Download Viral infections in the pediatric oncology patient.

Science against microbial pathogens: communicating current research and technological advances
_______________________________________________________________________________
A. Méndez-Vilas (Ed.)
Viral infections in the pediatric oncology patient.
Maria Moschovi, Maria Adamaki, and Ioannis Kopsidas
Haematology/Oncology Unit, 1st Department of Pediatrics, Aghia Sofia Children’s Hospital, Thivon & Levadeias Str.,
11527 Goudi, Athens, Greece.
The incidence of children diagnosed with all forms of invasive cancer has significantly increased over the past 30 years. At
the same time, high cure rates have also been achieved, with 5-year survival rates reaching 70-80% for most childhood
malignancies. This improvement has been accomplished through significant advances in treatment, also resulting in the
better management of infections during the immunosuppression period. Treatment failure is usually associated with a
negative response to chemotherapy (no remission status or relapse) and immunocompromise. The latter is usually caused
from the disease itself, especially in the case of lymphoid immune system malignancies, but chemotherapy and
radiotherapy can also enhance immunosuppression in the pediatric oncology patient. The direct consequence of the above
therapeutic modalities results in prolonged immunosuppression, which constitutes the particular patient group highly
susceptible to emerging viral pathogens, sometimes with serious complications that could lead to infectious morbidity. The
current chapter aims to present an updated review of the viral infections encountered in the field of pediatric oncology.
First, we give a brief overview of the nature of immunosuppression in the particular type of pediatric host, the factors
contributing to it, and the current principles in managing immunocompromise. Secondly, we review the types of viral
infection, both from the international literature and from the experience of our Oncology Unit, which resides in a tertiary
referral hospital serving 5 million people, and the available treatment strategies. Finally, we discuss possible ways for
prevention of infection in childhood cancer patients, including medicinal prophylactic treatments, special dietary regimes,
as well as active and passive immunisation strategies. At the same time we highlight the need for raising awareness in
medical providers and patient relatives about the essential prophylactic measures involved in the evaluation and
management of immunocompromised pediatric oncology patients. It is only through achieving a deeper understanding of
the factors contributing to viral infections and of the procedures that we can follow to treat or prevent them that we can
improve the quality of life of the children with cancer.
Keywords: immunosuppression, pediatric, oncology, infection, chemotherapy.
Introduction
The outcome of children with cancer has improved significantly over the last 30 years. This has been achieved through
the combined use of chemotherapy, radiotherapy, surgery and bone marrow transplantation (BMT). However, viral
infections are a common cause of severe complications in children with hematologic malignancies, solid tumors, or
following allogeneic BMT. Childhood cancer patients are often neutropenic during treatment, and immunodeficiency is
defined by both humoral and cellular immunity impairment, resulting in an increased risk for viral infections. The
reasons are both the disease itself and the antineoplastic therapy that leads to neutropenia, lymphopenia and to damages
of the natural anatomical barriers of the skin and mucosal membranes. Certain types of cancer, such as leukemias and
lymphomas, are often directly involved in the malfunctioning of the immune system, predisposing to infection with
particular pathogens (eg. herpes simplex virus, varicella-zoster virus). Additional deficiencies to host defence are
conferred by therapeutic modalities, resulting in prolonged immunosuppression, which in turn constitutes the particular
patient group highly susceptible to emerging viral pathogens, sometimes with serious, life-threatening complications.
Infection in the immunocompromised host
Childhood cancers and their respective therapeutic modalities compromise the immune system in a variety of ways.
Both qualitative and quantitative changes have been recorded as defects of immune response. Examples of quantitative
changes include: a reduction in lymphocyte numbers, delayed hypersensitivity, decreased mitogen responses, reduced
immunoglobulin (Ig) synthesis, reduced monocyte oxidative responses, a decrease in cytokine responses, and increased
monocyte suppressor activity; qualitative changes include deficiencies in chemotaxis and phagocytosis [1].
Antineoplastic treatment on the other hand may cause serious defects in humoral immunity, such as granulocytopenia
(chemotherapy), lymphopenia (irradiation), damage of the skin and mucosal membranes (surgery) and suppressed antiinflammatory responses (glucocorticoids and steroids). The severity of immunosuppression is usually directly correlated
to the intensity and the type of treatment.
The first line of defence against external pathogens is the mucocutaneous barrier, a specialised network of cells of the
skin and of the respiratory, gastrointestinal (GI) and genitourinary tracts. Infections can be transmitted through any
bodily fluid but the blood is an excellent means for transporting microorganisms. Indwelling surgical devices placed
during therapy (eg. central venus catheter, ventricular drain, chest tube, nasogastric tube and urinary catheter) and
frequent blood draws not only compromise the epidermal barrier, but also provide additional opportunity for
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introducing pathogens directly into the bloodstream. Although the most frequent complication of transfusion is regarded
to be the transmission of microbial infections, viral pathogens can also be transferred in this way. Viral infections can
be either primary or due to a reactivation of the virus that has remained dormant in the body of the patient. Unlike
bacterial and fungal infections which usually follow long periods of neutropenia, the reactivation of a virus appears to
be the result of increased immunosuppression.
The spleen is another organ that can contribute to immunosuppression. Since it is the principal organ involved in the
production of antibodies and in the filtering of the blood from damaged cells and opsonin-coated organisms, it can
logically be assumed that splenectomised patients have impaired antibody production and are at increased risk of
infections. In addition, obstruction of hollow organs such as the biliary tree and organs of the gastrointestinal,
genitourinary and respiratory tracts by growing tumor masses, make it easier for the pathogens colonizing the site of
obstruction to promote infection. Similarly, an impaired function of the central nervous system, which may be caused
by tumor obstruction or damage from radiation therapy, could lead to decreased levels of awareness and cognition and
an increased risk of aspiration pneumonia [2].
Patients undergoing BMT seem to be the most susceptible group of immunocompromised host and are at an
extremely high risk of developing infections with serious consequences for morbidity and mortality. The immunological
status of the patient and the susceptibility to infection greatly varies with the stage of BMT, with different infections
occurring at various phases following BMT. These greatly depend on: a) the underlying disease, b) the type of
preceding chemotherapy, c) the history of infections for the particular patient, d) the immune status of both donor and
recipient, e) the intensity of the preparatory treatment (such as myeloablative regimens and total body irradiation), f) the
specific treatment of the transplant (such as the removal of T-cells), g) the development of immunological
complications (such graft versus host disease, GVHD), and h) the compatibility of the transplant.
Finally, the nutritional status of the children with cancer is believed to influence their prognostic outcome, and
malnutrition is thought to make a compromising impact on immune function in a multitude of ways. Even though the
nutritional aspects of pediatric oncology have not been extensively studied, some reports have documented a link
between vitamin A deficiency and immunocompromise [3, 4]. Others have reported that children with low vitamin A
levels are more susceptible to cancer treatment-related complications (such as infections) and have a higher prevalence
of morbidity and mortality than children who were not vitamin A deficient during similar treatment [5].
In pediatric oncology, immunosuppression is usually deliberately induced in order to decrease the strength of the
abnormally proliferating cells of the immune system (as in the case of leukemia), or to prevent the rejection of an organ
transplant, or to treat GVHD after BMT. Since these therapeutic modalities seem to be very effective in the overall
outcome of the children with cancer, if immunosuppression was to be reversed it could have a negative influence in
disease progression and the overall survival. Therefore, the current principles in managing immunocompromise in
pediatric oncology patients are limited to the effective monitoring of the immunological state of these children and to
the control of severe complications by early diagnosis. The detection of certain antibodies in blood samples can greatly
assist in the diagnosis of viral infections, but there may be no antibody response in immunocompromised children. The
PCR techniques that detect the DNA or RNA of the viruses appear to have high sensitivity and specificity, and hence
are currently widely used in the rapid and timely diagnosis of viral infections.
Overview of the viruses most commonly encountered in the field of pediatric oncology
CYTOMEGALOVIRUS
Human cytomegalovirus (CMV), or otherwise human herpes virus 5 (HHV-5), belongs to the taxonomic family of
Herpesviridae (subfamily Betaherpesvirinae) and is regarded the most common cause of prenatal viral infection [6].
Children can be infected with CMV in utero, during birth, through breast feeding, through blood transfusions, and from
close contact with other children, mainly through salivary glands. Seroprevalence seems to be age-specific, with around
60% of children aged 6 or older being CMV positive. While the infection is usually asymptomatic in healthy children,
the virus can remain latent in the body for a long time and reactivate in periods of immunosuppression, thus establishing
persistent infections. Symptomatic CMV reactivation is mostly known to cause enterocolitis or interstitial pneumonia in
patients receiving BMT or organ transplantation, but it can also become life threatening to childhood patients outside
the transplant setting, especially in the context of delayed diagnosis and treatment [7, 8]. Ganciclovir and
valganciclovir are the first-choice antiviral therapies for the treatment of immunocompromised patients, while foscarnet
and cidofovir are reserved mainly for treatment of ganciclovir-resistant cytomegalovirus infections [9].
EBSTEIN BARR VIRUS
The Epstein Barr Virus (EBV), or otherwise called Human Herpes Virus 4 (HHV-4), is essentially one of the most
common viruses in humans, with around 90% of the world’s population being EBV positive [10]. Since its discovery in
1964 EBV has been linked to a variety of conditions, all associated with the latent cycle of the virus. Primary EBV
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infection is mostly asymptomatic or causes a self-limiting disease called infectious mononucleosis (IM), usually
characterized by fever, sore throat and fatigue. Infection usually occurs through close contacts between parents and
children within the first 3 years of life, hence why IM is also referred to as kissing disease, but in developed countries it
is estimated that up to 50% of the population encounter primary infection after the first decade of life [11, 12]. Infected
B cells express many highly immunogenic viral antigens so most people that become infected with EBV develop
adaptive immunity and clear the infection. In the case of immunosuppressed individuals, the risk clearly correlates with
impaired specific immunity to the virus and EBV infection may cause overt disease that is potentially lethal. One such
life-threatening complication is acquired hemophagocytic lymphohistiocytosis (HLH), a condition characterized by
excessive activation of the immune system, via over-stimulation of macrophages and lymphocytes. Symptoms include
hyperinflammation, fever, hepatosplenomegaly, hypertriglyceridemia, hypofibrinogenemia, and possible central
nervous system involvement such as seizures and encephalopathy [13]. The increased inflammatory response does not
result in increased immunity, but rather in an impairment of the cytolytic activity, leading to phagocytosis, cytopenia
and eventually multiple organ failure [14]. Treatment strategies aim at suppressing the increased inflammatory response
through chemotherapy/immunotherapy drugs such as etoposide, a macrophage cytotoxic drug, in conjunction with
dexamethasone or prednisolone [15, 16]. The second life-threatening condition that can be caused by EBV is “EBVinduced lymphoproliferative disease” (LPD), which is mostly related to post-transplant lymphoproliferative disorder
(PTLD) in organ and bone marrow recipients [17, 18]. LPD, as the name implies, is characterized by an uncontrolled
proliferation of EBV-infected lymphocytes, resulting in gross infiltration of the lymphatic system, the gastrointestinal
tract, the liver, and sometimes the central nervous system [19]. Symptoms include lymphadenopathy, interstitial
pneumonia, ileus, hepatomegaly and/or hepatic failure, increased intracranial pressure and seizures. Recent data suggest
that the risk of a transplant recipient developing EBV-LPD also largely depends on the pre-transplant EBV status of the
patient [20], so effective monitoring using real-time quantitative EBV-PCR prior to transplantation is highly
recommended [21]. Most patients respond well to a reduction or cessation of immunosuppression and additional
treatment with the chemotherapeutic drug rituximab. New immunotherapeutic approaches use adoptive T-cell based
therapies and monoclonal antibodies [22, 23].
VARICELLA ZOSTER VIRUS
The varicella-zoster virus (VZV) is a highly contagious virus, transmitted either via direct contact or through inhalation
of respiratory secretions from an affected individual. Primary infection results in chickenpox, but VZV can remain
dormant in the nervous system of affected individuals and reactivate later in life causing a disease known as shingles
[24]. Immunocompromised patients are at an increased risk of developing serious complications, such as disseminated
disease, pneumonia, and encephalitis. Others have reported an increased risk of secondary bacterial infection with
invasive Streptococcus pyogenes [25]. VZV infection in immunosuppressed patients is usually asymptomatic, though
some reports have documented a generalized maculopapulovesicular rash, skin lesions, severe abdominal or back pain
and, in cases of progressive disease, extensive spleen involvement [26, 27]. Antiviral therapy is highly recommended in
immunosuppressed patients within 1 week from the appearance of a rash or before the formation of full crusting of
lesions [28]. Acyclovir administered intravenously is the first-choice treatment for VZV infection in childhood cancer
patients, while foscarnet can also be administered in cases of acyclovir-resistant VZV [29, 30]. A live attenuated
vaccine is also available under the name Varivax.
HUMAN HERPES VIRUS 6
Primary infection with the Human Herpes Virus 6 (HHV-6) usually occurs before the age of 2, with infection rates
being highest in infants between 6 and 12 months old. HHV-6 has two variants: HHV-6A and HHV-6B. HHV-6A has
not been associated with any type of human disease but HHV-6B has been identified as the causal agent for the
childhood disease roseola infantum (or exanthema subitum). HHV-6 is transmitted through the saliva, with
seroprevalence in the world population considered to be as high as 90%. Immunocompromised patients are at a
relatively high-risk of HHV-6 infection, and it has been documented that latent HHV-6 may reactivate in up to 30% of
immunosuppressed children [8, 31]. Symptoms include fever, malaise, rash, leukopenia, lymphadenopathy,
convulsions, myocarditis, hepatitis, severe pneumonitis, encephalitis, and in BMT recipients delayed engraftment, graft
failure, or GVHD [32-35]. Treating HHV-6 infection following BMT is often a difficult task, since reversing the
immunosuppression could lead to the body rejecting the transplant. There are currently no available treatments specific
to HHV-6 infection and classic anti-herpes drugs produce secondary effects that are often problematic for transplant
patients [36]. However, it was recently reported that administration of cidofovir and foscarnet effectively clears HHV-6
infection in vitro, suggesting that a combination of these antivirals could hold promise for the treatment of pediatric
cancer patients with HHV-6 infection [37].
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HEPATITIS B AND HEPATITIS C
HBV and HCV infections are major causes of morbidity and mortality in oncologic pediatric patients [38]. HBV-DNA
may persist in intra-hepatic or extra-hepatic sites and therefore reactivate when the patient is immunosuppressed. This
makes a complete screening of HBV markers of the outmost importance in patients about to undergo hematopoietic
stem cell transplantation (HSCT) [39]. The infection is a two step process. At first, when the patient is treated with
cytotoxic or immunosuppressive agents, there is an abrupt rise of viral replication which is confirmed by higher HBV
DNA and HBeAg serum titres. Then, when the treatment is stopped the immune-mediated destruction of hepatocytes
occurs [40]. Nucleoside analogues and in particular Lamuvidine are used quite successfully to prevent the Hepatitis B
reactivation and consequently decrease clinical hepatitis and mortality associated with hepatitis B viral injury [41, 42].
It is recommended not to wait for signs of hepatic injury such as increased ALTs to start treatment. On the contrary, it
has been shown that it is better to start lamuvidine on hepatitis B surface antigen-positive lymphoma patients before the
initiation of chemotherapy or at least concurrently [43]. Of importance is also the increase of awareness of the risks of
hepatitis B reactivation amongst physicians. A recent study revealed that from a total of 134 physicians who specialize
in treatment of oncology patients, only 27 % screened all patients before chemotherapy [44]. On the other hand, chronic
HCV infection after chemotherapy for malignant diseases in childhood has a good prognosis with a 21-year follow-up
rate of cirrhosis of only 5% [45]. Treatment consists of interferon with or without ribavirin and in most cases it is
postponed until after the completion of chemotherapy [46]. However, there have been reports of successful concurrent
treatment [47]. A small report on combined HBV-HCV infection of oncologic patients showed that combined treatment
seems to be effective. However, there is a need of a research with larger groups to validate the effectiveness of
combined treatment of co-infected patients [48].
NOROVIRUS
Norovirus (NV) is the prototype strain of a genetically diverse group of RNA viruses (taxonomic family Calciviridae)
and is responsible for approximately 90% of non-bacterial gastroenteritis worldwide [49, 50]. NV can be transmitted
directly from person to person, or indirectly via contaminated food or water, or via aerosolization through subsequent
contamination of surfaces [51]. The virus is highly infectious, with only a few particles being capable of conferring
infection, whereas transmission from one person to another is still possible even when symptoms have subsided [52].
This property, along with the fact that NV is resilient to extreme environmental conditions (it may survive drying,
freezing, heating to 60°C, and even chlorine-based disinfectants), make it a serious cause of severe epidemic
gastroenteritis in closed communities such as schools, nursing homes, prisons, dormitories and hospitals. Diagnosis in
pediatric oncology patients is however difficult, since the main symptoms of nausea and emesis can also be induced by
chemotherapy. Other symptoms include: fever, sometimes presenting as febrile neutropenia, dehydration, anorexia,
headache, abdominal cramps, and myalgia, mostly presenting as an adverse reaction to treatment with vincristine and
corticosteroids [19]. More severe, life threatening complications, have recently been reported in the pediatric oncology
population, such as chronic diarrhoea, gastrointestinal bleeding, and peritonitis, [53, 54]. Currently, there is no antiviral
medication specific to NV, but the pharmaceutical company Ligocyte is testing an NV vaccine in human clinical trials.
ROTAVIRUS
Rotavirus (RV) is a double-stranded DNA virus (taxonomic family Reoviridae) and is considered one of the leading
viral pathogens of pediatric nosocomial gastroenteritis [55]. The virus has 5 strains, referred to as A, B, C, D, and E, but
it is RV-A that is responsible for over 90% of infections in humans [56]. RV rarely affects adults and it is estimated that
every child has been infected with RV at least once by the age of 5. Immunity develops with each infection, so
subsequent infections are usually less severe, unless reinfection by a different RV serotype takes place. The virus is
primarily transmitted via the faecal-oral route, but transmission via food, water, fomites and flies is also possible [57].
Gastroenteritis caused by RV is characterized by vomiting, diarrhoea and low-grade fever; in immunocompromised
children RV infection is a self-limiting disease with a duration of 3 to 6 days, but symptoms may become more severe
in infants, with dehydration being the most common and, if left untreated, the most serious life-threatening
complication. Many cases of RV infection in pediatric oncology units seem to be of nosocomial origin [58, 59] so RV is
regarded as a preventable pathogen. The few trials that have examined the potential preventive role of oral probiotics in
the spread of infection in hospitalized children have yielded conflicting results [60, 61], so the primary means of
prevention remain the early diagnosis and the implementation of the necessary sanitization and contact precautions.
With no antiviral treatment currently available, public health campaigns focus on providing dehydration therapy, and
two generation RV vaccines have been undergoing clinical trials [62].
HUMAN BOCAVIRUS
The Human Bocavirus (HBoV) is a single-stranded DNA virus and a relatively newly discovered member of the
taxonomic family Parvoviridae [63]. While it has been linked to both gastroenteritis and lower respiratory tract
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infections, HBoV is considered the fourth most common pathogen of respiratory disease, especially in young children,
following Adenovirus, Respiratory Syncytial Virus (RSV), and Rhinovirus [64, 65]. Clinical symptoms resemble those
of other viral acute infections (such as those inflicted by RSV and Human Metapneumovirus or hMPV) and include
fever, coughing, and weezing, with peribronchial infiltrates and bronchopneumonia being the most common clinical
observations [66-68]. Diarrhoea and other gastrointestinal symptoms may also manifest independently of respiratory
symptoms [69]. A few groups have reported EBoV infection in immunocompromised pediatric patients, including two
organ-transplant and an allogeneic stem cell transplant recipient [66, 70, 71]. Overall, there are no clinical presentations
specific to HBoV and diagnosis relies on specific PCR protocols [68, 72]. Further investigations are needed in order to
determine the exact pathogenic nature of HBoV and possible routes for its prevention and treatment.
INFLUENZA VIRUS
Influenza viruses are RNA viruses that spread mostly by droplets of respiratory secretions or with direct contact of
contaminated surfaces. Influenza virus infection can cause serious illness to immunocompromised patients. It poses one
extra challenge as the differentiation with a bacterial infection is difficult since the main symptom is high fever in
conjunction with other milder clinical signs. Older and newer studies, relate influenza infection with prolonged duration
of symptoms, high rate of concurrent bacteremia and delays in chemotherapy [73, 74]. Regarding recent H1N1
outbreaks, different reports agree that it caused mild symptoms in children with cancer and/or hematological conditions
and the main consequence was on the intensity of the anticancer treatment [75-77]. There is not enough data on the
efficacy of the influenza vaccines. A recent study concluded that seroconversion rates for the pediatric oncology
population are well below those for the general population. In addition, patients with ALL had better response when it
was given early in the course of treatment. Due to the seasonal nature of the of the influenza vaccine this causes an
additional problem to the possibility of arranging the timing of the vaccine to have the optimal result [78]. Overall,
however, it is not yet clear whether the seroconversion that occurs in these patients is efficient to protect them from an
influenza infection or its complications [79]. Treatment must be started within 48 hours of the onset of symptoms and
consists of neuraminidase inhibitors, oseltamivir and zanamivir, which are effective for both influenza A and B [80].
Lately there have been reports of oseltamivir resistant strands and more rarely of strains resistant to zanamivir [77, 81,
82].
RESPIRATORY SYNCYTIAL VIRUS
The human Respiratory Syncytial Virus (RSV) is a single-stranded RNA virus of the taxonomic family
Paramyxoviridae, subfamily Pneumoviridae, and is considered the leading cause of serious upper and lower respiratory
tract infection in infants and children worldwide, with additional predisposition to asthma development later in life [83,
84]. The virus is transmitted via direct contact from person-to-person but can not remain viable on hands or surfaces for
more than a few hours. Disinfection of hands, medical accessories (such as masks, gloves and gowns), and
contaminated surfaces is usually sufficient to prevent its spreading. The symptoms are often very mild, resembling
those of the common cold, with bronchiolitis and pneumonia being the most common RSV characteristic in young
children. However, in immunocompromised children, and especially in transplant recipients, bronchiolitis may lead to
acute respiratory failure and occasionally death, so PCR testing for RSV is highly recommended in this group of
patients. Treatment of RSV infections is usually symptomatic and supportive care includes adequate fluid intake and
oxygen supplementation until the illness runs its course. Salbutamol and epinephrine inhalations should only be used in
immunocompromised patients with a profound clinical response, otherwise the corticosteroids will enhance the
immunosuppression status and produce adverse effects [19]. Palivizumab, a monoclonal antibody specific for the RSV
surface protein, is the only available prophylactic drug but its effectiveness has not been thoroughly investigated in
pediatric oncology patients, while preliminary studies show conflicting results [85, 86]. Similarly, the use and efficacy
of the licensed antiviral drug ribavirin in pediatric oncology patients is still under debate [85, 87]. Recently, the
development of motavizumab, a second-generation monoclonal antibody that has evolved from palivizumab, has proved
superior to palivizumab in phase III clinical trials in reducing the incidence of lower respiratory tract infections in highrisk infants [88, 89]. Until a specific and safe vaccine against RSV is produced, motavizumab is the only promising
agent for the efficient prevention of RSV infection in pediatric oncology patients.
HUMAN METAPNEUMOVIRUS
Human metapneumovirus (HMPV) is a single-stranded RNA virus of the taxonomic family Paramyxoviridae
(subfamily Pneumovirinae) and is regarded the second most common cause of respiratory tract infection in young
children, following RSV. Whereas infection is usually milder compared to RSV, co-infection with both viruses is also
possible, and is associated with a worse clinical presentation. It is estimated that all children have been exposed to the
virus by the age of 5 and re-infections are very common throughout the life of an individual. Symptoms resemble those
of other respiratory tract infections and include fever (usually presenting as febrile neutropenia), coughing, wheezing,
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rhinorrhea, hypoxia, and in more severe cases apnea, bronchiolitis and pneumonitis [90-92]. HMPV infection may
cause serious complications in pediatric oncology patients and some reports have documented cases of acute respiratory
failure, severe lymphopenia and death [93, 94]. Even though there are currently no treatment protocols specific to
HMPV infection, ribavirin has shown some promising antiviral results in vitro [95].
BK VIRUS
The BK virus (BKV) is a member of the taxonomic family Polyomaviridae, known to affect the kidneys and the
genitourinary tract. Even though the exact mode of transmission of BKV has not yet been established, the virus is
believed to transfer from one person to the next by either respiratory fluids or urine [96, 97]. BKV infection is very
common and widespread in childhood, with seropositivety reaching 90% in children between the age of 5 and 9 [98].
Primary BKV infections are either asymptomatic or produce very mild symptoms, such as respiratory infection or fever.
However, the latent form of the virus is contained in up to 80% of the population [99], where it remains dormant until
the body undergoes some form of immunosuppression. For this reason, in immunocompromised patients the clinical
presentation is more severe and symptoms include renal dysfunction (accompanied by elevated levels of serum
creatinine), ureteral stenosis, interstitial nephritis, hemorrhagic cystitis (HC) in BMT recipients, graft loss in renal
transplant recipients, and BK-related nephropathy, a condition in which the immunosuppression allows the virus to
replicate within the graft [100]. Most studies regarding BKV infections in immunocompromised patients have been
conducted in adults but not in children with cancer, so there is limited information in this field. A recent study presented
three cases of pediatric oncology patients who developed HC after having been treated with high dose
cyclophosphamide, where the HC caused delays in the chemotherapy and prolonged supportive care [101]. The main
treatment against BKV infection is a reduction in immunosuppression but this could cause transplant failure in BMT
recipients. Other therapeutic options tested on adult patients include Leflunomide (combined immunosuppressive and
antiviral properties), Cidofovir (albeit associated with dose-related nephrotoxicity in some patients), intravenous
immunoglobulin (IVIG) (efficacy of treatment not yet established) and quinolone antibiotics such as Ciprofloxacin,
which are known to reduce the viral load in non-graft-recipients [102, 103].
General guidelines for the prevention of infectious complications in pediatric oncology
patients
Viral infections can cause the most serious complications in pediatric oncology, since not only may they limit the
effects of antineoplastic therapy, but they are also associated with significant morbidity and mortality in the particular
patient group. The pediatric oncologist should be aware of the potential pathogens, the clinical symptoms, as well as the
means for their prevention and treatment. The availability of sensitive quantitative RT-PCR-based diagnostic methods
that allow the rapid detection of most viruses can lead to an early diagnosis. Similarly, seroprevalence tests should be
performed before the induction of therapy for the timely detection of viruses in the latent phase. Sites of indwelling
surgical devices, as well as biopsy and resection sites, should be regularly examined for signs of infection. The ultimate
goal is the prompt diagnosis of infection and the precise identification of the pathogenic organism in order to allow for a
timely initiation of the appropriate treatment with the least side effects.
Nosocomial infections remain the main cause of infectious morbidity, with pathogens primarily transmitted from
patient to patient either via the hands of hospital workers or via contaminated surfaces in communal areas. Therefore,
the most important anti-infective measure identified so far is hand hygiene, including the use of alcohol-based hand
sanitizers, followed by effective sterilization of medical equipment and sanitization of communal hospital areas, such as
bathrooms, kitchens and playgrounds. Special attention should also be given to the personal oral hygiene of patients,
visitors, and health professionals. Educational campaigns of health care workers, patients, relatives and visitors using
educational material such as videos and information booklets should build the basis for the prevention of hospital
infections.
Another means that can aid significantly in the prevention of infection is a dietary regime that consists mainly of
cooked food; raw fruit and vegetables could carry dangerous pathogens regardless of washing, especially if imported
from foreign tropical countries.
In the case of severely immunocompromised patients such as BMT recipients, patient isolation in a total protective
environment (TPE) could also prove an effective means of protection. Reverse isolation in a high-efficiency air-filtered
room, accompanied by surface decontamination and sterilization of all objects in the room, has been shown to reduce
infection rates and improve survival for patients with profound neutropenia [104].
Τhe use of certain antivirals as prophylactic treatment could prove useful in the prevention of infectious
complications, provided that these are carefully considered after close consultation between an oncologist and an
infectious disease specialist.
Finally, immunization by vaccination is regarded as the most effective means in preventing infectious complications
in children receiving treatment for cancer. The obvious advantage is in preventing primary infection in infancy and
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early childhood so as to diminish the possibility of viral re-activation later in life. However, one has to take into account
that certain children with cancer are too young to have completed their primary immunizations. Even though there are
some general guidelines in suspending vaccinations during induction and consolidation chemotherapy, there has been
an ongoing debate on whether these should be performed during maintenance therapy or after the elective end of
neoplastic treatment [105-108]. Inactivated vaccines pose no risk to immunocompromised children, but they have
limited or no efficacy in eliciting an immune response during therapy due to inadequate antibody responses. On the
other hand, live virus immunizations can cause fatal complications in children with impaired immune function and so
are administered 3 to 6 months after the cessation of cancer therapy, when the immune system has fully reconstituted
itself. Nonetheless, taking into account the high morbidity rate and the serious complications of VZV infection in
pediatric oncology patients, varicella vaccination of children in continuous complete remission for 1 year while still
receiving chemotherapy (where the risk of VZV infection is high) is still considered a reasonable option, despite
controversial issues surrounding the risks and benefits [109, 110]. For the same reasons, hepatitis vaccination is also
approved in children with cancer receiving chemotherapy, whereas the combined hepatitis A/B vaccine seems to be
much more effective than the monovalent vaccine in cancer patients, characterized by high seroconversion of hepatitis
A [111-113]. Similarly, given the high risk of interruption and delaying of chemotherapy, as well as the high risk of
serious morbidity and mortality caused by influenza infection in pediatric oncology patients, annual influenza
vaccination is currently recommended for all children receiving chemotherapy, including those still within 6 months
from completion of therapy, despite the limited immunity response compared to healthy children [114-118]. Antiviral
prophylaxis instead of vaccination should be considered for those patients receiving intense chemotherapy or those
undergoing BMT, as the vaccine is unlikely to be immunogenic due to the extent of immunosuppression in these
patients. Family members and health care providers should also be vaccinated, and annual updating of the vaccine
should ensure that the antigens included match those of the circulating strains.
Recent advances in T-cell based immunotherapy have shown enough promise in preventing infectious complications
in pediatric oncology patients. Adoptive T-cell transfer has proved particularly effective in the prevention and treatment
of viral infections following allogeneic transplantation and in EBV-induced PTLD, whereas immunogenic epitopes
have also been identified for other viral pathogens such as CMV, HBV, and HPV [119-122].
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