; Watcharananan et al., 2010). Adenovirus infections in patients after stem cell transplantations can occur throughout the year but there are some reports suggesting seasonal fluctuations of adenoviral infections indicating greater incidence in autumn and winter, 52-70% (Bil-Lula et al., 2010).

An intensity of virus replication depends on a site of infection. The highest viral loads are observed in gastrointestinal tract infections (even more than 108 copies/g of stool) and in upper respiratory tract infections (104 -106 copies/ml). Whole blood viraemia remains at a moderate level and usually does not exceed 103 – 104 copies per ml, whereas in plasma samples only trace amounts of AdV particles can be detected (< 102 copies/ml). Some of patients with moderate viraemia are able to self-eliminate of the virus within 2-4 weeks. However most patients presenting disseminated infections (> 107 copies/ml) die due to

periodic shedding of virus in feaces and respiratory secretions (Akiyama et al., 2001; Braithwaite & Russell, 2001; Echavarri´a, 2008; Watzinger et al., 2004). The third possible outcome of adenoviral infection is an oncogenic transformation of infected cells, that is

Primary adenoviral infections affect predominantly pediatric population with more than 50% of children infected before the age of five (Cooper et al., 2003). Children are often infected with adenovirus types 1, 2, 3, 4, 5, 7 and 30 which are the most common causes of tonsillopharyngitis and pneumonia (Carballal et al., 2002; Faden et al., 2005). These antigenic types are also the most frequent in recipients of SCT indicating virus reactivation or droplets transmission as most reliable routes of virus spread. AdV infections in immunocompetent humans are usually asymptomatic, localized and tend to be self-limited. They are restricted to the respiratory system, genitourinary and gastrointestinal tract infections, occasionally affecting conjunctiva and cornea. Recipients of HSCT and other imunocompromised patients present much broader spectrum of clinical manifestations. According to different studies, the estimated rate of AdV infection after HSCT ranges from 3–47% (Akiyama et al., 2001; Arnberg et al., 2002; Ebner et al., 2005; Howard et al, 1999; Lauer et al., 2004; Mahr & Gooding, 1999; Rutala et al., 2006; Stone et al., 2003; Walls et al, 2003; Watcharananan et al, 2010; Watzinger et al., 2004;) with mortality reaching up to 80% in patients with disseminated disease (Akiyama et al., 2001; Kaneko et al., 2009; Russell, 2000; Walls et al., 2003; Watzinger et al., 2004). The wide range in reported AdV incidence can results from different diagnostic methods, variety of body sites analyzed as well as demographic differences and lack of strict criteria for defining adenovirus infection or disease. AdV infections in immunocompromised patients tend to be invasive. The most common are infections of AdVs from subgroup C, followed by A, B and D. They cause exudative pharyngitis, acute respiratory disease epidemics, febrile laryngitis, conjunctivitis, keratoconjunctivitis, necrotizing enterocolitis, pharyngeal−conjunctival fever and hemorrhagic cystitis. Less frequent are testitis, nephritis, arthritis, myocarditis and pericarditis. Infections of the gastrointestinal tract are especially frequent in young children and include gastroenteritis, mesenteric lymphadenitis, intussusception, hepatitis, and appendicitis (Table 2) (Akiyama et al., 2001; Arnberg et al., 2002; Benko, 2000; Chakrabarti et al., 2000; Chmielewicz et al., 2005; Ebner et al., 2005; Echavarria, 2009; Ephros et al., 2009; Howard et al., 1999; Ison, 2006; Jones et al., 2007; Kaneko et al., 2009; Lim et al., 2005; Mori et al., 2003; Robin et al., 2007; Runde et al., 2001; Venard et al., 2000; Walsh et al, 2009). Most adenoviral infections in patients following HSCT occur during an early posttransplantation period, within 2-3 months (Ephros et al., 2009; Lion et al., 2010; Watcharananan et al., 2010). Adenovirus infections in patients after stem cell transplantations can occur throughout the year but there are some reports suggesting seasonal fluctuations of adenoviral infections indicating greater incidence in autumn and

An intensity of virus replication depends on a site of infection. The highest viral loads are observed in gastrointestinal tract infections (even more than 108 copies/g of stool) and in upper respiratory tract infections (104 -106 copies/ml). Whole blood viraemia remains at a moderate level and usually does not exceed 103 – 104 copies per ml, whereas in plasma samples only trace amounts of AdV particles can be detected (< 102 copies/ml). Some of patients with moderate viraemia are able to self-eliminate of the virus within 2-4 weeks. However most patients presenting disseminated infections (> 107 copies/ml) die due to

observed in animal models (Russell, 2009).

winter, 52-70% (Bil-Lula et al., 2010).

adenoviral infection within short time (Ephros et al., 2009; Heim et al., 2003; Lion et al., 2003; Walls et al., 2005).


Table 2. Clinical manifestations of adenoviral infection in stem cell transplant recipients (summary table).

#### **5. Anti-viral response and viral immunoavoidance**

Virus penetration into human organism induces both specific and non-specific response to infection. Firstly, virus by binding with the cell receptors activates congenital mechanisms of anti-viral defense. An induction of the inflammatory response stimulates interferon production by both immunocompetent and non-immunocompetent cells. Macrophages, natural killers (NK cells) and complement proteins are also involved in anti-adenovirus defense indirectly by killing infected cells or due to production of cytokins such as Il-1, Il-6 and TNF-α. Additionally, Smith et al. (2008) confirmed the role of the epithelial defensins which coat the capsid vertex of adenoviral particle and inhibit virus uncoating in cytoplasm of infected cell (Smith & Nemerow, 2008). Another way of virus elimination from the organism is induction of pro-apoptotic mechanisms in infected cells due to e.g. p53, TNFα and Bax proteins (Randall & Goodbourn, 2008; Russell, 2000, 2009; Smith & Nemerow, 2008). Very important role in viral clearance is played by acquired immunity mechanisms. The cellular response is limited to CD3+ cells activation (both helper and cytotoxic lymphocytes) which also produce TNFα and INFɣ. Activation of CD8+ cells due to presentation of hexon determinants in MHC I complex leads to eradication of infected cells by means of cell perforation and lyses. This mechanism prevents virus replication and further spread of viral particles. The humoral response is focused on production of

Adenoviral Infection – Common Complication Following Hematopoietic Stem Cell Transplantation 541

can be responsible for graft rejection or delayed implantation of stem cells (Hierholzer, 1992;

Risk factors affecting patient`s susceptibility to adenovirus infections after stem cells transplantation are well known (Figure 2). Many reports indicate increased morbidity among recipients of allogeneic grafts from matched unrelated donors (MUD) in comparison to partially matched family donors (PMFD) (Baldwin et al. 2000; Bruno et al., 2003; Ebner et al., 2005; Gu et al., 2003; Hale et al., 1999; Howard et al., 1999; Ison, 2006; Legrand et al., 2001; Lion et al., 2003). An incidence of AdV infections and patient`s mortality due to infection in this group reach about 5-47% and 60%, respectively (Hierholzer, 1992; Howard et al., 1999; Leruez-Ville et al., 2006; Lim et al., 2005; Robin et al., 2007; Runde et al., 2001; Venard et al., 2000; Walls et al., 2005). In recipients of autologous transplantations AdV infections prevalence is much lower, about 1-14% (Baldwin et al., 2000; Bruno et al., 2003; Hale et al., 1999; Howard et al., 1999; Teramura et al., 2004). Significant differences in occurrence of adenoviral infections are believed to result from more aggressive and longer immunosuppressive therapy after allogeneic transplantations (Walls et al., 2003). Lack of endogenous T-cell immunity makes patient more predisposing to development of adenoviral infection and disseminated disease with fatal outcome (Bil-Lula et al., 2010; Feuchtinger et al., 2008; Watcharananan et al., 2010). Therefore, delayed immune recovery after stem cell transplantation has critical impact on progression of adenoviral infections. Moreover, second allotransplantation also increases patient`s susceptibility to AdV infection

Another risk factor for development of adenoviral infections in HSCT recipients is patient`s age. There are many reports confirming that children and adolescents are at greater risk of adenovirus infection than adults (Robin et al., 2007; Walls et al., 2005). Greater susceptibility of younger patients may results from immaturity and worse efficiency of immune system in comparison to older recipients. Moreover, persistent infections are predominantly caused by AdV from species C, which are common etiological factor of adenoviral infections in a childhood. Combination of immunosupression and young age of graft recipients can lead to intensified replication of adenoviruses and to greater viral load in clinical samples (more than 105 copies /ml) in comparison to adult recipient (viral load usually not exceeds 103 copies /ml) (Baldwin et al., 2000; Bruno et al., 2003; Chakrabarti et al., 2002; Howard et al.,

The role of T-cells in controlling the AdV infection is unquestionable. The graft engineering methods involving ex-vivo removal of T-cells by CD34+ positive selection or by lymphocyte depletion are very effective in respect of GvHD reduction but cause profound long-term Tcell deficiency and function impairment. Adenoviral infections due to reactivation of latent virus are also reported more frequently (more than 70%) in recipients of manipulated grafts in comparison to those who received graft containing donor`s lymphocytes (25%). Moreover, some reports suggested delayed recovery and lower overall survival in patients undergoing T-cells depletion (Chakrabarti et al, 2002; Ison, 2006; Lion et al., 2003; Venard et

The development and severity of graft versus host disease are typically identified independent risk factors for progression of adenoviral infection after stem cell transplantation. The mechanism of GvHD induction is multifactorial and despite intensive research only moderately understood, the incompatibilities in HLA and in minor histocompatibility antigens (mHA) are generally recognized causes for its occurrence

1999; Heim et al., 2003; Ison, 2006; Robin et al., 2007; Walls et al., 2003).

Ison, 2006).

(Bruno et al., 2003).

al., 2000; Walls et al., 2003, 2005).

neutralizing antibodies. The neutralizing antibodies recognize HVRs and the fiber determinants leading to agglutination of virus particles and interrupting infection of new cells. The presence of anti-adenoviral antibodies in patient serum grants permanent immunity against AdV (Baldwin et al., 2000; Crawford-Miksza & Schnurr, 1994; Leen et al, 2008; Russel, 2009; Rux et al., 2003; Schilham et al., 2002; Walls et al., 2003).

Intensity and length of immunosuppressive therapy are tailored to the risk of graft-rejection or graft versus host disease.

The prevention and therapy of GvHD is crucial in allogeneic HSCT recipients, which explains its intensity and diversity by combining drugs (cyclosporine, tacrolimus, mycophenolate mofetil) with biological agents (OKT-3, alemtuzumab, ATG) or graft engineering methods like T-cell depletion/CD34+ positive selection. Immunosupression determinates stable engraftment and prevents from GvHD, but increases risk of disease relapse or opportunistic infections, due to depletion of donor lymphocytes necessary for graft-versus-tumor (GVT) effects and delayed immune reconstitution (Gyurkocza et al., 2010).

Immune defense against adenoviral infections is hampered by viral abilities for avoidance of both humoral and cellular host immune response. By means of E1A (early region 1A) and VARNAs (virally associated RNAs) they developed the ability to inhibit human interferons α and β. The product of E1B inhibits apoptosis of infected cells. Moreover, product of E3 coding region can inhibit a transport of MHC I particles to the cell membrane disturbing viral antigens presentation to the cytotoxic lymphocytes (CLS) (Braithwaite & Russell, 2001; Lauer et al., 2004; Mahr & Gooding, 1999; Russell, 2000; Stone et al., 2003). Some of E3 products interfere with pro-inflammatory and cytolytic activity of TNF or remove Fas and TRAIL receptors from cell surface (Echavarria, 2009). The fact, that these proteins are expressed during early stage of transcription, protects infected cells from immune surveillance.

#### **6. Risk factors for development of adenoviral infection after HSCT**

The hematopoietic stem cell transplantation recipients constitute a group of patients with an extremely high risk of death due to opportunistic infections, and among them the AdVs are accounted to most challenging pathogens responsible for fatal outcome. The problem of AdV infections after HSCT is a consequence of different factors affecting recipient`s immunity. Development of graft versus host disease and its prophylaxis or therapy with potent immunosuppressants are the reasons for numerous opportunistic infections. The anti-leukemic efficacy and early complications of HSCT result from both intensity of the conditioning regimen and the graft-versus-leukaemia (GVL) effect. However, conditioning strategies with high doses of cytotoxic and immunosupressive drugs lead to tissue damage, cytokine storm and profound impairment of patients immunity, thus increasing patient`s risk of de novo infection or reactivation of latent adenovirus during a post-transplantation period. Reduced-intensity conditioning (RIC) regimens lower the risk for AdV infection due decreased organ damage and lower proinflammatory cytokines secretion, hence protecting the patient from aGvHD but maintaining an effect of GVL (Couriel et al., 2004; Gyurkocza et al., 2010; Hill& Ferrara, 2000; Pérez-Simón et al., 2002, 2005). The clinical course of AdV infection after HSCT is different from the one observed in immunocompetent individuals. AdVs usually cause permanent and stubborn infections in those patients because immunological response to adenoviruses following SCT is very poor. In rare situations, AdV

neutralizing antibodies. The neutralizing antibodies recognize HVRs and the fiber determinants leading to agglutination of virus particles and interrupting infection of new cells. The presence of anti-adenoviral antibodies in patient serum grants permanent immunity against AdV (Baldwin et al., 2000; Crawford-Miksza & Schnurr, 1994; Leen et al,

Intensity and length of immunosuppressive therapy are tailored to the risk of graft-rejection

The prevention and therapy of GvHD is crucial in allogeneic HSCT recipients, which explains its intensity and diversity by combining drugs (cyclosporine, tacrolimus, mycophenolate mofetil) with biological agents (OKT-3, alemtuzumab, ATG) or graft engineering methods like T-cell depletion/CD34+ positive selection. Immunosupression determinates stable engraftment and prevents from GvHD, but increases risk of disease relapse or opportunistic infections, due to depletion of donor lymphocytes necessary for graft-versus-tumor (GVT) effects and delayed immune reconstitution (Gyurkocza et al.,

Immune defense against adenoviral infections is hampered by viral abilities for avoidance of both humoral and cellular host immune response. By means of E1A (early region 1A) and VARNAs (virally associated RNAs) they developed the ability to inhibit human interferons α and β. The product of E1B inhibits apoptosis of infected cells. Moreover, product of E3 coding region can inhibit a transport of MHC I particles to the cell membrane disturbing viral antigens presentation to the cytotoxic lymphocytes (CLS) (Braithwaite & Russell, 2001; Lauer et al., 2004; Mahr & Gooding, 1999; Russell, 2000; Stone et al., 2003). Some of E3 products interfere with pro-inflammatory and cytolytic activity of TNF or remove Fas and TRAIL receptors from cell surface (Echavarria, 2009). The fact, that these proteins are expressed during early stage of transcription, protects infected cells from immune

**6. Risk factors for development of adenoviral infection after HSCT** 

The hematopoietic stem cell transplantation recipients constitute a group of patients with an extremely high risk of death due to opportunistic infections, and among them the AdVs are accounted to most challenging pathogens responsible for fatal outcome. The problem of AdV infections after HSCT is a consequence of different factors affecting recipient`s immunity. Development of graft versus host disease and its prophylaxis or therapy with potent immunosuppressants are the reasons for numerous opportunistic infections. The anti-leukemic efficacy and early complications of HSCT result from both intensity of the conditioning regimen and the graft-versus-leukaemia (GVL) effect. However, conditioning strategies with high doses of cytotoxic and immunosupressive drugs lead to tissue damage, cytokine storm and profound impairment of patients immunity, thus increasing patient`s risk of de novo infection or reactivation of latent adenovirus during a post-transplantation period. Reduced-intensity conditioning (RIC) regimens lower the risk for AdV infection due decreased organ damage and lower proinflammatory cytokines secretion, hence protecting the patient from aGvHD but maintaining an effect of GVL (Couriel et al., 2004; Gyurkocza et al., 2010; Hill& Ferrara, 2000; Pérez-Simón et al., 2002, 2005). The clinical course of AdV infection after HSCT is different from the one observed in immunocompetent individuals. AdVs usually cause permanent and stubborn infections in those patients because immunological response to adenoviruses following SCT is very poor. In rare situations, AdV

2008; Russel, 2009; Rux et al., 2003; Schilham et al., 2002; Walls et al., 2003).

or graft versus host disease.

2010).

surveillance.

can be responsible for graft rejection or delayed implantation of stem cells (Hierholzer, 1992; Ison, 2006).

Risk factors affecting patient`s susceptibility to adenovirus infections after stem cells transplantation are well known (Figure 2). Many reports indicate increased morbidity among recipients of allogeneic grafts from matched unrelated donors (MUD) in comparison to partially matched family donors (PMFD) (Baldwin et al. 2000; Bruno et al., 2003; Ebner et al., 2005; Gu et al., 2003; Hale et al., 1999; Howard et al., 1999; Ison, 2006; Legrand et al., 2001; Lion et al., 2003). An incidence of AdV infections and patient`s mortality due to infection in this group reach about 5-47% and 60%, respectively (Hierholzer, 1992; Howard et al., 1999; Leruez-Ville et al., 2006; Lim et al., 2005; Robin et al., 2007; Runde et al., 2001; Venard et al., 2000; Walls et al., 2005). In recipients of autologous transplantations AdV infections prevalence is much lower, about 1-14% (Baldwin et al., 2000; Bruno et al., 2003; Hale et al., 1999; Howard et al., 1999; Teramura et al., 2004). Significant differences in occurrence of adenoviral infections are believed to result from more aggressive and longer immunosuppressive therapy after allogeneic transplantations (Walls et al., 2003). Lack of endogenous T-cell immunity makes patient more predisposing to development of adenoviral infection and disseminated disease with fatal outcome (Bil-Lula et al., 2010; Feuchtinger et al., 2008; Watcharananan et al., 2010). Therefore, delayed immune recovery after stem cell transplantation has critical impact on progression of adenoviral infections. Moreover, second allotransplantation also increases patient`s susceptibility to AdV infection (Bruno et al., 2003).

Another risk factor for development of adenoviral infections in HSCT recipients is patient`s age. There are many reports confirming that children and adolescents are at greater risk of adenovirus infection than adults (Robin et al., 2007; Walls et al., 2005). Greater susceptibility of younger patients may results from immaturity and worse efficiency of immune system in comparison to older recipients. Moreover, persistent infections are predominantly caused by AdV from species C, which are common etiological factor of adenoviral infections in a childhood. Combination of immunosupression and young age of graft recipients can lead to intensified replication of adenoviruses and to greater viral load in clinical samples (more than 105 copies /ml) in comparison to adult recipient (viral load usually not exceeds 103 copies /ml) (Baldwin et al., 2000; Bruno et al., 2003; Chakrabarti et al., 2002; Howard et al., 1999; Heim et al., 2003; Ison, 2006; Robin et al., 2007; Walls et al., 2003).

The role of T-cells in controlling the AdV infection is unquestionable. The graft engineering methods involving ex-vivo removal of T-cells by CD34+ positive selection or by lymphocyte depletion are very effective in respect of GvHD reduction but cause profound long-term Tcell deficiency and function impairment. Adenoviral infections due to reactivation of latent virus are also reported more frequently (more than 70%) in recipients of manipulated grafts in comparison to those who received graft containing donor`s lymphocytes (25%). Moreover, some reports suggested delayed recovery and lower overall survival in patients undergoing T-cells depletion (Chakrabarti et al, 2002; Ison, 2006; Lion et al., 2003; Venard et al., 2000; Walls et al., 2003, 2005).

The development and severity of graft versus host disease are typically identified independent risk factors for progression of adenoviral infection after stem cell transplantation. The mechanism of GvHD induction is multifactorial and despite intensive research only moderately understood, the incompatibilities in HLA and in minor histocompatibility antigens (mHA) are generally recognized causes for its occurrence

Adenoviral Infection – Common Complication Following Hematopoietic Stem Cell Transplantation 543

et al., 2003; Robin et al, 2007; Schilham et al., 2002; Watcharananan et al., 2010). High viral load in plasma samples (106-107 copies/ml) should be considered as a risk factor for serious post-transplantation complications (Ison, 2006; Claas et al., 2005), but the issue is still controversial because other authors did not confirm the relationship between viral load and severity of infection (Walls et al., 2005). In some studies were reported patients who despite high viral load in blood recovered from adenoviral infection without any treatment. It suggests that not each adenoviral infection needs antiviral treatment (Lankester et al., 2002;

It needs to be mentioned that the source of progenitor cells also plays a significant role in development of adenoviral infection. It was confirmed that transplantation of peripheral blood progenitor cells (PBPCs) increases an incidence of AdV infections in hematological patients in comparison to bone marrow transplantations (BMT) due to high number of lymphocytes transferred with the graft. Adenovirus latency in peripheral lymphocytes may be a source of infection in those patients (Runde et al., 2001). On the other hand, unrelated cord blood transplantations (UCB) are suggested to be an independent risk factor for AdV infections (Robin et al., 2007) due to lack of mature lymphocytes in CB regarded as the major

Recipients of stem cell transplantations with AdV infection are prone to life-threatening multiple opportunistic infections. Simultaneous infections of adenoviruses and CMV (4,3- 73%), EBV (2,8-34%), polyoma BK (BKV) (1,7-20%), HSV (6,7-26,6%) or RSV (3,8-13%) are most frequently reported (Baldwin et al., 2000; Bruno et al., 2003; Chakrabarti et al., 2002; Leruez-Ville et al., 2006; Lion et al., 2003; Myers et al., 2005; Watcharananan et al., 2010). Coinfections of AdV and BKV are usually detected in urinary tract of immunocompromised patients leading to intensification of hemorrhagic cystitis sympthoms (Akiyama et al., 2001). It was also found that CMV viraemia leads to more than 4-fold increase in patient`s risk for development of AdV infection (Baldwin et al., 2000; Watcharananan et al., 2010). In rare cases, co-infections of AdV and other viruses such as: HSV1, RSV, EBV and rotaviruses were observed (Legrand et al., 2001; Robin et al., 2007). Many reports suggested that infection of one AdV serotype increases patient`s risk for co-infection with second type of human adenovirus leading to extensive organ and whole system involvement (Echavarria et al.,

component of antiviral defense. Therefore it is still controversial issue.

2006; Kroes et al., 2007; Watcharananan et al., 2010).

molecular methods found their way into clinical practice.

rounding can be observed (Figure 3).

**7. Co-infections in patients undergoing stem cell transplantation** 

**8. Diagnostic methods for adenovirus detection and identification** 

Permanently growing number of hematopoietic transplantations in recent years and high risk of viral complications following this procedure demands an implementation of better and more effective diagnostics methods for detection and monitoring of viral infections. There are several methods commonly used for adenovirus detection and identification in clinical samples. Serological tests, virus isolation in cell culture, microscopic techniques and

Virus isolation in cell culture is still considered a "gold standard" for detection of adenoviral infection. Different cell lines like A549, Graham 293 and HEp-2 can be used for virus isolation from clinical samples such as stool, throat swabs, conjunctival swabs, urine and biopsy specimens. Within several days of culturing, cythopatic effect as clumping and cell

Schilham et al., 2002).

(Gyurkocza et al., 2010). It was reported that moderate to severe aGvHD and its therapy may facilitate virus replication in recipients of SCT (Baldwin et al., 2000; Bil-Lula et al, 2010; Bruno et al., 2003; Ison, 2006; Robin et al., 2007; Runde et al., 2001; Watcharananan et al., 2010). GvHD requires immunosuppressive therapy which lowers the number of lymphocytes and hampers the immunity of the recipient, thus enabling adenoviral infections. A low lymphocyte count due to non-specific T-cell depletion or delayed T-cell reconstitution is considered as important predictor for detection of adenoviral infections. An inadequate humoral response due to B lymphocyte impairment contributes to greater susceptibility to AdV infection (Chakrabarti et al., 2000, 2002; Heemskerk et al., 2005). Some authors emphasize that presence of adenovirus in peripheral blood or plasma is an indicator of impending symptomatic adenoviral disease and multiorgan failure in patients undergoing HSCT. Chakrabarti et al. (2002) and others confirmed a strong correlation between the presence of adenovirus in whole blood/plasma and an increased mortality due to infection (9-86%) (Chakrabarti et al., 2002; Ebner et al., 2005; Echavarria et al, 2001; Lion

Fig. 2. Risk factors for adenoviral infections in patients after haematopoietic stem cell transplantation.

(Gyurkocza et al., 2010). It was reported that moderate to severe aGvHD and its therapy may facilitate virus replication in recipients of SCT (Baldwin et al., 2000; Bil-Lula et al, 2010; Bruno et al., 2003; Ison, 2006; Robin et al., 2007; Runde et al., 2001; Watcharananan et al., 2010). GvHD requires immunosuppressive therapy which lowers the number of lymphocytes and hampers the immunity of the recipient, thus enabling adenoviral infections. A low lymphocyte count due to non-specific T-cell depletion or delayed T-cell reconstitution is considered as important predictor for detection of adenoviral infections. An inadequate humoral response due to B lymphocyte impairment contributes to greater susceptibility to AdV infection (Chakrabarti et al., 2000, 2002; Heemskerk et al., 2005). Some authors emphasize that presence of adenovirus in peripheral blood or plasma is an indicator of impending symptomatic adenoviral disease and multiorgan failure in patients undergoing HSCT. Chakrabarti et al. (2002) and others confirmed a strong correlation between the presence of adenovirus in whole blood/plasma and an increased mortality due to infection (9-86%) (Chakrabarti et al., 2002; Ebner et al., 2005; Echavarria et al, 2001; Lion

Fig. 2. Risk factors for adenoviral infections in patients after haematopoietic stem cell

transplantation.

et al., 2003; Robin et al, 2007; Schilham et al., 2002; Watcharananan et al., 2010). High viral load in plasma samples (106-107 copies/ml) should be considered as a risk factor for serious post-transplantation complications (Ison, 2006; Claas et al., 2005), but the issue is still controversial because other authors did not confirm the relationship between viral load and severity of infection (Walls et al., 2005). In some studies were reported patients who despite high viral load in blood recovered from adenoviral infection without any treatment. It suggests that not each adenoviral infection needs antiviral treatment (Lankester et al., 2002; Schilham et al., 2002).

It needs to be mentioned that the source of progenitor cells also plays a significant role in development of adenoviral infection. It was confirmed that transplantation of peripheral blood progenitor cells (PBPCs) increases an incidence of AdV infections in hematological patients in comparison to bone marrow transplantations (BMT) due to high number of lymphocytes transferred with the graft. Adenovirus latency in peripheral lymphocytes may be a source of infection in those patients (Runde et al., 2001). On the other hand, unrelated cord blood transplantations (UCB) are suggested to be an independent risk factor for AdV infections (Robin et al., 2007) due to lack of mature lymphocytes in CB regarded as the major component of antiviral defense. Therefore it is still controversial issue.

#### **7. Co-infections in patients undergoing stem cell transplantation**

Recipients of stem cell transplantations with AdV infection are prone to life-threatening multiple opportunistic infections. Simultaneous infections of adenoviruses and CMV (4,3- 73%), EBV (2,8-34%), polyoma BK (BKV) (1,7-20%), HSV (6,7-26,6%) or RSV (3,8-13%) are most frequently reported (Baldwin et al., 2000; Bruno et al., 2003; Chakrabarti et al., 2002; Leruez-Ville et al., 2006; Lion et al., 2003; Myers et al., 2005; Watcharananan et al., 2010). Coinfections of AdV and BKV are usually detected in urinary tract of immunocompromised patients leading to intensification of hemorrhagic cystitis sympthoms (Akiyama et al., 2001). It was also found that CMV viraemia leads to more than 4-fold increase in patient`s risk for development of AdV infection (Baldwin et al., 2000; Watcharananan et al., 2010). In rare cases, co-infections of AdV and other viruses such as: HSV1, RSV, EBV and rotaviruses were observed (Legrand et al., 2001; Robin et al., 2007). Many reports suggested that infection of one AdV serotype increases patient`s risk for co-infection with second type of human adenovirus leading to extensive organ and whole system involvement (Echavarria et al., 2006; Kroes et al., 2007; Watcharananan et al., 2010).

#### **8. Diagnostic methods for adenovirus detection and identification**

Permanently growing number of hematopoietic transplantations in recent years and high risk of viral complications following this procedure demands an implementation of better and more effective diagnostics methods for detection and monitoring of viral infections. There are several methods commonly used for adenovirus detection and identification in clinical samples. Serological tests, virus isolation in cell culture, microscopic techniques and molecular methods found their way into clinical practice.

Virus isolation in cell culture is still considered a "gold standard" for detection of adenoviral infection. Different cell lines like A549, Graham 293 and HEp-2 can be used for virus isolation from clinical samples such as stool, throat swabs, conjunctival swabs, urine and biopsy specimens. Within several days of culturing, cythopatic effect as clumping and cell rounding can be observed (Figure 3).

Adenoviral Infection – Common Complication Following Hematopoietic Stem Cell Transplantation 545

accurate and rapid diagnostics and surveillance. PCR is currently the most widespread method used for detection of microbial infections. In comparison to conventional techniques it offers high sensitivity and specificity as well as possibility to obtain a reliable result within several hours. This method allows detecting even small number of viral particles in largely cell-free fluids such as plasma, serum, urine (centrifuged), cerebrospinal fluids and others, preferably before clinical manifestation and tissue damage (Ephros et al., 2009). It can also be implemented for detection of AdV serotypes which are potentially considered as not growing in routine cell culture. Moreover, polymerase chain reaction may be employed for detection of variance and mutations in virus genome (Powledge, 2004). In combination with other methods such as sequencing of hyper variation regions (HVRs) or restriction fragment length analysis, PCR may be used for AdV typing. During last years, the quantitative realtime PCR (RQ-PCR) technique has been successfully implemented more often in viral diagnostics (Bil-Lula et al., 2010; Claas et al., 2005; Echavarria et al., 1999, 2001; Gu et al., 2003; Heim et al., 2003; Hierholzer et al., 1993; Lankester et al., 2002; Lion et al., 2003; Watzinger et al., 2004). Use of highly specific probes allows sensitive detection and quantification of viral equivalents in clinical samples. Sensitive and reliable monitoring of viral replication in immunocompromised patient is extremely important due to possibility for dissemination of infection and poor outcome. It has also a prognostic significance for the patient. Moreover, monitoring of active replication and increasing viral load in clinical samples constitutes the basis for differentiation of active and latent infection in recipients of stem cell transplantations. On the other hand, an early detection of adenovirus due to highly sensitive RQ-PCR creates the opportunity for reduction of immunosuppressive therapy or early initiation of preemptive anti-viral agents before onset of fulminant disease, simultaneously determining therapy effectiveness (Mori et al., 2003). It was confirmed that weekly surveillance of samples for AdVs and early intervention with anti-AdV agents results in significant reduction in the disseminated disease rate and fatal outcomes

There are many reports describing treatment trials of adenoviral infections in recent years. However, treatment of AdV infections remains a serious problem due to lack of unequivocally proven effectiveness of used drugs. Therefore adenoviral infections in immunocompromised patients should be considered as a serious, life-threatening

Due to numerous toxicities and limitations, administration of anti-AdV drugs should be tailored to the patients situation and risk of dismal outcome. In severe AdV infections usually cidofovir (CDV) or ganciclovir are administered (Bordigoni et al., 2001; Hoffman et al., 2001; Legrand et al., 2001). Other anti-viral drugs such as vidarabine and ribavirine may be implemented (Bordigoni et al., 2001; Miyamura et al., 2000). It was demonstrated that ribavirin (usually used in treatment of HCV and RSV infections) is highly effective in treatment of localized AdV infections in urinary tract but is of limited efficacy in disseminated infections (Bordigoni et al., 2001; Gavin & Katz, 2002; Hoffman et al., 2000; Lankester et al., 2004). Some studies also confirmed partially the ability to virus elimination from urine samples after cidofovir administration in patients suffering from hemorrhagic cystitis. Unfortunately, CDV shows numerous side effects such as renal toxicity, carcinogenicity and toxic injury of muscles (Bordigoni et al., 2001; Feuchtinger et al., 2006,

(Sivaprakasam et al., 2007; Yusuf et al., 2006).

complication.

**9. Treatment strategies for adenoviral infections** 

Fig. 3. Microscope image of A549 cells. (A) native culture; (B) cythopatic effect occurring within 48 hours since AdV21 infection (species B). Own collection.

This reference method provides virus identification and typing by means of serum neutralization (SN), hemagglutination inhibition (HI) and complement fixation tests. Unfortunately, the culture technique is laborious, time-consuming and lacks sensitivity to detect virus in the early phase of infection. It can also be inhibited by neutralizing antibodies or other interfering substances (Echavarria, 2009; Huang & Turchek, 2000; Raboni et al., 2003). Nowadays, due to its disadvantages it is replaced by new, more reliable methods like molecular tests.

The next conventional methods for detection of adenoviral infection are serological tests. They are used for indirect antigen detection on capsid surface (IFA, RIA) allowing for virus identification in highly concentrated samples of respiratory secretion, pharyngeal swabs and stool or to confirm AdV infection on the basis of specific antibodies detection. ELISA tests are also used for identification of AdV-antibodies in patient`s serum (Echavarria, 2009; Hierholzer et al., 1993; Madisch et al., 2005; Raboni et al., 2003). Although serological tests are commonly used in routine diagnostics of viral infections they are not recommended in adenoviral infections due to their insensitivity, low specificity, false negative results during the window period and difficulties arising from virus variability (Chirmule et al., 1999; Chmielewicz et al., 2005; Crawford-Miksza & Schnurr, 1994; Echavarria, 2009; Raboni et al., 2003). Furthermore, serological tests are useless in recipients of SCT due to profound immunosuppression and using of anti-viral drugs.

The characteristic icosahedral morphology of adenoviruses can be utilized in virus detection by use of electron microscopy (EM) and other microscopic techniques. Infected cell are characterized by presence of enlarged nuclei containing crystalline inclusions of adenoviral particles. Nonetheless, this method is limited by access to unique equipment and EM requires a large number of viral particles in clinical sample hence it can be mainly used in diagnostics of acute gastroenteritis and upper respiratory tract infections (Chirmule et al., 1999; Roingeard, 2008).

Numerous limitations of conventional methods make these techniques impractical in routine diagnostics. The culture collection, serological tests and microscopic techniques are laborious, time-consuming, and insensitive especially in an early phase of the infection. Hence in recent years, molecular methods dominate virus detection and identification in clinical practice. Identification of adenovirus by polymerase chain reaction (PCR) facilitates accurate and rapid diagnostics and surveillance. PCR is currently the most widespread method used for detection of microbial infections. In comparison to conventional techniques it offers high sensitivity and specificity as well as possibility to obtain a reliable result within several hours. This method allows detecting even small number of viral particles in largely cell-free fluids such as plasma, serum, urine (centrifuged), cerebrospinal fluids and others, preferably before clinical manifestation and tissue damage (Ephros et al., 2009). It can also be implemented for detection of AdV serotypes which are potentially considered as not growing in routine cell culture. Moreover, polymerase chain reaction may be employed for detection of variance and mutations in virus genome (Powledge, 2004). In combination with other methods such as sequencing of hyper variation regions (HVRs) or restriction fragment length analysis, PCR may be used for AdV typing. During last years, the quantitative realtime PCR (RQ-PCR) technique has been successfully implemented more often in viral diagnostics (Bil-Lula et al., 2010; Claas et al., 2005; Echavarria et al., 1999, 2001; Gu et al., 2003; Heim et al., 2003; Hierholzer et al., 1993; Lankester et al., 2002; Lion et al., 2003; Watzinger et al., 2004). Use of highly specific probes allows sensitive detection and quantification of viral equivalents in clinical samples. Sensitive and reliable monitoring of viral replication in immunocompromised patient is extremely important due to possibility for dissemination of infection and poor outcome. It has also a prognostic significance for the patient. Moreover, monitoring of active replication and increasing viral load in clinical samples constitutes the basis for differentiation of active and latent infection in recipients of stem cell transplantations. On the other hand, an early detection of adenovirus due to highly sensitive RQ-PCR creates the opportunity for reduction of immunosuppressive therapy or early initiation of preemptive anti-viral agents before onset of fulminant disease, simultaneously determining therapy effectiveness (Mori et al., 2003). It was confirmed that weekly surveillance of samples for AdVs and early intervention with anti-AdV agents results in significant reduction in the disseminated disease rate and fatal outcomes (Sivaprakasam et al., 2007; Yusuf et al., 2006).

#### **9. Treatment strategies for adenoviral infections**

544 New Advances in Stem Cell Transplantation

Fig. 3. Microscope image of A549 cells. (A) native culture; (B) cythopatic effect occurring

This reference method provides virus identification and typing by means of serum neutralization (SN), hemagglutination inhibition (HI) and complement fixation tests. Unfortunately, the culture technique is laborious, time-consuming and lacks sensitivity to detect virus in the early phase of infection. It can also be inhibited by neutralizing antibodies or other interfering substances (Echavarria, 2009; Huang & Turchek, 2000; Raboni et al., 2003). Nowadays, due to its disadvantages it is replaced by new, more reliable methods like

The next conventional methods for detection of adenoviral infection are serological tests. They are used for indirect antigen detection on capsid surface (IFA, RIA) allowing for virus identification in highly concentrated samples of respiratory secretion, pharyngeal swabs and stool or to confirm AdV infection on the basis of specific antibodies detection. ELISA tests are also used for identification of AdV-antibodies in patient`s serum (Echavarria, 2009; Hierholzer et al., 1993; Madisch et al., 2005; Raboni et al., 2003). Although serological tests are commonly used in routine diagnostics of viral infections they are not recommended in adenoviral infections due to their insensitivity, low specificity, false negative results during the window period and difficulties arising from virus variability (Chirmule et al., 1999; Chmielewicz et al., 2005; Crawford-Miksza & Schnurr, 1994; Echavarria, 2009; Raboni et al., 2003). Furthermore, serological tests are useless in recipients of SCT due to profound

The characteristic icosahedral morphology of adenoviruses can be utilized in virus detection by use of electron microscopy (EM) and other microscopic techniques. Infected cell are characterized by presence of enlarged nuclei containing crystalline inclusions of adenoviral particles. Nonetheless, this method is limited by access to unique equipment and EM requires a large number of viral particles in clinical sample hence it can be mainly used in diagnostics of acute gastroenteritis and upper respiratory tract infections (Chirmule et al.,

Numerous limitations of conventional methods make these techniques impractical in routine diagnostics. The culture collection, serological tests and microscopic techniques are laborious, time-consuming, and insensitive especially in an early phase of the infection. Hence in recent years, molecular methods dominate virus detection and identification in clinical practice. Identification of adenovirus by polymerase chain reaction (PCR) facilitates

within 48 hours since AdV21 infection (species B). Own collection.

immunosuppression and using of anti-viral drugs.

molecular tests.

1999; Roingeard, 2008).

There are many reports describing treatment trials of adenoviral infections in recent years. However, treatment of AdV infections remains a serious problem due to lack of unequivocally proven effectiveness of used drugs. Therefore adenoviral infections in immunocompromised patients should be considered as a serious, life-threatening complication.

Due to numerous toxicities and limitations, administration of anti-AdV drugs should be tailored to the patients situation and risk of dismal outcome. In severe AdV infections usually cidofovir (CDV) or ganciclovir are administered (Bordigoni et al., 2001; Hoffman et al., 2001; Legrand et al., 2001). Other anti-viral drugs such as vidarabine and ribavirine may be implemented (Bordigoni et al., 2001; Miyamura et al., 2000). It was demonstrated that ribavirin (usually used in treatment of HCV and RSV infections) is highly effective in treatment of localized AdV infections in urinary tract but is of limited efficacy in disseminated infections (Bordigoni et al., 2001; Gavin & Katz, 2002; Hoffman et al., 2000; Lankester et al., 2004). Some studies also confirmed partially the ability to virus elimination from urine samples after cidofovir administration in patients suffering from hemorrhagic cystitis. Unfortunately, CDV shows numerous side effects such as renal toxicity, carcinogenicity and toxic injury of muscles (Bordigoni et al., 2001; Feuchtinger et al., 2006,

Adenoviral Infection – Common Complication Following Hematopoietic Stem Cell Transplantation 547

and therefore there is a large chance that successful DLI may become a new therapeutic strategy for treatment of adenoviral infections after SCT, as antiviral therapy has revealed limited success (Bordigoni et al, 2001; Feuchtinger et al., 2008; Lion et al., 2010). Lion et al. (2010) suggested that initiation of cidofovir/adoptive transfer of AdV-specific T cells may reduce proliferation of adenovirus until recovery of host immune system. These considerations suggest that simultaneous detection and treatment of adenoviral infection at early stage might prevent life-treatening disseminated infections in recipients of

Anti-adenovirus treatment needs careful consideration in many clinical aspects. The knowledge on AdV pathogeneicity needs more elucidation. The retrospective studies of Wall et al. (2005), Hale et al. (2003) and others proved that there is a possibility for elimination of high viraemia without any treatment due to sufficient host T-cell response (Ephros et al., 2009). The opportunity for 'watch and wait' strategy is a new unexplored clinical option, but the identification of patients with benign clinical course is impossible yet.

Taking into account that more than 50000 of hematopoietic stem cell transplantations are performed every year and nearly 10000 originate from unrelated donors, the number of patients who may be affected from adenoviral infections seems to be significant. In view of worldwide distribution of adenoviruses, numerous routes of infection and limited effectiveness of anti-AdV treatment, adenoviral infections in patients undergoing hematopoietic stem cell transplantations should be always considered as serious, lifethreatening post-transplant complication which demands rapid and unequivocal diagnosis

Akiyama, H., Kurosu, T., Sakashita, C., Inoue, T., Mori, Si., Ohashi, K., Tanikawa, S.,

Amrolia, P,.J., Muccioli-Casadei, G., Huls, H., Adams, S., Durett, A., Gee, A., Yvon, E.,

transplantation. *Clin. Infect. Dis*.,Vol.32, No.9, pp.1325–1330.

*Microbiol. Clin*., Vol.28, No.10, pp.690-693.

Sakamaki, H., Onozawa, Y., Chen, Q., Zheng, H. & Kitamura T. (2001). Adenovirus is a key pathogen in hemorrhagic cystitis associated with bone marrow

Weiss, H., Cobbold, M., Gaspar, H.B., Rooney, C., Kuehnle, I., Ghetie, V., Schindler, J., Krance, R., Heslop, H.E., Veys, P., Vitetta, E. & Brenner M.K. (2006). Adoptive immunotherapy with allodepleted donor T-cells improves immune reconstitution after haploidentical stem cell transplantation. *Blood*, Vol.108, No.6, pp.1797-1808. Arnberg, N., Pring-Akerblom, P. & Wadell, G. (2002). Adenovirus type 37 uses sialic acid as a cellular receptor on Chang C cells. *J. Virol.*, Vol.76, No,17, pp.8834–8841. Artieda, J., Montes, M., Vicente, D., Martínez, C., Piñeiro, L. & Mendiola, J. (2010). Outbreak

of follicular conjunctivitis caused by adenovirus in a geriatric centre. *Enferm. Infecc.* 

Oakhill, A., Pamphilon, D.H., Steward, C.G. & Marks D.I. (2000). Outcome and clinical course of 100 patients with adenovirus infection following bone marrow

Baldwin, A., Kingman, H., Darville, M., Foot, A.B., Grier, D., Cornish, J.M., Goulden, N.,

transplantation. *Bone Marrow Transplant*., Vol.26, No,12, pp.1333-1338.

hematopoietic stem cell.

**10. Conclusion** 

defining patient`s outcome.

**11. References** 

2008). Despite all these side effects, lack of other more effective medicaments dictates the application of these drugs in therapy of adenoviral infections of urinary tract, gastroenterititis and pneumonia (Bruno et al., 2003; Ebner et al., 2006; Heim et al., 2003; Hoffman et al., 2001; Legrand et al., 2001, Uchio et al., 2007). New antiviral agents are under development. CMX001 is a new formulation of cidofovir. It is oral lipid conjugate of CDV, potentially highly effective against all dsDNA viruses, including adenoviruses (Fowler et al., 2010; Randhawa et al., 2006). Novel form of cidofovir is characterized by convenient oral supply, decreased dose and lack of affinity to kidney tissue. Due to insufficient effectiveness of previously used drugs, new clinical trials are still carrying on. New candidates for treatment of adenoviral infections are also zalcitabine and stavudine, commonly used as anti-HIV agents (Inoue et al., 2009; Romanowski et al., 2009). Zalcitabine is a reverse transcriptase inhibitor which may be used in treatment of AdV infections caused by serotypes: 2, 3, 4, 8, 19 and 37. Unfortunately, only low dosed of zalcitabine may be administrated because of its mitochondrial toxicity and possibility of peripheral neuropathy and esophageal varices. Stavudine, in turn, is an analogue of pyrimidine nucleoside which inhibits the activity of reverse transcription. It may be potentially used in treatment of AdV3 and AdV4 infections (Inoue et al., 2009; Romanowski et al., 2009; Uchio et al., 2007).

Timing of therapeutical intervention plays important role, too. There are many reports confirming the significant role of early detection of viraemia before the appearance of clinical symptoms (Legrand et al, 2001; Teramura et al., 2004; Watzinger et al., 2004). Initiation of antiviral treatment before the onset of invasive disease is beneficial. It was documented that even intravenous supplementation of antiviral agent during active virus replication does not result in recovery in some patients (Chakrabarti et al, 1999). Therefore, an early diagnosis of infection and adequately early implementation of antiviral therapy can significantly reduce the effects of AdV infections (Chakrabarti et al., 2002; Gavin & Katz, 2002; Sivaprakasam et al., 2007; Walls et al., 2003). Drug cytotoxicity and its limited efficacy in adenoviral infections should encourage clinicians to focus on an earlier diagnostics and monitoring of adenoviral infections.

In recent years, immunomodulation has been most frequently proposed as a new therapeutic strategy. Adoptive transfer of T-cell immunity from the donor to the recipient (DLI) and infusion of donor immunoglobulins (IVIG) combined with reduced immunosupression has become a new treatment option for patients with an insufficient number of AdV-specific T-cells. It was demonstrated that infusion of donor AdV-specific lymphocytes T is well tolerated and may lead to partially reconstruction of recipient`s immune system leading to prophylactics or treatment of adenoviral infections (Amrolia et al., 2006; Bordigoni et al., 2001; Feuchtinger et al., 2008; Fujita et al., 2008; Ison, 2006; Lion et al., 2010). Successful reduction of AdV replication is achieved mainly due to infusion of selected AdV-specific lymphocytes. Infusion of unselected donor lymphocytes is associated with higher risk of aGvHD due to high alloreactivity which requires more aggressive immunosupresive therapy conducing development of viral infections (Walter et al., 1995). The sufficient immune response is achieved mainly due to infusion of combined CD4+/CD8+ (60%) or solely CD4+ (40%) cells (Feuchtinger et al., 2008). However, heterogeneity of *Adenoviridae* family in the context of immunomodulation is questionable. Human immune system recognizes the surface determinants of AdV capsid which are highly variable between AdV serotypes. Hence, the success of T-cells administration may be dependent on infecting serotype (Ebner et al., 2006). On the other hand, human adenoviruses exhibit high cross-reactivity against different clinically relevant species of AdV and therefore there is a large chance that successful DLI may become a new therapeutic strategy for treatment of adenoviral infections after SCT, as antiviral therapy has revealed limited success (Bordigoni et al, 2001; Feuchtinger et al., 2008; Lion et al., 2010). Lion et al. (2010) suggested that initiation of cidofovir/adoptive transfer of AdV-specific T cells may reduce proliferation of adenovirus until recovery of host immune system. These considerations suggest that simultaneous detection and treatment of adenoviral infection at early stage might prevent life-treatening disseminated infections in recipients of hematopoietic stem cell.

Anti-adenovirus treatment needs careful consideration in many clinical aspects. The knowledge on AdV pathogeneicity needs more elucidation. The retrospective studies of Wall et al. (2005), Hale et al. (2003) and others proved that there is a possibility for elimination of high viraemia without any treatment due to sufficient host T-cell response (Ephros et al., 2009). The opportunity for 'watch and wait' strategy is a new unexplored clinical option, but the identification of patients with benign clinical course is impossible yet.

#### **10. Conclusion**

546 New Advances in Stem Cell Transplantation

2008). Despite all these side effects, lack of other more effective medicaments dictates the application of these drugs in therapy of adenoviral infections of urinary tract, gastroenterititis and pneumonia (Bruno et al., 2003; Ebner et al., 2006; Heim et al., 2003; Hoffman et al., 2001; Legrand et al., 2001, Uchio et al., 2007). New antiviral agents are under development. CMX001 is a new formulation of cidofovir. It is oral lipid conjugate of CDV, potentially highly effective against all dsDNA viruses, including adenoviruses (Fowler et al., 2010; Randhawa et al., 2006). Novel form of cidofovir is characterized by convenient oral supply, decreased dose and lack of affinity to kidney tissue. Due to insufficient effectiveness of previously used drugs, new clinical trials are still carrying on. New candidates for treatment of adenoviral infections are also zalcitabine and stavudine, commonly used as anti-HIV agents (Inoue et al., 2009; Romanowski et al., 2009). Zalcitabine is a reverse transcriptase inhibitor which may be used in treatment of AdV infections caused by serotypes: 2, 3, 4, 8, 19 and 37. Unfortunately, only low dosed of zalcitabine may be administrated because of its mitochondrial toxicity and possibility of peripheral neuropathy and esophageal varices. Stavudine, in turn, is an analogue of pyrimidine nucleoside which inhibits the activity of reverse transcription. It may be potentially used in treatment of AdV3

and AdV4 infections (Inoue et al., 2009; Romanowski et al., 2009; Uchio et al., 2007).

monitoring of adenoviral infections.

Timing of therapeutical intervention plays important role, too. There are many reports confirming the significant role of early detection of viraemia before the appearance of clinical symptoms (Legrand et al, 2001; Teramura et al., 2004; Watzinger et al., 2004). Initiation of antiviral treatment before the onset of invasive disease is beneficial. It was documented that even intravenous supplementation of antiviral agent during active virus replication does not result in recovery in some patients (Chakrabarti et al, 1999). Therefore, an early diagnosis of infection and adequately early implementation of antiviral therapy can significantly reduce the effects of AdV infections (Chakrabarti et al., 2002; Gavin & Katz, 2002; Sivaprakasam et al., 2007; Walls et al., 2003). Drug cytotoxicity and its limited efficacy in adenoviral infections should encourage clinicians to focus on an earlier diagnostics and

In recent years, immunomodulation has been most frequently proposed as a new therapeutic strategy. Adoptive transfer of T-cell immunity from the donor to the recipient (DLI) and infusion of donor immunoglobulins (IVIG) combined with reduced immunosupression has become a new treatment option for patients with an insufficient number of AdV-specific T-cells. It was demonstrated that infusion of donor AdV-specific lymphocytes T is well tolerated and may lead to partially reconstruction of recipient`s immune system leading to prophylactics or treatment of adenoviral infections (Amrolia et al., 2006; Bordigoni et al., 2001; Feuchtinger et al., 2008; Fujita et al., 2008; Ison, 2006; Lion et al., 2010). Successful reduction of AdV replication is achieved mainly due to infusion of selected AdV-specific lymphocytes. Infusion of unselected donor lymphocytes is associated with higher risk of aGvHD due to high alloreactivity which requires more aggressive immunosupresive therapy conducing development of viral infections (Walter et al., 1995). The sufficient immune response is achieved mainly due to infusion of combined CD4+/CD8+ (60%) or solely CD4+ (40%) cells (Feuchtinger et al., 2008). However, heterogeneity of *Adenoviridae* family in the context of immunomodulation is questionable. Human immune system recognizes the surface determinants of AdV capsid which are highly variable between AdV serotypes. Hence, the success of T-cells administration may be dependent on infecting serotype (Ebner et al., 2006). On the other hand, human adenoviruses exhibit high cross-reactivity against different clinically relevant species of AdV Taking into account that more than 50000 of hematopoietic stem cell transplantations are performed every year and nearly 10000 originate from unrelated donors, the number of patients who may be affected from adenoviral infections seems to be significant. In view of worldwide distribution of adenoviruses, numerous routes of infection and limited effectiveness of anti-AdV treatment, adenoviral infections in patients undergoing hematopoietic stem cell transplantations should be always considered as serious, lifethreatening post-transplant complication which demands rapid and unequivocal diagnosis defining patient`s outcome.

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**27** 

M. Jarden

*Copenhagen Denmark* 

**A Systematic Review of Nonpharmacological** 

**Exercise-Based Rehabilitative Interventions in** 

**Adults Undergoing Allogeneic Hematopoietic** 

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an established treatment. More than 15,000 procedures are performed worldwide each year for a number of hematological malignancies such as acute myeloid and lymphoid leukemia, and bone marrow failure syndromes (Gratwohl et al. 2002; Frassoni, 2004). It is predicted that transplantation rates for allo-HSCT will continue at the same or higher level in the immediate future (Gratwohl et al. 2002). Despite clinical cure in 20-70% of all patients, depending on disease presentation, long term sequelae of immunosuppression, chemotherapy toxicities and graft-versus-host disease (GvHD) debilitate a large number of patients (Gratwohl et al. 2002). Moderate to severe GvHD develops in 40-50% of patients undergoing allo-HSCT (Bearman et al. 1988; Weisdorf et al. 1990; Roy et al. 1992; Hings et al. 1994). Factors limiting the efficacy of this treatment are death due to recurrence or treatment-related death due to infection or organ failure in the cytopenia and later immunosuppressed phase immediately post-HSCT. Over the last decades, the cumulative effects of improvements in supportive care, drug dosing, stem cell technology and prophylaxis of GvHD have led to an increased number of complete remissions (Devergie, 2004). However, with the increasing number of transplants performed and the growing number of survivors, a shift in clinical focus from not only improving survival but also improving short and long-term quality of life has emerged (Andrykowski et al. 1995). Patients in the treatment and recovery phase of HSCT commonly experience adverse physical and emotional reactions. Fatigue and muscle weakness can limit ability to accomplish activities of daily living. Additionally, depression, anxiety, fear, and frustration add to the difficulties of recovering from HSCT (Syrjala et al. 1993; Andrykowski et al. 1995). Several studies confirm that high levels of physical and psychological stress have been observed in patients prior to and at the start of HSCT and during follow-up periods (Baker et al. 1997; Molassiotis & Morris, 1997; McQuellon et al. 1998; Fife et al. 2000). The mechanisms are not fully known, but it is assumed that several factors such as total body

**1. Introduction** 

*Department of Haematology, The University Hospital of Copenhagen, The University Hospital's Centre for Nursing and Care Research,* 

**Stem Cell Transplantation** 


### **A Systematic Review of Nonpharmacological Exercise-Based Rehabilitative Interventions in Adults Undergoing Allogeneic Hematopoietic Stem Cell Transplantation**

M. Jarden

*Department of Haematology, The University Hospital of Copenhagen, The University Hospital's Centre for Nursing and Care Research, Copenhagen Denmark* 

#### **1. Introduction**

556 New Advances in Stem Cell Transplantation

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Leung, W., Srivastava, D.K., Handgretinger, R. & Hayden, R.T. (2006). Cidofovir for the treatment of adenoviral infection in pediatric hematopoietic stem cell transplant Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an established treatment. More than 15,000 procedures are performed worldwide each year for a number of hematological malignancies such as acute myeloid and lymphoid leukemia, and bone marrow failure syndromes (Gratwohl et al. 2002; Frassoni, 2004). It is predicted that transplantation rates for allo-HSCT will continue at the same or higher level in the immediate future (Gratwohl et al. 2002). Despite clinical cure in 20-70% of all patients, depending on disease presentation, long term sequelae of immunosuppression, chemotherapy toxicities and graft-versus-host disease (GvHD) debilitate a large number of patients (Gratwohl et al. 2002). Moderate to severe GvHD develops in 40-50% of patients undergoing allo-HSCT (Bearman et al. 1988; Weisdorf et al. 1990; Roy et al. 1992; Hings et al. 1994). Factors limiting the efficacy of this treatment are death due to recurrence or treatment-related death due to infection or organ failure in the cytopenia and later immunosuppressed phase immediately post-HSCT. Over the last decades, the cumulative effects of improvements in supportive care, drug dosing, stem cell technology and prophylaxis of GvHD have led to an increased number of complete remissions (Devergie, 2004). However, with the increasing number of transplants performed and the growing number of survivors, a shift in clinical focus from not only improving survival but also improving short and long-term quality of life has emerged (Andrykowski et al. 1995). Patients in the treatment and recovery phase of HSCT commonly experience adverse physical and emotional reactions. Fatigue and muscle weakness can limit ability to accomplish activities of daily living. Additionally, depression, anxiety, fear, and frustration add to the difficulties of recovering from HSCT (Syrjala et al. 1993; Andrykowski et al. 1995). Several studies confirm that high levels of physical and psychological stress have been observed in patients prior to and at the start of HSCT and during follow-up periods (Baker et al. 1997; Molassiotis & Morris, 1997; McQuellon et al. 1998; Fife et al. 2000). The mechanisms are not fully known, but it is assumed that several factors such as total body

A Systematic Review of Nonpharmacological Exercise-Based Rehabilitative

specific impairments experienced by patients undergoing allo-HSCT.

Interventions in Adults Undergoing Allogeneic Hematopoietic Stem Cell Transplantation 559

include physical dysfunction and female gender (Kirchhoff AC et al. 2010). Maintaining daily function and reducing fatigue and treatment-related symptoms can be important goals and there is therefore, a continued need for nonpharmacological strategies that address the

There is a rapidly increasing literature on the effects of exercise on cancer rehabilitation, especially for breast cancer patients, on whom the majority of research has been conducted (Courneya et al. 2011, Conn et al. 2006). Despite that physical exercise showed positive effects on cardiorespiratory fitness, treatment-related symptoms and physiological effects, the extent of these positive results still need to be established. A qualitative and quantitative review and meta-analysis found only small to moderate effect of physical activity interventions on these outcomes (Schmitz et al. 2005; Conn et al. 2006). Physical activity is reported as being well tolerated in cancer survivors during and after treatment, however, conclusions about adverse effects are inconclusive (Schmitz et al. 2005). Recent guidelines for exercise prescription for cancer survivors from the American College of Sports Medicine (Schmitz et al. 2010) report no contraindication for starting an exercise program in patients undergoing either autologous or allogeneic HSCT – however, issues regarding, the ideal time for starting a program safely and effectively, type of program, frequency, intensity and duration is not confirmed, especially in relation to the HSCT treatment trajectory. Exercise has been proposed as a nonpharmacologic adjuvant therapy to combat the physiological and psychological symptoms of HSCT (Wiskemann & Huber, 2008). However, little work exists in utilizing exercise interventions specifically in the allo-HSCT setting. It is documented that there is a decline in exercise levels in cancer patients from prediagnosis to postdiagnosis (Courneya et al.1997) and more specifically, a low level of "naturallyoccurring" exercise amongst patients undergoing HSCT is reported, suggesting that a structured intervention may be necessary in order to promote exercise in this population (Courneya et al. 2000). The majority of the earlier research done in adult patients with hematological disease is in the context of high dose chemotherapy with stem cell support (autologous HSCT or HD-SCS). To date, there are eight published studies that incorporated exercise regimes in the high dose chemotherapy-stem cell support context (HD- SCS) (Coleman et al. 2003; Decker et al 1989; Hayes et al. 2003, Dimeo et al. 1996, 1997, 1999, 2003, including one on-going study (Peerson et al. 2010), and five studies in mixed HD-SCS and allo-HSCT populations (Dimeo et al. 1999, Baumann et al. 2005; Wilson et al. 2005, Knols et al. 2010, Danaher Hacker et al. 2011). There are however fundamental and important differences in the two types of treatment (HD-SCS and allo-HSCT) including the conditioning regimes, i.e. total body irradiation in allo-HSCT, and origin of stem cells, i.e. patients undergoing HD-SCS are supported with their own stem cells, and therefore the donor related challenges (GvHD) in allo-HSCT are not present, and lastly, the overall duration of hospitalization for HD-SCS is much shorter compared to allo-HSCT. One 3 year prospective study, found that patients undergoing HD-SCS had better self-rated physical function (symptomotology, physical status and energy level) as compared to the allo-HSCT group (Prieto et al 2005). The HD-SCS and mixed group (HD-SCS and allo-HSCT, and age) exercise-based study sizes ranged between 12-70 participants. There are five randomized trials (Peerson et al. 2010; Baumann et al. 2005; Coleman et al. 2003; Hayes et al. 2004; Dimeo et al. 1996), one study used a minimization procedure (Knols et al. 2010) and six singlegroup trials (Danaher Hacker et al. 2011; Wilson et al. 2005; Decker et al 1989; Dimeo et al.

irradiation (TBI), chemotherapy, GvHD, infections, long-term inactivity or bed rest and sideeffects from medication can contribute to the physical and emotional weakening of the patient. Recipients of allo-HSCT with low Vitamin D levels and low bone mineral density were likely to have received corticosteroids, have experienced GVHD and an elevated parathyroid hormone level (Sproat et al. 2011; Massenkeil et al. 2001). Vitamin D insufficiency and deficiency can cause osteomalacia, bone pain, muscle weakness, musculoskeletal pain, headache, fatigue, and may precipitate or exacerbate osteopenia and osteoporosis and increase risk of skeletal fracture (Knutsen et al. 2010; Sproat et al. 2011). Patients that have undergone HSCT experience treatment-related symptoms during and after treatment that can affect health related quality of life (HR-QOL). Patients experience multiple somatic, affective and cognitive symptoms during and after aggressive cancer treatment, where eleven to thirteen simultaneously occurring symptoms have been reported (Portenoy et al. 1994). During hospitalization for standard allo-HSCT, patients are typically on prolonged bed rest, and experience complications from the myeloablative treatment, ie. acute GvHD, side effects from medications (immunosuppression & steroids), frequent infections and psychological reactions that can be debilitating. It is reported that HR-QOL is lowest during inpatient time (Grulke et al. 2011). The most commonly reported symptoms are fatigue, diarrhea, insomnia, poor appetite, diminished concentration, mouth dryness, dyspnoea, loss of hair and poor body image perception (Jarden et al. 2009; Molassitis et al.1997; Larsen et al. 2007). After HSCT, fatigue, dyspnoea and insomnia remain at elevated levels (Grulke et al. 2011). Psychosocial wellbeing after transplant is influenced by mucositis toxicity, and other side effects, and psychological factors as anxiety, distress and social support have a significant impact on how severely patients experience mouth pain (Schulz-Kindermann et al. 2002) Fatigue is one of the most frequent and distressful side effects reported by patients who have undergone HSCT (Jarden et al. 2009; So et al. 2003), and it has been shown that physical activity decreased and this decline coincided with diminished physical, emotional, role and cognitive functioning during the initial post transplantation period (Danaher et al. 2006). Bevans et al. found that patients experienced multiple symptoms and high symptom distress after allo-HSCT conditioning (Bevans et al. 2008) Further, fatigue was the main symptom interfering with daily life in 79% of patients (Molassiotis & Morris, 1999), and in 11% of patients at 100 days post allo-HSCT (Bevans et al. 2008). Loss of physical strength seem to be more pronounced in patients on corticosteroid treatment, and the causes of an impairment of physical performance are not fully understood, though low activity levels have been suggested to be a substantial contributor (Carlson et al. 2006). One study in patients undergoing HSCT showed a correlation between the number of symptoms experienced and poor functional status and general health (Larsen et al. 2007) and in another study, changes in HRQoL could be explained entirely by changes in functional limitations and somatic symptoms (Broers et al. 2000). Further, symptom bother from GVHD had a direct effect on functional performance (Mitchell et al. 2010). A Danish study found patients prior to allo-HSCT to have lower VO2 max scores and elevated fatigue levels than the normal population, and these scores were unchanged six months after transplantation (Kalo et al. 2007). Furthermore, persons diagnosed with hematological disease have difficulty returning to the work force (deBoer et al. 2008) and have an increased risk for early retirement (Carlsen et al. 2008), while unemployed leukaemia patients, especially those with lower social support have significantly elevated levels of stress, anxiety, and depression (deBoer et al. 2008). In HSCT, predictors of slower return to work

irradiation (TBI), chemotherapy, GvHD, infections, long-term inactivity or bed rest and sideeffects from medication can contribute to the physical and emotional weakening of the patient. Recipients of allo-HSCT with low Vitamin D levels and low bone mineral density were likely to have received corticosteroids, have experienced GVHD and an elevated parathyroid hormone level (Sproat et al. 2011; Massenkeil et al. 2001). Vitamin D insufficiency and deficiency can cause osteomalacia, bone pain, muscle weakness, musculoskeletal pain, headache, fatigue, and may precipitate or exacerbate osteopenia and osteoporosis and increase risk of skeletal fracture (Knutsen et al. 2010; Sproat et al. 2011). Patients that have undergone HSCT experience treatment-related symptoms during and after treatment that can affect health related quality of life (HR-QOL). Patients experience multiple somatic, affective and cognitive symptoms during and after aggressive cancer treatment, where eleven to thirteen simultaneously occurring symptoms have been reported (Portenoy et al. 1994). During hospitalization for standard allo-HSCT, patients are typically on prolonged bed rest, and experience complications from the myeloablative treatment, ie. acute GvHD, side effects from medications (immunosuppression & steroids), frequent infections and psychological reactions that can be debilitating. It is reported that HR-QOL is lowest during inpatient time (Grulke et al. 2011). The most commonly reported symptoms are fatigue, diarrhea, insomnia, poor appetite, diminished concentration, mouth dryness, dyspnoea, loss of hair and poor body image perception (Jarden et al. 2009; Molassitis et al.1997; Larsen et al. 2007). After HSCT, fatigue, dyspnoea and insomnia remain at elevated levels (Grulke et al. 2011). Psychosocial wellbeing after transplant is influenced by mucositis toxicity, and other side effects, and psychological factors as anxiety, distress and social support have a significant impact on how severely patients experience mouth pain (Schulz-Kindermann et al. 2002) Fatigue is one of the most frequent and distressful side effects reported by patients who have undergone HSCT (Jarden et al. 2009; So et al. 2003), and it has been shown that physical activity decreased and this decline coincided with diminished physical, emotional, role and cognitive functioning during the initial post transplantation period (Danaher et al. 2006). Bevans et al. found that patients experienced multiple symptoms and high symptom distress after allo-HSCT conditioning (Bevans et al. 2008) Further, fatigue was the main symptom interfering with daily life in 79% of patients (Molassiotis & Morris, 1999), and in 11% of patients at 100 days post allo-HSCT (Bevans et al. 2008). Loss of physical strength seem to be more pronounced in patients on corticosteroid treatment, and the causes of an impairment of physical performance are not fully understood, though low activity levels have been suggested to be a substantial contributor (Carlson et al. 2006). One study in patients undergoing HSCT showed a correlation between the number of symptoms experienced and poor functional status and general health (Larsen et al. 2007) and in another study, changes in HRQoL could be explained entirely by changes in functional limitations and somatic symptoms (Broers et al. 2000). Further, symptom bother from GVHD had a direct effect on functional performance (Mitchell et al. 2010). A Danish study found patients prior to allo-HSCT to have lower VO2 max scores and elevated fatigue levels than the normal population, and these scores were unchanged six months after transplantation (Kalo et al. 2007). Furthermore, persons diagnosed with hematological disease have difficulty returning to the work force (deBoer et al. 2008) and have an increased risk for early retirement (Carlsen et al. 2008), while unemployed leukaemia patients, especially those with lower social support have significantly elevated levels of stress, anxiety, and depression (deBoer et al. 2008). In HSCT, predictors of slower return to work include physical dysfunction and female gender (Kirchhoff AC et al. 2010). Maintaining daily function and reducing fatigue and treatment-related symptoms can be important goals and there is therefore, a continued need for nonpharmacological strategies that address the specific impairments experienced by patients undergoing allo-HSCT.

There is a rapidly increasing literature on the effects of exercise on cancer rehabilitation, especially for breast cancer patients, on whom the majority of research has been conducted (Courneya et al. 2011, Conn et al. 2006). Despite that physical exercise showed positive effects on cardiorespiratory fitness, treatment-related symptoms and physiological effects, the extent of these positive results still need to be established. A qualitative and quantitative review and meta-analysis found only small to moderate effect of physical activity interventions on these outcomes (Schmitz et al. 2005; Conn et al. 2006). Physical activity is reported as being well tolerated in cancer survivors during and after treatment, however, conclusions about adverse effects are inconclusive (Schmitz et al. 2005). Recent guidelines for exercise prescription for cancer survivors from the American College of Sports Medicine (Schmitz et al. 2010) report no contraindication for starting an exercise program in patients undergoing either autologous or allogeneic HSCT – however, issues regarding, the ideal time for starting a program safely and effectively, type of program, frequency, intensity and duration is not confirmed, especially in relation to the HSCT treatment trajectory. Exercise has been proposed as a nonpharmacologic adjuvant therapy to combat the physiological and psychological symptoms of HSCT (Wiskemann & Huber, 2008). However, little work exists in utilizing exercise interventions specifically in the allo-HSCT setting. It is documented that there is a decline in exercise levels in cancer patients from prediagnosis to postdiagnosis (Courneya et al.1997) and more specifically, a low level of "naturallyoccurring" exercise amongst patients undergoing HSCT is reported, suggesting that a structured intervention may be necessary in order to promote exercise in this population (Courneya et al. 2000). The majority of the earlier research done in adult patients with hematological disease is in the context of high dose chemotherapy with stem cell support (autologous HSCT or HD-SCS). To date, there are eight published studies that incorporated exercise regimes in the high dose chemotherapy-stem cell support context (HD- SCS) (Coleman et al. 2003; Decker et al 1989; Hayes et al. 2003, Dimeo et al. 1996, 1997, 1999, 2003, including one on-going study (Peerson et al. 2010), and five studies in mixed HD-SCS and allo-HSCT populations (Dimeo et al. 1999, Baumann et al. 2005; Wilson et al. 2005, Knols et al. 2010, Danaher Hacker et al. 2011). There are however fundamental and important differences in the two types of treatment (HD-SCS and allo-HSCT) including the conditioning regimes, i.e. total body irradiation in allo-HSCT, and origin of stem cells, i.e. patients undergoing HD-SCS are supported with their own stem cells, and therefore the donor related challenges (GvHD) in allo-HSCT are not present, and lastly, the overall duration of hospitalization for HD-SCS is much shorter compared to allo-HSCT. One 3 year prospective study, found that patients undergoing HD-SCS had better self-rated physical function (symptomotology, physical status and energy level) as compared to the allo-HSCT group (Prieto et al 2005). The HD-SCS and mixed group (HD-SCS and allo-HSCT, and age) exercise-based study sizes ranged between 12-70 participants. There are five randomized trials (Peerson et al. 2010; Baumann et al. 2005; Coleman et al. 2003; Hayes et al. 2004; Dimeo et al. 1996), one study used a minimization procedure (Knols et al. 2010) and six singlegroup trials (Danaher Hacker et al. 2011; Wilson et al. 2005; Decker et al 1989; Dimeo et al.

A Systematic Review of Nonpharmacological Exercise-Based Rehabilitative

**1/7/2011** "Bone Marrow Cell Transplantation"

Allogeneic[tw] Autologous[tw]

"Physical activity" "Physical fitness" "Exercise"

**1/7/2011** "Bone Marrow Cell Transplantation".

"Allogeneic" "Autologous".

"Physical activity". "Physical fitness" "Exercise"

"Bone Marrow Transplantation". "Stem Cell Transplantation".

"Bone Marrow Transplantation" "Stem Cell Transplantation"

Interventions in Adults Undergoing Allogeneic Hematopoietic Stem Cell Transplantation 561

English

Publication date from 1986/01/01 to 2011/07/01

English language

EMBASE (OvidSP)

 Studies that include auto-HSCT/HD-SCT Studies that include a mixed population of

auto-HSCT and allo-HSCT Review articles or case study

Editorials or letters to the editor

 Clinical reports Dissertations

Conference abstracts

90

Publication year: 1986-Current

Medline (NLM) 90

**Date Search Limits Database Results** 

("Bone Marrow Cell Transplantation" OR "Bone Marrow Transplantation" OR "Stem Cell Transplantation") AND (Allogeneic OR Autologous[ AND ("Physical activity" OR "Physical

**Date Search Limits Database Results** 

(("Bone Marrow Cell Transplantation" or "Bone Marrow Transplantation" or "Stem Cell Transplantation") and ("Allogeneic" or " Autologous") and ("Physical activity" or "Physical

Allo-HSCT indicates allogeneic stem cell transplantation; auto-SCT, autologous stem cell

fitness" or "Exercise")), (English[lang] AND ("1986/01/01" : "2011/07/01")

Table 1. Results of a systematic literature search with keywords

 Journal articles reporting primary research of exercise-based intervention studies prior to,

Randomized clinical trials or controlled studies

Published in English between 1986 and 2011

Recipients of allo-HSCT for a hematologic

during or after allo-HSCT

Participants >18 years

Table 2. Eligibility criteria

disease

 **Inclusion criteria Exclusion criteria** 

transplantation; HD-SCT, high dose chemotherapy with stem cell support

fitness" OR Exercise) AND (English[lang] AND ("1986/01/01" : "2011/07/01")

1997, 1999, 2003). Exercise was tested during hospitalization in three studies ( Baumann et al. 2005; Dimeo et al. 1996; 2003), one study during hospitalization and continued to outpatient (Dimeo 1999), and eight studies after hospital discharge (outpatient and home based programs) (Wilson et al. 2005; Decker et al 1989; Coleman et al. 2003; Hayes et al. 2004; Dimeo et al. 1997, Knols et al. 2010; Peerson et al. 2010; Danaher Hacker et al. 2011). Feasibility was established, no adverse events registered and beneficial effects were reported on aerobic capacity (Hayes et al. 2004; Dimeo et al. 2003; Dimeo et al. 1996); muscle strength (Hayes et al. 2004; Knols et al. 2010), body composition (Coleman et al. 2003; Hayes et al. 2003), immunological function (Dimeo et al. 1997; Hayes et al. 2003; Knols et al. 2010), treatment-related symptoms i.e. fatigue (Dimeo et al. 1999; Wilson et al. 2005) and HRQoL (Wilson et al. 2005; Hayes et al. 2004). These positive and potentially important results for HD-SCS and mixed groups are encouraging, but we need to look exclusively at the allo-HSCT adult patient group in order to evaluate the role and impact of exercise rehabilitation in this treatment context alone.

The primary objective of the systematic review is to summarize the exercise-based rehabilitative interventions in adults with haematological disease undergoing allogeneic hematopoetic stem cell transplantation (allo-HSCT) on feasibility and safety, and effectiveness related to physical and functional capacity, health related quality of life, treatment-related symptoms and medical related outcomes.

#### **2. Method**

The systematic literature search is based on PRISMA guidelines (preferred reporting items for systematic reviews and metaanalyses) developed from Cochrane Collaboration (Moher D et al. 2009).This review includes 1) a systematic literature search with the identification of all intervention trials in adult patients in the allo-HSCT setting during the past 25 years, 2) a uniform presentation of all trials and a synthesis of the characteristics and findings, 3) an appraisal of the methodological quality of the trials, 4) a summary and 5) conclusions and future research.

#### **2.1 Search strategy and data extraction**

The systematic literature review covers 25 years of research: 1986 – 2011 (Table 1). Searches were carried out in MEDLINE and EMBASE using search items bone marrow cell transplantation, bone marrow transplantation, stem cell transplantation, physical activity, physical fitness and exercise. Identified articles were searched for additional references. The search was limited to include randomized controlled trials (RCT), controlled clinical trials, adults and English articles. Eligibility criteria are shown in Table 2. Only studies that included patients from the allogeneic setting are included in this review. Studies that included patients in either the auto-HSCT / HD-SCS setting or mixed settings (both autologous and allogeneic) were excluded, though compiled in the literature search for background and reference purposes. Full articles were obtained for remaining abstracts and information was extracted from identified articles and organized under the following headings: authors, sample (n, type of treatment), age, design and study period, exercisebased intervention, duration, frequency/intensity, and results (Table 3). All articles were independently reviewed and appraised for rigor of method and analysis.

1997, 1999, 2003). Exercise was tested during hospitalization in three studies ( Baumann et al. 2005; Dimeo et al. 1996; 2003), one study during hospitalization and continued to outpatient (Dimeo 1999), and eight studies after hospital discharge (outpatient and home based programs) (Wilson et al. 2005; Decker et al 1989; Coleman et al. 2003; Hayes et al. 2004; Dimeo et al. 1997, Knols et al. 2010; Peerson et al. 2010; Danaher Hacker et al. 2011). Feasibility was established, no adverse events registered and beneficial effects were reported on aerobic capacity (Hayes et al. 2004; Dimeo et al. 2003; Dimeo et al. 1996); muscle strength (Hayes et al. 2004; Knols et al. 2010), body composition (Coleman et al. 2003; Hayes et al. 2003), immunological function (Dimeo et al. 1997; Hayes et al. 2003; Knols et al. 2010), treatment-related symptoms i.e. fatigue (Dimeo et al. 1999; Wilson et al. 2005) and HRQoL (Wilson et al. 2005; Hayes et al. 2004). These positive and potentially important results for HD-SCS and mixed groups are encouraging, but we need to look exclusively at the allo-HSCT adult patient group in order to evaluate the role and impact of exercise rehabilitation

The primary objective of the systematic review is to summarize the exercise-based rehabilitative interventions in adults with haematological disease undergoing allogeneic hematopoetic stem cell transplantation (allo-HSCT) on feasibility and safety, and effectiveness related to physical and functional capacity, health related quality of life,

The systematic literature search is based on PRISMA guidelines (preferred reporting items for systematic reviews and metaanalyses) developed from Cochrane Collaboration (Moher D et al. 2009).This review includes 1) a systematic literature search with the identification of all intervention trials in adult patients in the allo-HSCT setting during the past 25 years, 2) a uniform presentation of all trials and a synthesis of the characteristics and findings, 3) an appraisal of the methodological quality of the trials, 4) a summary and 5) conclusions and

The systematic literature review covers 25 years of research: 1986 – 2011 (Table 1). Searches were carried out in MEDLINE and EMBASE using search items bone marrow cell transplantation, bone marrow transplantation, stem cell transplantation, physical activity, physical fitness and exercise. Identified articles were searched for additional references. The search was limited to include randomized controlled trials (RCT), controlled clinical trials, adults and English articles. Eligibility criteria are shown in Table 2. Only studies that included patients from the allogeneic setting are included in this review. Studies that included patients in either the auto-HSCT / HD-SCS setting or mixed settings (both autologous and allogeneic) were excluded, though compiled in the literature search for background and reference purposes. Full articles were obtained for remaining abstracts and information was extracted from identified articles and organized under the following headings: authors, sample (n, type of treatment), age, design and study period, exercisebased intervention, duration, frequency/intensity, and results (Table 3). All articles were

independently reviewed and appraised for rigor of method and analysis.

in this treatment context alone.

**2. Method** 

future research.

**2.1 Search strategy and data extraction** 

treatment-related symptoms and medical related outcomes.


fitness" or "Exercise")), (English[lang] AND ("1986/01/01" : "2011/07/01")

Table 1. Results of a systematic literature search with keywords


Allo-HSCT indicates allogeneic stem cell transplantation; auto-SCT, autologous stem cell transplantation; HD-SCT, high dose chemotherapy with stem cell support

Table 2. Eligibility criteria


A Systematic Review of Nonpharmacological Exercise-Based Rehabilitative

**Results** 

Interventions in Adults Undergoing Allogeneic Hematopoietic Stem Cell Transplantation 563


**Results** 


A Systematic Review of Nonpharmacological Exercise-Based Rehabilitative

**Results** 

Interventions in Adults Undergoing Allogeneic Hematopoietic Stem Cell Transplantation 565


**Results** 


A Systematic Review of Nonpharmacological Exercise-Based Rehabilitative

**Results** 

Interventions in Adults Undergoing Allogeneic Hematopoietic Stem Cell Transplantation 567


**Results** 


\*median age AA indicates aplastic anemia, AML, acute myelogenous leukemia**;** ALL, acute lymphocytic or lymphoblastic leukemia ; CLL, chronic lymphocytic leukemia; CML, chronic myelogenous leukemia; CMML, chronic myelomonocytic leukemia; HD, Hodgkins disease; MDS, myelodysplastic syndrome; MF, myelofibrosis; MM, multiple myeloma; MPS, myeloproliferative syndrome; NHL, Non-Hodgkin lymphoma; PNH, paroxysmal nocturnal hemoglobinuria; WM, waldenstrom macroglobulinemia RPE, Rate of Perceived Exertion; St.v, Stroke Volume; HR, Heart Rate; IG, Intervention Group; IG2, Intervention Group 2; CG, Control Group; TPN, Total Parenteral Nutrition; 

MHR, Maximal Heart Rate; DM and NDM, Dominant Non Dominant; KPS, Karnofsky Score; PT, Physical therapy; PRO, patient reported outcome; HR-QoL, health related Quality of Life; TR-symptoms, treatment related symptoms; SCT-SAS, Stem cell transplantation-Symptom Assessment Scale; EORTC-QLQ-C30 European Organization for Research and Treatment of Cancer Quality of Life Questionnaire; HADS, Hospital Anxiety and Depression Scale; FACT-An or FACT-F, Functional Assessment of Cancer therapy – Anemia or Fatigue scale; POMS, Profile of Mood States; MFI, Multidimensional Fatigue Inventory; BFI, Brief Fatigue Inventory; BDI, Beck Depression Inventory; STAI, State Trait Anxiety Inventory; 6MWD, 6 minute walk distance , → no change; ↑ increase; ↓ decrease.. 

Table 3. Physical exercise based studies in allogeneic HSCT on aerobic capacity, muscle strength, health-related quality of life and treatment related symptoms

A Systematic Review of Nonpharmacological Exercise-Based Rehabilitative

**3.1 Exercise-based studies in the allo-HSCT setting** 

**3. Results** 

Interventions in Adults Undergoing Allogeneic Hematopoietic Stem Cell Transplantation 569

In this review, 10 studies met the inclusion criteria (Baumann et al. 2011; Carlson et al. 2006; Cunningham et al. 1986; Defor et al. 2007; Inoue et al., 2010; Jarden et al., 2009; Kim and Kim 2006; Mello et al. 2003; Shelton et al. 2009; Wiskemann et al. 2011). Of these, three were from the USA and two from Germany, and respectively, one from Brazil, Canada, Denmark, Japan and South Korea. Cunningham et al. carried out the very first exercise training trial for the allo-HSCT population in 1986 and although the participants included children and adults (range 14 – 41 years), this study is included in the review because of its focus being in the allo-HSCT setting only. Jarden et al. published three articles and Kim et al. two articles,

All studies were designed as prospective intervention trials that tested an exercise-based program. The primary and secondary outcomes were study feasibility and safety; physiological outcomes i.e. aerobic, muscle strength and function; psychosocial outcomes i.e. health-related QoL, emotional wellbeing; treatment-related symptoms i.e. fatigue; and hospital or disease-related outcomes i.e. days of hospitalization, creatinine excretion, lymphocyte counts. Baseline to post assessment ranged between 4 – 16 weeks [mean 7.3] and

In all, 406 patients with different haematological diseases (AA,, AML, ALL, CLL , CML, CMML, FL, HD, MDS, MF, MM, MPS, NHL, PNH, WM, other lymphomas)1 across 10

1 AA indicates aplastic anemia, AML, acute myelogenous leukemia; ALL, acute lymphocytic or lymphoblastic leukemia ; CLL, chronic lymphocytic leukemia; CML, chronic myelogenous leukemia; CMML, chronic myelomonocytic leukemia; HD, Hodgkins disease; MDS, myelodysplastic syndrome; MF, myelofibrosis; MM, multiple myeloma; MPS, myeloproliferative syndrome; NHL, Non**-**Hodgkin lymphoma; PNH, paroxysmal nocturnal hemoglobinuria; WM, waldenstrom macroglobulinemia

each based on one trial, however each article has a different focus and purpose.

one study had follow-up tests to 6 months (Jarden et. al. 2009).

**3.2 Sample characteristics** 

Table 4. Intervention phase

### **3. Results**

568 New Advances in Stem Cell Transplantation

**Results** 

Table 3. Physical exercise based studies in allogeneic HSCT on aerobic capacity, muscle

\*median age AA indicates aplastic anemia, AML,

acute myelogenous leukemia**;** ALL, acute lymphocytic or lymphoblastic leukemia ; CLL, chronic

lymphocytic leukemia; CML, chronic myelogenous leukemia; CMML, chronic myelomonocytic leukemia; HD, Hodgkins disease; MDS, myelodysplastic syndrome; MF, myelofibrosis; MM, multiple myeloma; MPS, myeloproliferative syndrome; NHL, Non-Hodgkin

lymphoma; PNH, paroxysmal nocturnal hemoglobinuria; WM, waldenstrom macroglobulinemia RPE, Rate of Perceived Exertion; St.v, Stroke Volume; HR, Heart Rate; IG, Intervention Group; IG2, Intervention Group 2; CG, Control

MHR, Maximal Heart Rate; DM and NDM, Dominant Non Dominant; KPS, Karnofsky Score; PT, Physical therapy; PRO, patient reported

outcome; HR-QoL, health related Quality of Life; TR-symptoms, treatment related symptoms; SCT-SAS, Stem cell transplantation-Symptom Assessment Scale; EORTC-QLQ-C30 European Organization for Research and Treatment of Cancer Quality of Life Questionnaire; HADS, Hospital Anxiety and Depression Scale; FACT-An or FACT-F, Functional Assessment of Cancer therapy – Anemia

or Fatigue scale; POMS, Profile of Mood States; MFI, Multidimensional Fatigue Inventory; BFI, Brief Fatigue Inventory; BDI, Beck

→ no change; ↑ increase; ↓ decrease..

Depression Inventory; STAI, State Trait Anxiety Inventory; 6MWD, 6 minute walk distance ,

Group; TPN, Total Parenteral Nutrition;

strength, health-related quality of life and treatment related symptoms

#### **3.1 Exercise-based studies in the allo-HSCT setting**

In this review, 10 studies met the inclusion criteria (Baumann et al. 2011; Carlson et al. 2006; Cunningham et al. 1986; Defor et al. 2007; Inoue et al., 2010; Jarden et al., 2009; Kim and Kim 2006; Mello et al. 2003; Shelton et al. 2009; Wiskemann et al. 2011). Of these, three were from the USA and two from Germany, and respectively, one from Brazil, Canada, Denmark, Japan and South Korea. Cunningham et al. carried out the very first exercise training trial for the allo-HSCT population in 1986 and although the participants included children and adults (range 14 – 41 years), this study is included in the review because of its focus being in the allo-HSCT setting only. Jarden et al. published three articles and Kim et al. two articles, each based on one trial, however each article has a different focus and purpose.

All studies were designed as prospective intervention trials that tested an exercise-based program. The primary and secondary outcomes were study feasibility and safety; physiological outcomes i.e. aerobic, muscle strength and function; psychosocial outcomes i.e. health-related QoL, emotional wellbeing; treatment-related symptoms i.e. fatigue; and hospital or disease-related outcomes i.e. days of hospitalization, creatinine excretion, lymphocyte counts. Baseline to post assessment ranged between 4 – 16 weeks [mean 7.3] and one study had follow-up tests to 6 months (Jarden et. al. 2009).

#### **3.2 Sample characteristics**

In all, 406 patients with different haematological diseases (AA,, AML, ALL, CLL , CML, CMML, FL, HD, MDS, MF, MM, MPS, NHL, PNH, WM, other lymphomas)1 across 10

Table 4. Intervention phase

<sup>1</sup> AA indicates aplastic anemia, AML, acute myelogenous leukemia; ALL, acute lymphocytic or lymphoblastic leukemia ; CLL, chronic lymphocytic leukemia; CML, chronic myelogenous leukemia; CMML, chronic myelomonocytic leukemia; HD, Hodgkins disease; MDS, myelodysplastic syndrome; MF, myelofibrosis; MM, multiple myeloma; MPS, myeloproliferative syndrome; NHL, Non**-**Hodgkin lymphoma; PNH, paroxysmal nocturnal hemoglobinuria; WM, waldenstrom macroglobulinemia

A Systematic Review of Nonpharmacological Exercise-Based Rehabilitative

**3.4 Feasibility and safety** 

cardio and nephrotoxic chemotherapy.

**3.5 Physiological outcomes - aerobic/endurance** 

decreased RPE (p<0.005) (Carlson et al. 2006).

significantly in the control group (p=0.022).

between intervention and control groups were not significant.

**3.6 Muscle strength** 

**3.7 Functional capacity** 

Interventions in Adults Undergoing Allogeneic Hematopoietic Stem Cell Transplantation 571

No adverse events, reactions or injuries were reported, though not all studies reported safety outcomes. The overall attrition rates ranged between 0 and 44% (mean 18.7). Program compliance was reported by five studies (Carlson et al. 2006; DeFor et al. 2007; Jarden et al. 2009; Shelton et al. 2009; Wiskemann et al. 2011). Carlson et al. reported an overall 89% compliance. Defor et al. reported that 24% of all patients had 100% compliance and that 62% of the study's population exercised at least 5 times/wk for at least 15 min during hospitalization and after discharge, respectively. Jarden et al. reported 90% intervention compliance (range 67-100), and 83% in-hospital and 87% at-home compliance (Wiskemann et al. 2011), while Shelton et al. reported 75% for the supervised intervention, though did not report for the self-directed intervention. Some studies had safety screening parameters, in which contraindication for exercise included platelet counts <10 and 20 x 109/l (Cunningham et al. 1986, Mello et al. 2003, Jarden et al. 2009; Wiskemann et al. 2011, Baumann et al. 2011), and haemoglobin <5 g/dl (Jarden et al. 2009), <8 (Wiskemann et al. 2011, Baumann et al. 2011), and <10 (Mello et al. 2003); temp>38oC (Cunningham et al. 1986; Jarden et al. 2009; Wiskemann et al. 2011, Baumann et al. 2011), and adverse symptoms as bleeding, petecchiae, pain, nausea, dizziness. Baumann et al. interrupted training during

A mixed-type exercise program 5 days/week at moderate intensity during the entire hospitalization was able to maintain aerobic capacity, while the control group decreased, and this difference was highly significant (p<0.01) (Jarden et al. 2009). Another similar mixed-exercise program during hospitalization showed a significant decrease in aerobic endurance (p=0.009) in the control group, but no significant difference between intervention and control groups (Baumann et al. 2011). A 12 wk. aerobic training program on cycle ergometer initiated between 9 and 92 months after HSCT showed cardiovascular effects through increased stroke volume (p<0.005) and decreased heart rate (p<0.005), with a

Mello et al. combined aerobic (treadmill) and ROM exercise program initiated during hospitalization and continued into the outpatient facility over 6 weeks showed significant decrease in upper and lower extremity strength in the control group, however differences

During hospitalization, four muscle strength tests (chest press 1 RM, leg extension 1 RM, elbow flexor and knee extensor Newton) decreased by 2 - 4 % in the intervention group, while decreasing between 19 - 25 % in the control group. This difference was significant (p<0.01) (Jarden et al. 2009). Baumann et al., however, did not find a significant difference between groups for muscle strength, but the pre to post muscle strength scores decreased

Wiskemann et al. maintained the 6 minute walk distance (6MWD) in the intervention group, while the control group decreased and the intergroup difference was significant (p=0.02). The 2 minute stair climb test in the intervention group decreased by 14 % and for the control

studies are included in this review. The sample size of the studies ranged from 12 to 105 [Mean 50.7] and the patients were of mixed gender between 14 and 71 years [mean 42.6]. Cunningham was the only study that included patients less than 18 years of age. Four studies were initiated prior to conditioning and throughout the hospitalization period (Baumann et al. 2011; Cunningham et al. 1986; Defor et al. 2007; Jarden et al. 2009; Kim and Kim 2006; Wiskemann et al. 2011), two studies after marrow engraftment and throughout hospitalization (Mello et al., 2003; Inoue et al., 2010), and three of these continued post allo-HSCT (Defor et al. 2007; Mello et al. 2003; Wiskemann et al. 2011). Two studies were initiated post allo-HSCT in the out-patient or home setting, within 6 and 39 months (range 9- 92), respectively (Shelton et al. 2009; Carlson et al. 2006). The approximate start and endpoint of each intervention is illustrated in Table 4.

#### **3.3 Type of exercise-based interventions**

The duration of the exercise-based interventions ranged between 4-16 weeks [mean 7.3]. For interventions initiated prior to and during hospitalization, 6 of the studies were supervised (Cunningham et al. 1986; Mello et al. 2003; Kim and Kim 2006; Jarden et al. 2009; Inoue et al. 2010; Baumann et al. 2011) and 2 were partly supervised (DeFor et al. 2007, Wiskemann et al. 2011). In the out-patient context, Carlson's study was fully supervised, while Shelton's study had one supervised and one self-directed study arm. The frequency of all interventions ranged between 3 and 5 days/week or daily. When reported, the intensity of training in general was between low/mild and comfortable to moderate but not exceeding 70-75% of maximum heart rate or in Rate of Perceived Exertion (RPE) - being somewhat hard.

In the in-patient context, one study tested strength resistive training (Cunningham et al. 1986), one a walking program (treadmill or walking) (Defor et al. 2007) and another mixedtype low intensity bed exercises of stretching and relaxation breathing (Kim and Kim 2006), and 5 studies instituted mixed-type exercise up to moderate intensity (Mello et al. 2003, Jarden et al. 2009, Inoue et al. 2010, Wiskemann et al. 2011, Baumann et al. 2011) by combining aerobic training (treadmill, cycle, walking or stair climbing) with one or more other moderate intensity exercise (range of motion or ADL (activities of daily living), coordination exercises, muscle stretching, resistive exercises with free weights or elastic bands) and low intensity progressive relaxation training and education (Jarden et al. 2009). Three studies (Mello et al. 2003; Wiskemann et al. 2011, Defor et al. 2007) continued the programs after hospital discharge. In the out-patient only context, one study tested an ergometer cycle program (Carlson et al. 2006), and the other, aerobic (cycle or treadmill) and resistive exercises (weight machines) vs. selfdirected walking and resistive exercises including patient information regarding exercise safety (Shelton et al. 2009). All in all, three studies were unidimensional (one exercise component), of which, two were aerobic training (Carlson et al. 2006; DeFor et al. 2007), and one resistance training (Cunningham et al. 1986), and seven studies had mixed type training (Baumann et al. 2011; Inoue et al. 2010; Jarden et al. 2009; Kim and Kim 2006; Mello et al. 2003; Shelton et al. 2009; Wiskemann 2011), of which, one was of low intensity (Kim and Kim 2006), and one study included both low and moderate intensity components (Jarden et al. 2009). Only two studies incorporated educational (Shelton et al. 2009) or psychoeducational (Jarden et al. 2009) elements in the program.

#### **3.4 Feasibility and safety**

570 New Advances in Stem Cell Transplantation

studies are included in this review. The sample size of the studies ranged from 12 to 105 [Mean 50.7] and the patients were of mixed gender between 14 and 71 years [mean 42.6]. Cunningham was the only study that included patients less than 18 years of age. Four studies were initiated prior to conditioning and throughout the hospitalization period (Baumann et al. 2011; Cunningham et al. 1986; Defor et al. 2007; Jarden et al. 2009; Kim and Kim 2006; Wiskemann et al. 2011), two studies after marrow engraftment and throughout hospitalization (Mello et al., 2003; Inoue et al., 2010), and three of these continued post allo-HSCT (Defor et al. 2007; Mello et al. 2003; Wiskemann et al. 2011). Two studies were initiated post allo-HSCT in the out-patient or home setting, within 6 and 39 months (range 9- 92), respectively (Shelton et al. 2009; Carlson et al. 2006). The approximate start and

The duration of the exercise-based interventions ranged between 4-16 weeks [mean 7.3]. For interventions initiated prior to and during hospitalization, 6 of the studies were supervised (Cunningham et al. 1986; Mello et al. 2003; Kim and Kim 2006; Jarden et al. 2009; Inoue et al. 2010; Baumann et al. 2011) and 2 were partly supervised (DeFor et al. 2007, Wiskemann et al. 2011). In the out-patient context, Carlson's study was fully supervised, while Shelton's study had one supervised and one self-directed study arm. The frequency of all interventions ranged between 3 and 5 days/week or daily. When reported, the intensity of training in general was between low/mild and comfortable to moderate but not exceeding 70-75% of maximum heart rate or in Rate of Perceived

In the in-patient context, one study tested strength resistive training (Cunningham et al. 1986), one a walking program (treadmill or walking) (Defor et al. 2007) and another mixedtype low intensity bed exercises of stretching and relaxation breathing (Kim and Kim 2006), and 5 studies instituted mixed-type exercise up to moderate intensity (Mello et al. 2003, Jarden et al. 2009, Inoue et al. 2010, Wiskemann et al. 2011, Baumann et al. 2011) by combining aerobic training (treadmill, cycle, walking or stair climbing) with one or more other moderate intensity exercise (range of motion or ADL (activities of daily living), coordination exercises, muscle stretching, resistive exercises with free weights or elastic bands) and low intensity progressive relaxation training and education (Jarden et al. 2009). Three studies (Mello et al. 2003; Wiskemann et al. 2011, Defor et al. 2007) continued the programs after hospital discharge. In the out-patient only context, one study tested an ergometer cycle program (Carlson et al. 2006), and the other, aerobic (cycle or treadmill) and resistive exercises (weight machines) vs. selfdirected walking and resistive exercises including patient information regarding exercise safety (Shelton et al. 2009). All in all, three studies were unidimensional (one exercise component), of which, two were aerobic training (Carlson et al. 2006; DeFor et al. 2007), and one resistance training (Cunningham et al. 1986), and seven studies had mixed type training (Baumann et al. 2011; Inoue et al. 2010; Jarden et al. 2009; Kim and Kim 2006; Mello et al. 2003; Shelton et al. 2009; Wiskemann 2011), of which, one was of low intensity (Kim and Kim 2006), and one study included both low and moderate intensity components (Jarden et al. 2009). Only two studies incorporated educational (Shelton et al. 2009) or psychoeducational (Jarden et al. 2009) elements in the

endpoint of each intervention is illustrated in Table 4.

**3.3 Type of exercise-based interventions** 

Exertion (RPE) - being somewhat hard.

program.

No adverse events, reactions or injuries were reported, though not all studies reported safety outcomes. The overall attrition rates ranged between 0 and 44% (mean 18.7). Program compliance was reported by five studies (Carlson et al. 2006; DeFor et al. 2007; Jarden et al. 2009; Shelton et al. 2009; Wiskemann et al. 2011). Carlson et al. reported an overall 89% compliance. Defor et al. reported that 24% of all patients had 100% compliance and that 62% of the study's population exercised at least 5 times/wk for at least 15 min during hospitalization and after discharge, respectively. Jarden et al. reported 90% intervention compliance (range 67-100), and 83% in-hospital and 87% at-home compliance (Wiskemann et al. 2011), while Shelton et al. reported 75% for the supervised intervention, though did not report for the self-directed intervention. Some studies had safety screening parameters, in which contraindication for exercise included platelet counts <10 and 20 x 109/l (Cunningham et al. 1986, Mello et al. 2003, Jarden et al. 2009; Wiskemann et al. 2011, Baumann et al. 2011), and haemoglobin <5 g/dl (Jarden et al. 2009), <8 (Wiskemann et al. 2011, Baumann et al. 2011), and <10 (Mello et al. 2003); temp>38oC (Cunningham et al. 1986; Jarden et al. 2009; Wiskemann et al. 2011, Baumann et al. 2011), and adverse symptoms as bleeding, petecchiae, pain, nausea, dizziness. Baumann et al. interrupted training during cardio and nephrotoxic chemotherapy.

#### **3.5 Physiological outcomes - aerobic/endurance**

A mixed-type exercise program 5 days/week at moderate intensity during the entire hospitalization was able to maintain aerobic capacity, while the control group decreased, and this difference was highly significant (p<0.01) (Jarden et al. 2009). Another similar mixed-exercise program during hospitalization showed a significant decrease in aerobic endurance (p=0.009) in the control group, but no significant difference between intervention and control groups (Baumann et al. 2011). A 12 wk. aerobic training program on cycle ergometer initiated between 9 and 92 months after HSCT showed cardiovascular effects through increased stroke volume (p<0.005) and decreased heart rate (p<0.005), with a decreased RPE (p<0.005) (Carlson et al. 2006).

#### **3.6 Muscle strength**

Mello et al. combined aerobic (treadmill) and ROM exercise program initiated during hospitalization and continued into the outpatient facility over 6 weeks showed significant decrease in upper and lower extremity strength in the control group, however differences between intervention and control groups were not significant.

During hospitalization, four muscle strength tests (chest press 1 RM, leg extension 1 RM, elbow flexor and knee extensor Newton) decreased by 2 - 4 % in the intervention group, while decreasing between 19 - 25 % in the control group. This difference was significant (p<0.01) (Jarden et al. 2009). Baumann et al., however, did not find a significant difference between groups for muscle strength, but the pre to post muscle strength scores decreased significantly in the control group (p=0.022).

#### **3.7 Functional capacity**

Wiskemann et al. maintained the 6 minute walk distance (6MWD) in the intervention group, while the control group decreased and the intergroup difference was significant (p=0.02). The 2 minute stair climb test in the intervention group decreased by 14 % and for the control

A Systematic Review of Nonpharmacological Exercise-Based Rehabilitative

showed a significant decrease in fatigue (p<0.001) (BFI and FACT-F).

**3.10 Medical related outcomes** 

(r=-.71; p=0.0071).

**4. Summary** 

**3.11 Methodological quality of the studies** 

Interventions in Adults Undergoing Allogeneic Hematopoietic Stem Cell Transplantation 573

(p=0.01) (POMS). Baumann et al. was unable to show between group differences in fatigue scores, but the control group increased fatigue at post testing (p=0.046). Carlson et al.

Cunningham et al. did not find significant changes in body composition, though a decreased creatinine excretion in the intervention group (Cunningham et al. 1986). Kim et al. tested a bed exercise effect on lymphocyte counts, and reported no significant differences between groups, however there was an interaction between groups and times (p=0.031), there was also a decrease in lymphocyte count in the control group (p<0.05). Jarden et al. reported the intervention group as receiving fewer days of TPN (p=0.019) with no changes in BMI between groups at post testing. There were no other differences between groups regarding hospitalization days, bone marrow engraftment days, days with fever, and though there was a 19% difference in the incidence of GvHD favoring the intervention group, this was not statistically different. Defor et al. and Inoue et al. showed no difference in days of hospitalization between groups, but Inoue et al. showed that the degree of physical activity had a negative correlation with the duration of hospitalization

Seven studies were designed as randomized trials (Cunningham et al. 1986; Mello et al. 2003; Kim and Kim 2006; Defor et al. 2007; Jarden et al. 2009; Shelton et al. 2009; Baumann et al. 2011), one study allocated through the minimization method (Wiskeman et al. 2011), one study was a convenience sample studying the effect of the same exercise intervention on two different allo-HSCT treatment groups (myeloablative or nonmyeloablative conditioning regime) (Inoue et al. 2010) and one study did not have a control group (Carlson et al. 2006). Further, Shelton et al. studied the effect of two different interventions (supervised vs. self directed) in the outpatient/home setting. The control group was described in most studies as receiving standard or usual care, including either no formal training or the hospital units' standard physical therapy (PT). Generally, standard PT was described as being introduced later during hospitalization, i.e. after stem cell infusion, and at less frequent intervals and lower intensity levels. The study arms were not similar at baseline in two (Kim and Kim 2006; Baumann et al. 2011) of the eight groups in which there was an intervention and control group present. The control group in Kim et al. had a significant higher lymphocyte level at baseline compared to the intervention group and Baumann et al. had twice as many males as females in the exercise group as compared to the control group at baseline. All studies reported the eligibility criteria to which the study population was chosen. Only one study stated that the outcome assessor was blinded (DeFor et al. 2007). In the relevant studies, none reported blinding of the exercise trainer or the patients. Two studies reported

performing intention-to-treat analyses (Jarden et al. 2009; Wiskemann et al. 2011).

This is the first literature review of exercise-based interventions in the allo-HSCT context. The purpose of this systematic review was to summarize the exercise-based rehabilitative interventions in adults with haematological disease undergoing allogeneic hematopoetic

group 38%, and the difference between groups was significant (p<0.01) (Jarden et al. 2009). A walking program did not show significant differences between groups for the Karnofsky score, though a subgroup analysis of the nonmyeloablative conditioned patients showed that this patient group decreased significantly less than the control group (p=0.04) (DeFor et al. 2007). There were no significant differences for the 6MWD between a supervised and self directed intervention, still both groups significantly improved by 12% (p<0.05) and 9.8% (p<0.05), respectively (Shelton et al. 2009). Also, the supervised group improved the 50 foot walk time (p=0.05) and maintained other performance tests, though no significance between groups.

#### **3.8 Health-related quality of life**

A bed exercise study with relaxation breathing, ROM and stretching during hospitalization decreased depression (BDI) p=0.0001 and anxiety (STAI) p=0.0001 as compared to the control group (Kim and Kim 2006). An in- to out-patient walking program showed improvements in physical and emotional wellbeing on a self reported score from 1 – 10, with 1 being very poor and 10 being very good. At discharge, physical wellbeing was better in the exercise group (p<0.01). Among the nonmyeloablative group, emotional wellbeing was better in the exercise group (p=0.02) at discharge and at 100 days, physical wellbeing was superior in the exercise group (p<0.01) (DeFor et al. 2007). A mixed exercise intervention during the entire hospitalization showed no difference in QoL and emotional wellbeing between groups (EORTC-QLQ-C30, FACT-An, HADS), though HRQOL was maintained in the intervention group at post testing, and there was significant improvement in emotional wellbeing at 3 and 6 months, p=0.045 and p=0.012, respectively (FACT-An) and significant decrease in anxiety at 3 and 6 months, p=0.021 and p<0.0001, respectively (HADS). The control group significantly decreased overall HRQOL p=0.0005 (FACT-An) at post testing, and significantly reduced physical functioning (p=0.004) and worsened three gastrointestinal symptoms (nausea and vomiting (p=0.048), appetite loss (p=0.004) and diarrhea (p=0.011) (EORTC QLQ C-30) (Jarden et al. 2009). Wiskemann et al. study beyond discharge showed between group differences in favor of the intervention group in physical functioning (p=0.03)(EORTC-QLQ-C30) and decreased depression (p=0.05), though showed a significant increase in anxiety (p=0.01) in the intervention group (HADS). Baumann et al. found no significant difference between groups on the EORTC-QLQ-C30, though the prepost differences in the intervention and control group decreased significantly for physical functioning (p=0.005 and p=0.002). Intervention group improved emotional state (p=0.028), but again, no differences between groups (Baumann et al. 2011). Carlson et al.'s out-patient endurance program significantly improved intergroup vigor scores (p<0.001) on POMS.

#### **3.9 Treatment-related symptoms**

There was a decreased symptom prevalence in diminished concentration, memory loss, nausea and nervousness (p<0.01) and decreased symptom severity in fatigue, loss of appetite, sleep difficulties and nausea (p<0.05) on the SCT-SAS scale (Jarden et al. 2009). Further, diarrhea was significantly decreased (EORTC-QLQ-C30) (p=0.014) (Jarden et al. 2009). Symptom cluster analyses revealed a significant decrease in symptom severity in gastrointestinal, cognitive, functional and mucositis clusters over time and up to 6 months after allo-HSCT (p<0.01). Wiskemann et al. found a significant decrease between groups in both general and physical fatigue (p=0.009, p=0.01) MFI and a significant decrease in fatigue (p=0.01) (POMS). Baumann et al. was unable to show between group differences in fatigue scores, but the control group increased fatigue at post testing (p=0.046). Carlson et al. showed a significant decrease in fatigue (p<0.001) (BFI and FACT-F).

#### **3.10 Medical related outcomes**

572 New Advances in Stem Cell Transplantation

group 38%, and the difference between groups was significant (p<0.01) (Jarden et al. 2009). A walking program did not show significant differences between groups for the Karnofsky score, though a subgroup analysis of the nonmyeloablative conditioned patients showed that this patient group decreased significantly less than the control group (p=0.04) (DeFor et al. 2007). There were no significant differences for the 6MWD between a supervised and self directed intervention, still both groups significantly improved by 12% (p<0.05) and 9.8% (p<0.05), respectively (Shelton et al. 2009). Also, the supervised group improved the 50 foot walk time (p=0.05) and maintained other performance tests, though no significance between

A bed exercise study with relaxation breathing, ROM and stretching during hospitalization decreased depression (BDI) p=0.0001 and anxiety (STAI) p=0.0001 as compared to the control group (Kim and Kim 2006). An in- to out-patient walking program showed improvements in physical and emotional wellbeing on a self reported score from 1 – 10, with 1 being very poor and 10 being very good. At discharge, physical wellbeing was better in the exercise group (p<0.01). Among the nonmyeloablative group, emotional wellbeing was better in the exercise group (p=0.02) at discharge and at 100 days, physical wellbeing was superior in the exercise group (p<0.01) (DeFor et al. 2007). A mixed exercise intervention during the entire hospitalization showed no difference in QoL and emotional wellbeing between groups (EORTC-QLQ-C30, FACT-An, HADS), though HRQOL was maintained in the intervention group at post testing, and there was significant improvement in emotional wellbeing at 3 and 6 months, p=0.045 and p=0.012, respectively (FACT-An) and significant decrease in anxiety at 3 and 6 months, p=0.021 and p<0.0001, respectively (HADS). The control group significantly decreased overall HRQOL p=0.0005 (FACT-An) at post testing, and significantly reduced physical functioning (p=0.004) and worsened three gastrointestinal symptoms (nausea and vomiting (p=0.048), appetite loss (p=0.004) and diarrhea (p=0.011) (EORTC QLQ C-30) (Jarden et al. 2009). Wiskemann et al. study beyond discharge showed between group differences in favor of the intervention group in physical functioning (p=0.03)(EORTC-QLQ-C30) and decreased depression (p=0.05), though showed a significant increase in anxiety (p=0.01) in the intervention group (HADS). Baumann et al. found no significant difference between groups on the EORTC-QLQ-C30, though the prepost differences in the intervention and control group decreased significantly for physical functioning (p=0.005 and p=0.002). Intervention group improved emotional state (p=0.028), but again, no differences between groups (Baumann et al. 2011). Carlson et al.'s out-patient endurance program significantly improved intergroup vigor scores (p<0.001) on POMS.

There was a decreased symptom prevalence in diminished concentration, memory loss, nausea and nervousness (p<0.01) and decreased symptom severity in fatigue, loss of appetite, sleep difficulties and nausea (p<0.05) on the SCT-SAS scale (Jarden et al. 2009). Further, diarrhea was significantly decreased (EORTC-QLQ-C30) (p=0.014) (Jarden et al. 2009). Symptom cluster analyses revealed a significant decrease in symptom severity in gastrointestinal, cognitive, functional and mucositis clusters over time and up to 6 months after allo-HSCT (p<0.01). Wiskemann et al. found a significant decrease between groups in both general and physical fatigue (p=0.009, p=0.01) MFI and a significant decrease in fatigue

groups.

**3.8 Health-related quality of life** 

**3.9 Treatment-related symptoms** 

Cunningham et al. did not find significant changes in body composition, though a decreased creatinine excretion in the intervention group (Cunningham et al. 1986). Kim et al. tested a bed exercise effect on lymphocyte counts, and reported no significant differences between groups, however there was an interaction between groups and times (p=0.031), there was also a decrease in lymphocyte count in the control group (p<0.05). Jarden et al. reported the intervention group as receiving fewer days of TPN (p=0.019) with no changes in BMI between groups at post testing. There were no other differences between groups regarding hospitalization days, bone marrow engraftment days, days with fever, and though there was a 19% difference in the incidence of GvHD favoring the intervention group, this was not statistically different. Defor et al. and Inoue et al. showed no difference in days of hospitalization between groups, but Inoue et al. showed that the degree of physical activity had a negative correlation with the duration of hospitalization (r=-.71; p=0.0071).

#### **3.11 Methodological quality of the studies**

Seven studies were designed as randomized trials (Cunningham et al. 1986; Mello et al. 2003; Kim and Kim 2006; Defor et al. 2007; Jarden et al. 2009; Shelton et al. 2009; Baumann et al. 2011), one study allocated through the minimization method (Wiskeman et al. 2011), one study was a convenience sample studying the effect of the same exercise intervention on two different allo-HSCT treatment groups (myeloablative or nonmyeloablative conditioning regime) (Inoue et al. 2010) and one study did not have a control group (Carlson et al. 2006). Further, Shelton et al. studied the effect of two different interventions (supervised vs. self directed) in the outpatient/home setting. The control group was described in most studies as receiving standard or usual care, including either no formal training or the hospital units' standard physical therapy (PT). Generally, standard PT was described as being introduced later during hospitalization, i.e. after stem cell infusion, and at less frequent intervals and lower intensity levels. The study arms were not similar at baseline in two (Kim and Kim 2006; Baumann et al. 2011) of the eight groups in which there was an intervention and control group present. The control group in Kim et al. had a significant higher lymphocyte level at baseline compared to the intervention group and Baumann et al. had twice as many males as females in the exercise group as compared to the control group at baseline. All studies reported the eligibility criteria to which the study population was chosen. Only one study stated that the outcome assessor was blinded (DeFor et al. 2007). In the relevant studies, none reported blinding of the exercise trainer or the patients. Two studies reported performing intention-to-treat analyses (Jarden et al. 2009; Wiskemann et al. 2011).

#### **4. Summary**

This is the first literature review of exercise-based interventions in the allo-HSCT context. The purpose of this systematic review was to summarize the exercise-based rehabilitative interventions in adults with haematological disease undergoing allogeneic hematopoetic

A Systematic Review of Nonpharmacological Exercise-Based Rehabilitative

correlation with the number of hospitalization days (Inoue et al. 2010).

al. (Battaglini 2011).

Interventions in Adults Undergoing Allogeneic Hematopoietic Stem Cell Transplantation 575

symptoms and symptom clusters, including fatigue up to 6 months (Jarden et al. 2009) and in two studies exercising after discharge, a significant decrease in fatigue scores was reported (Wiskemann et al. 2011, Carlson et al. 2006). Hospital or treatment-related outcomes as body composition or immunological and infectious parameters i.e. lymphocyte counts, days to bone marrow engraftment, days with fever, incidence of GvHD., number of transfusions received) was not affected by exercise. One exercising group received significantly fewer days of TPN as compared to the control group (Jarden et al. 2009). There was no effect on duration of hospitalization (Inoue et al. 2010, Jarden et al. 2009, Defor et al. 2007), though Inoue et al. reported that the level of physical activity had a negative

It is suggested in recent literature that the optimal training program for persons with cancer combine both aerobic and muscle strength training (Neiman & Courneya, 2006, Courneya & Friedenreich, 2011). A review from 2008 of 15 exercise trials in the in-patient and out-patient HSCT setting, included patients in the allo-HSCT and HD-SCS context and resulted in tentative recommendations (Wiskemann & Huber, 2008): mixed exercise: endurance (up to daily) and resistance training (2-3 x/wk)), from 10 - 30 minutes at moderate intensity (BORG scale 12-14, 70-80% maximum HR) before, during and after hospitalization. In Liu et al. literature review from 2009 of physical exercise interventions in hæmatological cancer patients suggested it feasible to conduct exercise in this patient population, but concluded that there was a lack in methodological quality in the physical exercise studies and therefore effectiveness could not be established (Liu et al. ). Recommendations based on a more recent review from 2011 of patients with mixed hematologic disease propose 'supervised' exercise during and after hematological cancer treatments 2 to 5 days per week, with adjustment for health conditions. Further, a combination of aerobic and resistance exercise is suggested, with a varying intensity between 40-70% of maximum heart rate and full body resistance exercises at 8-12 reps and 2-3 sets with slow progression over time. Health and neutropenic screening for exercise participation is also recommended according to Jones et

Exercise recommendations, however for patients during and after hospitalization for specifically allo-HSCT have not been developed, and in order to determine the appropriate and optimal exercise prescription / intervention for patients undergoing allo-HSCT, trials in the allo-HSCT context were examined in this review for type, duration, frequency and intensity. Taken the methodological limitations into consideration, a partly to fully supervised and daily, mixed-type exercise (aerobic and resistant exercises, also ROM and stretching) at moderate intensity (70-75% MHR) started at least prior to conditioning and carried out during allo-HSCT is feasible and can maintain or decrease loss of aerobic capacity, muscle strength and function at hospital discharge. However, continuing the program after hospital discharge had further physical, functional and symptom related benefits (decrease fatigue, reduced depression). Attaining positive results require a relatively high compliance rate, over 85%. Therefore, screening parameters and contraindication for training criteria should be instituted to not only keep the patient safe, but also enable adequate participation in the program. Based on this review, it can be suggested that postponement or modification of training include: platelets < 20 x 109/l, haemoglobin < 5-8 g/l, temp > 38oC and adverse symptoms as bleeding, petecchiae, pain, nausea, dizziness. It is not clear from this review, whether training during conditioning inkl. cardio and nephrotoxic chemotherapy should be postponed, and to what extent, that is, during active infusion or hours/days following chemotherapy. We may also consider

stem cell transplantation (allo-HSCT) on feasibility and safety, and effectiveness related to physical and functional capacity, health related quality of life, treatment-related symptoms and medical related outcomes. To date, 10 intervention studies and 13 articles have been published that incorporated exercise-based regimes in the allo-HSCT context, and though we have found encouraging and important results, making direct trial comparisons can be a challenge due to the small sample sizes, the wide range of different primary and secondary outcomes and measurements, varying types of interventions, and different start and end points, duration, frequency and intensity of the different exercise components. Most of the studies in this review were randomized trials, however, control groups received varying standard care regimes, and there was a lack of outcome assessor blinding, trainer blinding and patient blinding which decreases the general methodological quality of the studies. Taking these methodological limitations into consideration, this review however finds important results pertinent to the allo-HSCT clinical setting.

The results suggest that exercise interventions are feasible and safe. No study reported adverse events as a direct result of testing or exercising, though not all studies reported safety. Five studies reported safety screening parameters, which may have contributed to patients being able to exercise safely. Of the five studies that reported compliance rates, it would suggest that patients are capable of participating adequately in a daily exercise program during and after allo-HSCT. Two mixed type exercise studies implemented during the entire hospitalization suggest a stabilization in aerobic endurance during hospitalization (Jarden et al. 2009; Baumann et al. 2011), and one 12 week out-patient endurance study found significant positive cardiovascular effects (Carlson et al. 2006). In regards to muscle strength, mixed type exercise during hospitalization (Baumann et al. 2011; Jarden et al. 2009) and continuing in the outpatient context (Mello et al. 2003) showed significant muscle strength decreases in control group, but only one study found significant differences between groups (Jarden et al. 2009) suggesting that the loss of muscle strength was minimized. Mixed type exercise during hospitalization (Jarden et al. 2009) and continued after discharge (Wiskemann et al. 2011) significantly decreased loss of function (2 minute stair climb) (Jarden et al. 2009) and significantly maintained function (6MWT) (Wiskemann et al. 2011). DeFor et al.'s walking program during and after discharge did not show significant differences between groups for Karnofsky score, though a subgroup analysis of the nonmyeloablative group showed a significant reduction in loss of performance in the intervention group. (DeFor et al. 2007). Both supervised and self directed mixed type exercise in the post HSCT was shown to improve function significantly on the 6MWD and for the supervised group improvement was reported for the 50 foot walk time (Shelton et al. 2009). A mixed type low intensity exercise program during hospitalization significantly decreased depression (BDI) and anxiety as compared to the control group (Kim and Kim 2006), while two mixed-type moderate intensity exercise programs during hospitalization did not show a significant effect on HR-QoL (Baumann et al. 2011, Jarden et al. 2009), but Wiskemann et al.'s mixed type exercise that continued after discharge showed a significant improvement in physical functioning and decreased depression, but also a significant increase in anxiety (Wiskemann et al. 2011). DeFor's in- to out-patient walking program reported significant improvements in emotional wellbeing among the nonmyeloablative patient group at hospital discharge and by 100 days, physical wellbeing was significantly improved. Carlson et al.'s 12 week out-patient endurance program significantly increased vigor. There was a significant longitudinal decrease in prevalence and intensity of several

stem cell transplantation (allo-HSCT) on feasibility and safety, and effectiveness related to physical and functional capacity, health related quality of life, treatment-related symptoms and medical related outcomes. To date, 10 intervention studies and 13 articles have been published that incorporated exercise-based regimes in the allo-HSCT context, and though we have found encouraging and important results, making direct trial comparisons can be a challenge due to the small sample sizes, the wide range of different primary and secondary outcomes and measurements, varying types of interventions, and different start and end points, duration, frequency and intensity of the different exercise components. Most of the studies in this review were randomized trials, however, control groups received varying standard care regimes, and there was a lack of outcome assessor blinding, trainer blinding and patient blinding which decreases the general methodological quality of the studies. Taking these methodological limitations into consideration, this review however finds

The results suggest that exercise interventions are feasible and safe. No study reported adverse events as a direct result of testing or exercising, though not all studies reported safety. Five studies reported safety screening parameters, which may have contributed to patients being able to exercise safely. Of the five studies that reported compliance rates, it would suggest that patients are capable of participating adequately in a daily exercise program during and after allo-HSCT. Two mixed type exercise studies implemented during the entire hospitalization suggest a stabilization in aerobic endurance during hospitalization (Jarden et al. 2009; Baumann et al. 2011), and one 12 week out-patient endurance study found significant positive cardiovascular effects (Carlson et al. 2006). In regards to muscle strength, mixed type exercise during hospitalization (Baumann et al. 2011; Jarden et al. 2009) and continuing in the outpatient context (Mello et al. 2003) showed significant muscle strength decreases in control group, but only one study found significant differences between groups (Jarden et al. 2009) suggesting that the loss of muscle strength was minimized. Mixed type exercise during hospitalization (Jarden et al. 2009) and continued after discharge (Wiskemann et al. 2011) significantly decreased loss of function (2 minute stair climb) (Jarden et al. 2009) and significantly maintained function (6MWT) (Wiskemann et al. 2011). DeFor et al.'s walking program during and after discharge did not show significant differences between groups for Karnofsky score, though a subgroup analysis of the nonmyeloablative group showed a significant reduction in loss of performance in the intervention group. (DeFor et al. 2007). Both supervised and self directed mixed type exercise in the post HSCT was shown to improve function significantly on the 6MWD and for the supervised group improvement was reported for the 50 foot walk time (Shelton et al. 2009). A mixed type low intensity exercise program during hospitalization significantly decreased depression (BDI) and anxiety as compared to the control group (Kim and Kim 2006), while two mixed-type moderate intensity exercise programs during hospitalization did not show a significant effect on HR-QoL (Baumann et al. 2011, Jarden et al. 2009), but Wiskemann et al.'s mixed type exercise that continued after discharge showed a significant improvement in physical functioning and decreased depression, but also a significant increase in anxiety (Wiskemann et al. 2011). DeFor's in- to out-patient walking program reported significant improvements in emotional wellbeing among the nonmyeloablative patient group at hospital discharge and by 100 days, physical wellbeing was significantly improved. Carlson et al.'s 12 week out-patient endurance program significantly increased vigor. There was a significant longitudinal decrease in prevalence and intensity of several

important results pertinent to the allo-HSCT clinical setting.

symptoms and symptom clusters, including fatigue up to 6 months (Jarden et al. 2009) and in two studies exercising after discharge, a significant decrease in fatigue scores was reported (Wiskemann et al. 2011, Carlson et al. 2006). Hospital or treatment-related outcomes as body composition or immunological and infectious parameters i.e. lymphocyte counts, days to bone marrow engraftment, days with fever, incidence of GvHD., number of transfusions received) was not affected by exercise. One exercising group received significantly fewer days of TPN as compared to the control group (Jarden et al. 2009). There was no effect on duration of hospitalization (Inoue et al. 2010, Jarden et al. 2009, Defor et al. 2007), though Inoue et al. reported that the level of physical activity had a negative correlation with the number of hospitalization days (Inoue et al. 2010).

It is suggested in recent literature that the optimal training program for persons with cancer combine both aerobic and muscle strength training (Neiman & Courneya, 2006, Courneya & Friedenreich, 2011). A review from 2008 of 15 exercise trials in the in-patient and out-patient HSCT setting, included patients in the allo-HSCT and HD-SCS context and resulted in tentative recommendations (Wiskemann & Huber, 2008): mixed exercise: endurance (up to daily) and resistance training (2-3 x/wk)), from 10 - 30 minutes at moderate intensity (BORG scale 12-14, 70-80% maximum HR) before, during and after hospitalization. In Liu et al. literature review from 2009 of physical exercise interventions in hæmatological cancer patients suggested it feasible to conduct exercise in this patient population, but concluded that there was a lack in methodological quality in the physical exercise studies and therefore effectiveness could not be established (Liu et al. ). Recommendations based on a more recent review from 2011 of patients with mixed hematologic disease propose 'supervised' exercise during and after hematological cancer treatments 2 to 5 days per week, with adjustment for health conditions. Further, a combination of aerobic and resistance exercise is suggested, with a varying intensity between 40-70% of maximum heart rate and full body resistance exercises at 8-12 reps and 2-3 sets with slow progression over time. Health and neutropenic screening for exercise participation is also recommended according to Jones et al. (Battaglini 2011).

Exercise recommendations, however for patients during and after hospitalization for specifically allo-HSCT have not been developed, and in order to determine the appropriate and optimal exercise prescription / intervention for patients undergoing allo-HSCT, trials in the allo-HSCT context were examined in this review for type, duration, frequency and intensity. Taken the methodological limitations into consideration, a partly to fully supervised and daily, mixed-type exercise (aerobic and resistant exercises, also ROM and stretching) at moderate intensity (70-75% MHR) started at least prior to conditioning and carried out during allo-HSCT is feasible and can maintain or decrease loss of aerobic capacity, muscle strength and function at hospital discharge. However, continuing the program after hospital discharge had further physical, functional and symptom related benefits (decrease fatigue, reduced depression). Attaining positive results require a relatively high compliance rate, over 85%. Therefore, screening parameters and contraindication for training criteria should be instituted to not only keep the patient safe, but also enable adequate participation in the program. Based on this review, it can be suggested that postponement or modification of training include: platelets < 20 x 109/l, haemoglobin < 5-8 g/l, temp > 38oC and adverse symptoms as bleeding, petecchiae, pain, nausea, dizziness. It is not clear from this review, whether training during conditioning inkl. cardio and nephrotoxic chemotherapy should be postponed, and to what extent, that is, during active infusion or hours/days following chemotherapy. We may also consider

A Systematic Review of Nonpharmacological Exercise-Based Rehabilitative

employment.

**6. Conflict of interest** 

**7. Acknowledgements** 

1997;38:10-19

Cancer;16:1243-54.

Health;36(2):117-25.

**8. References** 

The author declares no conflict of interest.

Interventions in Adults Undergoing Allogeneic Hematopoietic Stem Cell Transplantation 577

a need to study the patients' own experience as a participant in an exercise-based intervention in order to develop programs that are tailored to fit the needs of patients during and after allo-HSCT. Finally, translational intervention studies are needed that support and improve the ability of patients to cope with their life situation during treatment, as well as to function optimally after allo-HSCT in daily life, including return to

I thank Anders Larsen (Information specialist - The University Hospital's Centre for Nursing and Care Research, Copenhagen Denmark) for verifying and assisting with the literature search strategy. I would also like to thank Kristine Marie Jarden (Research assistant - University of Southern Denmark) for her assistance in manuscript preparation.

Andrykowski MA, Breiner CB, Altmaier EM. (1995) Quality of life following bone marrow transplantation: findings from a multicenter study. Br J Cancer; 71:1322-9. Baker F, Marcellus D, Zabora J, Polland A, Jodrey D. (1997) Psychological distress among

Battaglini CL. (2011) Physical Activity and hematological Cancer Survivorship. *Physical* 

Baumann FT, Zopf EM, Nykamp E, Kraut L, Schüle K, Elter T, Fauser AA, Bloch W. (2011)

Bearman SI, Applebaum FR, Buckner CD. (1988) Regimen-related toxicity in patients

Bevans MF, Mitchell SA, Marden S. (2008) The symptom experience in the first 100 days

Broers S, Kaptein AA, Le Cessie S, Fibbe W, Hengeveld MW. (2000) Psychological

Carlsen K, Oksbjerg Dalton S, Frederiksen K, Diderichsen F, Johansen C. (2008) Cancer and

Carlson LE, Smith D, Russell J, Fibich C, Whittaker T. (2006) Individualized exercise

04321-7\_12, Springer-Verlag Berlin Heidelberg, 275-304.

follow-up study. J Psychosom Res;48:11-21.

Haematology; accepted article: 10.1111/j.1600-0609.2011.01640.x

undergoing bone marrow transplantation. J Clin Oncol;6:1562-68.

adult patients being evaluated for bone marrow transplantation. Psychosomatics

*Activity and Cancer*, Recent Results in Cancer Research 186, DOI: 10.1007/978-3-642-

Physical activity for patients undergoing an allogenic hematopoietic stem cell transplantation: benefits of a moderate exercise intervention. European Journal of

following allogeneic hematopoietic stem cell transplantation (HSCT).Support Care

functioning and quality of life following bone marrow transplantation: a 3-year

the risk for taking early retirement pension: a Danish cohort study. Scand J Public

program for the treatment of severe fatigue in patients after allogeneic

incorporation of low intensity exercise as relaxation breathing or progressive relaxation in the program, especially when a higher exercise intensity level is not possible (Kim and Kim, 2006; Jarden et al. 2009). Psychosocial, educational and motivational approaches may be integrated to maintain compliance levels, support exercise motivation and efficacy and increase independent activity and lifestyle changes.

#### **5. Conclusion and future research**

This chapter is a systematic review of the rehabilitation research carried out in the allo-HSCT context during the past 25 years. These findings, despite a number of methodological issues, indicate positive physiological and emotional benefits from exercise in patients during and after allo-HSCT. Exercise during treatment may help patients decrease loss of or maintain aerobic and functional capacity, and muscle strength, and when exercise is continued or instituted in the outpatient/home context there are improvements in aerobic and functional capacity. These results also indicate that exercise-based interventions have multidimensional benefits, including maintaining or improving HRQOL and reducing the most persistent treatment-related symptoms, especially fatigue. This review provides general guidelines for exercise in the allo-HSCT context. However, with improved methodological approaches, future research may provide clinicians with more specific rehabilitation guidelines.

#### **5.1 Future research**

Future studies are encouraged to institute certain methodological stringencies, including inclusion of homogenous groups (same diagnosis or treatment group), larger patient populations, perhaps, multi-institutional studies, randomized designs that clearly describe treatment allocation and stratification methods, as well as details regarding the control group. Further, point estimates for primary outcomes, effect size calculations, as well as Intention-to-Treat analyses are recommended. When and if possible, an effort to blind outcome assessors, data entry keyers and statisticians would improve methodological quality. It is also important that future studies justify the chosen intervention and clearly describe the individual exercise components duration, intensity and frequency as well as screening parameters for intervention participation, and lastly, documentation of compliance rates in order to properly evaluate the effect of the intervention. Decisions regarding test time-points and the most relevant and comprehensive outcome measurements need to be associated with challenges directly related to allo-HSCT. Therefore, GvHD, treatment related symptoms i.e. fatigue, insomnia, pain, gastrointestinal complaints, skin and bodily changes, poor physical, functional and muscle capacity, low levels of physical activity and decreased bone density, low Vitamin D levels and reduced HRQOL including problems with sexuality, body image, social wellbeing and job function need to be considered in this treatment group. More studies are needed that examine the entire treatment trajectory and continue well into the out-patient and home setting. Research that aims to promote multidimensional benefits may consider multimodal interventional designs that combine physical exercise with other psychosocial and educational approaches. Additionally the role of vitamin D and exposure to sunlight in combination with physical exercise on bone health, function and general wellbeing may be warranted. Further, there is a need to study the patients' own experience as a participant in an exercise-based intervention in order to develop programs that are tailored to fit the needs of patients during and after allo-HSCT. Finally, translational intervention studies are needed that support and improve the ability of patients to cope with their life situation during treatment, as well as to function optimally after allo-HSCT in daily life, including return to employment.

#### **6. Conflict of interest**

576 New Advances in Stem Cell Transplantation

incorporation of low intensity exercise as relaxation breathing or progressive relaxation in the program, especially when a higher exercise intensity level is not possible (Kim and Kim, 2006; Jarden et al. 2009). Psychosocial, educational and motivational approaches may be integrated to maintain compliance levels, support exercise motivation and efficacy and

This chapter is a systematic review of the rehabilitation research carried out in the allo-HSCT context during the past 25 years. These findings, despite a number of methodological issues, indicate positive physiological and emotional benefits from exercise in patients during and after allo-HSCT. Exercise during treatment may help patients decrease loss of or maintain aerobic and functional capacity, and muscle strength, and when exercise is continued or instituted in the outpatient/home context there are improvements in aerobic and functional capacity. These results also indicate that exercise-based interventions have multidimensional benefits, including maintaining or improving HRQOL and reducing the most persistent treatment-related symptoms, especially fatigue. This review provides general guidelines for exercise in the allo-HSCT context. However, with improved methodological approaches, future research may provide clinicians with more specific

Future studies are encouraged to institute certain methodological stringencies, including inclusion of homogenous groups (same diagnosis or treatment group), larger patient populations, perhaps, multi-institutional studies, randomized designs that clearly describe treatment allocation and stratification methods, as well as details regarding the control group. Further, point estimates for primary outcomes, effect size calculations, as well as Intention-to-Treat analyses are recommended. When and if possible, an effort to blind outcome assessors, data entry keyers and statisticians would improve methodological quality. It is also important that future studies justify the chosen intervention and clearly describe the individual exercise components duration, intensity and frequency as well as screening parameters for intervention participation, and lastly, documentation of compliance rates in order to properly evaluate the effect of the intervention. Decisions regarding test time-points and the most relevant and comprehensive outcome measurements need to be associated with challenges directly related to allo-HSCT. Therefore, GvHD, treatment related symptoms i.e. fatigue, insomnia, pain, gastrointestinal complaints, skin and bodily changes, poor physical, functional and muscle capacity, low levels of physical activity and decreased bone density, low Vitamin D levels and reduced HRQOL including problems with sexuality, body image, social wellbeing and job function need to be considered in this treatment group. More studies are needed that examine the entire treatment trajectory and continue well into the out-patient and home setting. Research that aims to promote multidimensional benefits may consider multimodal interventional designs that combine physical exercise with other psychosocial and educational approaches. Additionally the role of vitamin D and exposure to sunlight in combination with physical exercise on bone health, function and general wellbeing may be warranted. Further, there is

increase independent activity and lifestyle changes.

**5. Conclusion and future research** 

rehabilitation guidelines.

**5.1 Future research** 

The author declares no conflict of interest.

#### **7. Acknowledgements**

I thank Anders Larsen (Information specialist - The University Hospital's Centre for Nursing and Care Research, Copenhagen Denmark) for verifying and assisting with the literature search strategy. I would also like to thank Kristine Marie Jarden (Research assistant - University of Southern Denmark) for her assistance in manuscript preparation.

#### **8. References**


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### *Edited by Taner Demirer*

This book documents the increased number of stem cell-related research, clinical applications, and views for the future. The book covers a wide range of issues in cell-based therapy and regenerative medicine, and includes clinical and preclinical chapters from the respected authors involved with stem cell studies and research from around the world. It complements and extends the basics of stem cell physiology, hematopoietic stem cells, issues related to clinical problems, tissue typing, cryopreservation, dendritic cells, mesenchymal cells, neuroscience, endovascular cells and other tissues. In addition, tissue engineering that employs novel methods with stem cells is explored. Clearly, the continued use of biomedical engineering will depend heavily on stem cells, and this book is well positioned to provide comprehensive coverage of these developments.

New Advances in Stem Cell Transplantation

New Advances in

Stem Cell Transplantation

*Edited by Taner Demirer*

Photo by Sinhyu / iStock