Rare Viral Infections in Children Receiving Hemopoietic Stem Cell Transplant

ORIGINAL ARTICLE Rare viral infections in children receiving hemopoietic stem cell transplant

E Castagnola1, M Faraci2, C Moroni1, E Di Marco3, C Cirillo3, AM Rabagliati3, R Ricci3, AR Natalizia1, V de Fazio2, G Morreale2, C Granata4, E Lanino2, G Dini2 and R Haupt5

1Infectious Diseases Unit, Department of Hematology and Oncology, G Gaslini Children Hospital, Genoa, Italy; 2Bone Marrow Transplant Unit, Department of Hematology and Oncology, G Gaslini Children Hospital, Genoa, Italy; 3Laboratory of Virology, G Gaslini Children Hospital, Genoa, Italy; 4Service of Radiology, G Gaslini Children Hospital, Genoa, Italy and 5Epidemiology and Biostatistics Section, Scientiﬁc Directorate, G Gaslini Children Hospital, Genoa, Italy

Viral infections are a rare complication in autologous (for example, respiratory syncytial virus may cause an hemopoietic stem cell transplant (HSCT) recipients but upper respiratory tract disease in adults and bronchiolitis in represent a frequent cause of disease after allogeneic infants) and that any infectious disease is generally more HSCT. In the last years, there has been an increase in the severe in immunocompromised patients. All these aspects number of viral diseases observed in these patients. This should be considered for the development of infectious fact may be at least partially due to an improvement in diseases prevention strategies. diagnostic facilities, but the increasing number of In the following paragraphs, we will brieﬂy describe some transplant procedures and the more severe immunosup- features of rare viral diseases occurring after HSCT in pression may also have played an important role. children. Table 1 summarizes the different clinical pictures Bone Marrow Transplantation (2008) 41, S100–S103; associated with viral infections according to the type of doi:10.1038/bmt.2008.65 HSCT. Keywords: virus; autologous HSCT; allogeneic HSCT; pediatrics

Autologous HSCT

Introduction Viral infections are generally rare after autologous HSCT. The most frequent is probably herpes simplex virus Viral infections represent a well-known complication in reactivation during pre-engraftment stomatitis,6 while children receiving hemopoietic stem cell transplant CMV has been reported as the cause of severe infection (HSCT). Their epidemiology is related to the type of in no more than 3% of patients, mainly because of primary HSCT donor (autologous vs allogeneic), the immune status infection.7 of the donor and/or the recipient, and the time elapsed Rotavirus and adenovirus have been reported as a cause from the HSCT.1,2 of clinically relevant dehydration, metabolic acidosis, Overall, viral infections are a rare event after autologous mucositis and neutropenia in cancer patients, including HSCT, while many viruses have been demonstrated to autologous HSCT recipients,8 and many pediatric cases cause disease in allogeneic HSCT recipients. However, seem to be nosocomial in origin.9,10 Norovirus, another some viral diseases may have been considered ‘rare’ until important cause of gastroenteritis in hospitalized children,11 recently because of the absence of diagnostic tools that led caused an outbreak in a pediatric oncology unit, with to many clinical pictures being undiagnosed (for example, some patients experiencing severe or life-threatening human meta-pneumovirus (hMPV), pneumonia).3 diseases,12 but at present no case in HSCT recipients has Viral diseases may frequently represent the reactivation been reported. Viral gastroenteritis may represent an of a latent infection,3 but primary viral infections are also a important cause of mucous damage (other than chemo- possible feature, especially in children.4,5 In this case, therapy-induced mucositis) that may cause the penetration healthy household contacts and health-care workers may of enteric bacteria into the bloodstream.13 Therefore, represent an important source of the disease. Moreover, it HSCT recipients with viral enteritis must be followed must be kept in mind that in some cases the clinical picture very carefully, especially in the presence of concomitant in adults may be different from that observed in children neutropenia, and every effort must be made to prevent the diffusion of these infections to other patients admitted in the same Unit. Therefore, since the shedding of these viruses may be prolonged,9,12 during the acute phase of the Correspondence: Dr E Castagnola, Infectious Diseases Unit, Department of Hematology and Oncology, G Gaslini Children Hospital, L go illness, health-care workers should wear masks in addition G.Gaslini, Genova 5—16147, Italy. to practicing meticulous hand hygiene with a disinfectant of E-mail: [email protected] proven activity against viruses. Rare viral infections in HSCT E Castagnola et al S101 Table 1 Viral diseases observed in children receiving autologous or syncytial virus pneumonia has been reported to be 1.5% allogeneic HSCT in adults or adolescents undergoing autologous HSCT.17 HSCT source Virus Clinical syndrome No data in younger children are available.

Autologous HSV Stomatitis CMV Pneumonia Rotavirus Gastroenteritis Allogeneic HSCT Adenovirus Gastroenteritis Norovirus (?) Gastroenteritis Viral infections represent a frequent complication in HSCT HHV-6 (?) Fever recipients, especially those receiving transplant from an Encephalitis alternative donor.1,2 HHV-7 (?) Encephalitis (?) RSV(?) Pneumonia HHV-6 and HHV-7 have been frequently detected in the Hepatitis viruses: Acute or chronic blood of allogeneic HSCT recipients. Prolonged HHV-6 HAV (?) HBV, HCV, hepatitis reactivation has been associated with fever, rash, delayed HGV (?) engraftment and encephalitis, and in this case viral DNA 14,18 Allogeneic has been detected in the cerebrospinal fluid by PCR. CMV Fever Also, HHV-7 has been reported as a cause of severe central Pneumonia nervous system disease after allogeneic HSCT.16,19 More- Gastroenteritis over, HHV-7 was associated with severe GvHD and sepsis Encephalitis secondary to severe immunosuppression after HSCT from Hemorrhagic cystitis 20 Delayed bone marrow matched unrelated donors. recovery HHV-8 has been associated with the development of EBV Post transplant visceral Kaposi’s sarcoma or lymphomas in immunocom- lymphoproliferative disease promised patients,21–23 and de Medeiros et al.24 have Adenoviruses Disseminated disease Gastroenteritis reported a case of Kaposi’s sarcoma after allogeneic Hepatitis HSCT. However, a survey on the presence of serum Hemorrhagic cystitis HHV-8 DNA after bone marrow transplantation per- HSV Stomatitis formed in 187 Italian HSCT donor–recipient pairs did not VZV Varicella show any HHV-8-related complications after a median of 6 Herpes zoster 25 (also disseminated) years of follow-up. Influenza/parainfluenza Fever BK virus is the main cause of hemorrhagic cystitis after Pneumonia allogeneic HSCT,3,26 especially in the presence of GvHD.27 RSV Pneumonia However, it must be remembered that CMV and adeno- HHV6 Pneumonia 28 Encephalitis virus also have been associated with the development of Delayed bone hemorrhagic cystitis, sometimes in association with BK marrow recovery virus.28–32 Among the papovavirus family, JC virus has HHV7 Encephalitis been reported as a cause of multifocal leukoencephalopathy HHV8 (?) Visceral Kaposi sarcoma in cancer patients receiving chemotherapy and rituximab, BK virus Hemorrhagic cystitis 33,34 Nephropathy (?) in one case combined with autologous HSCT. JC virus (?) Multifocal Parvovirus B19 has been reported to cause persistent leukoencephalopahy (?) infection (several months or years) in immunocompromised Parvovirus B19 Pure red cell aplasia hosts mainly due to impairment of B-cell function.35,36 This hMPV Upper respiratory tract disease infection is associated with viremia and may result in pure Pneumonia (hemorrhagic) red cell aplasia or pancytopenia, also in allogeneic HSCT Acute respiratory recipients.37,38 In this case, the quantitative determination distress syndrome of B19 DNA correlated inversely with the reticulocyte Norovirus Gastroenteritis count.38 Rotavirus (?) Gastroenteritis Hepatitis viruses: Acute or chronic hepatitis Recently, infection with hMPV has been associated with HAV (?) HBV, HCV, the presence of hemorrhagic pneumonia after HSCT.39 HGV (?) However, the same virus has also been detected in 21 asymptomatic patients.40 Therefore, at present, the real Abbreviations: HHV ¼ human herpesvirus; HSCT ¼ hemopoietic stem cell pathogenic role of hMPV in allogeneic HSCT recipients is transplant; HSV ¼ herpes simplex virus; RSV ¼ respiratory syncytial virus. (?) ¼ uncertain pathogenic role of the virus, or clinical syndrome not well still unclear. described in HSCT recipients. Rotavirus and norovirus may also represent important causes of gastroenteritis after allogeneic HSCT, but data are scarce.8,12 On the contrary, adenovirus represents a well-known cause of disease (gastroenteritis, hepatitis and Other viruses, such as human herpesvirus-6 (HHV-6) and disseminated diseases have been described), especially in HHV-7, have been detected in the blood of autologous children.3 In any case, strict isolation of patients with viral HSCT recipients, but their pathogenic role in these settings gastroenteritis is mandatory for decreasing the risk of is unclear.14–16 Finally, the incidence of respiratory epidemic diffusion within HSCT units.

Bone Marrow Transplantation Rare viral infections in HSCT E Castagnola et al S102 Hepatitis viruses in autologous and allogeneic HSCT 3 Boeckh M, Erard V, Zerr D, Englund J. Emerging viral infections after hematopoietic cell transplantation. Pediatr The last paragraph must be reserved for hepatitis viruses, Transplant 2005; 9: 48–54. which may cause liver damage in both autologous and 4 Asano Y, Yoshikawa T, Suga S, Nakashima T, Yazaki T, allogeneic HSCT. Fukuda M et al. Reactivation of herpesvirus type 6 in children N Engl J Med At present, hepatitis B virus (HBV) and hepatitis C virus receiving bone marrow transplants for leukemia. 1991; 324: 634–635. (HCV) could not represent an important cause of disease in 5 Castagnola E, Cappelli B, Erba D, Rabagliati A, Lanino E, children receiving HSCT in developed countries, but they Dini G. Cytomegalovirus infection after bone marrow may be an important problem for patients living in endemic transplantation in children. Hum Immunol 2004; 65: 416–422. areas (for HBV) and/or in the presence of inadequate pre- 6 Carrega G, Castagnola E, Canessa A, Argenta P, Haupt R, transfusion blood screening (both HBV and HCV). These Dini G et al. Herpes simplex virus and oral mucositis in aspects must be kept in mind in developed countries, children with cancer. Support Care Cancer 1994; 2: 266–269. especially in an era of increasing health-care immigration. 7 Castagnola E, Dallorso S, Rabagliati M, Sacco O, Kotitsa Z, The presence of HBV or HCV infection is a matter of Dini G. Survival after cytomegalovirus pneumonia in two concern for its consequences both early after BMT and for children receiving autologous peripheral blood progenitor cell transplantation (PBPCT). Bone Marrow Transplant 1998; 21: long-term survivors.41 In a retrospective study on liver 529–531. disease in HBV- or HCV-positive patients undergoing 8 Troussard X, Bauduer F, Gallet E, Freymuth F, Boutard P, allogeneic HSCT or in negative patients who received Ballet JJ et al. Virus recovery from stools of patients transplant from positive donors, liver disease represented undergoing bone marrow transplantation. Bone Marrow an important cause of morbidity and mortality42 during a Transplant 1993; 12: 573–576. relatively short-term follow-up (median 24 months). In this 9 Rayani A, Bode U, Habas E, Fleischhack G, Engelhart S, survey, 13% of the patients presented severe liver disease, Exner M et al. Rotavirus infections in paediatric oncology with a 47% of fulminant hepatitis and 29% of veno- patients: a matched-pairs analysis. Scand J Gastroenterol 2007; occlusive disease. Reverse seroconversion of HBV is not a 42: 81–87. rare complication in autologous HSCT,43 and in allogeneic 10 Krajden M, Brown M, Petrasek A, Middleton PJ. Clinical Pediatr HSCT recipients the risk seems to be higher during the features of adenovirus enteritis: a review of 127 cases. 42 Infect Dis J 1990; 9: 636–641. tapering of the immunosuppressive therapy. Moreover, in 11 Goodgame R. Norovirus gastroenteritis. Curr Infect Dis Rep 44,45 46 this setting, fulminant hepatitis due to HCV or HBV 2007; 9: 102–109. has been described. Therefore, even if infection with 12 Simon A, Schildgen O, Maria Eis-Hu¨ binger A, Hasan C, Bode hepatotropic viruses does not represent a major contra- U, Buderus S et al. Norovirus outbreak in a pediatric oncology indication for HSCT,47 a careful follow-up is recommend- unit. Scand J Gastroenterol 2006; 41: 693–699. able, especially during immunosuppression tapering.42 As 13 Viscoli C, Castagnola E, Rogers D. 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