BK and other polyomavirus associated diseases in children

General population

The exact mode of natural BKPyV and JCPyV transmission is undefined but most likely involves contact with mucosal surfaces in the oral/pharyngeal, gastrointestinal, or respiratory tract. Seroprevalence studies indicate that primary infection with BKPyV occurs in toddlers, reaching IgG positivity rates of greater than 90% between the ages of 2 and 4 years. There are no known symptoms associated with primary BKPyV infection and a nonspecific, constitutional illness cannot be excluded. Primary JCPyV infection appears to occur significantly later as only 35% of adolescents have JCPyV-specific IgG antibodies compared with 60% of blood donors. In a study of 18 patients undergoing thymectomy in children owing to congenital heart surgery, the IgG seroprevalence of BKPyV and JCPyV was 70% and 25%, respectively. However, some differences in seroprevalence rates across different studies reflect patient age and waning antibody responses over time, but particular attention should be paid to the different antigens used (e.g., Vp1 monomers or fusion proteins, Vp1-pentamers or Vp1-virus-like particles).

HPyVs have been detected in the urine of 30% of healthy children and adults as well as 40% of stool samples from hospitalized children. Detection of BKPyV and JCPyV in human sewage systems supports the possibility of secondary indirect environmental exposures other than the direct transmission route (e.g., from child to child). Indeed, PyV particles are fairly resistant to environmental inactivation and can withstand heating to 60°C for 30 minutes and many disinfectants. Other routes of transmission are less well defined and even controversial (e.g., via transfusion, transplacental, seminal fluids, or organ transplantation), with the notable exception of kidney transplantation, where transmission has been shown to occur from donor to recipient.

After primary infection, BKPyV and JCPyV reach the renourinary tract presumably by DNAemia, where they preferentially infect the renal tubular and bladder epithelial cells in the case of BKPyV and the urothelial cells of the renal pelvis and the bladder in the case of JCPyV. ^, Moreover, detection of JCPyV DNA has been reported in tonsils, bone marrow, and the central nervous system. Taken together, large parts of the general human population have been infected with HPyVs, including BKPyV and JCPyV, but neither primary infection, persistence, nor shedding has been linked to significant pathology or disease in immunocompetent persons. Conversely, as outlined in Table 23.2 , immunocompromise appears to be a conditio sine qua non for HPyV disease, but the differences in incidence rates in the respective clinical settings strongly suggest that specific risk signatures beyond mere immunodeficiency appear to play a role. Thus BKPyV-associated nephropathy is most frequently diagnosed in adult and pediatric kidney transplant recipients at rates of 1% to 15%, but only rarely in non-kidney SOT or allogeneic HCT, despite similar or higher intensity of immunosuppression as evidenced by other opportunistic infectious diseases caused by Pneumocystis jirovecii or cytomegalovirus (CMV) replication. Conversely, hemorrhagic cystitis is most frequently seen after allogeneic HCT, but only rarely after kidney transplantation, wherein local toxic damage of the bladder urothelia from conditioning and impaired immune control are followed by increased inflammatory responses postengraftment. JCPyV-mediated PML has reached the highest rates in human immunodeficiency virus/AIDS before the availability of combination antiretroviral therapy or in refractory relapsing multiple sclerosis treated with natalizumab, but less data are available for treatment with dimethyl fumarate or fingolimod, or in SOT or HCT. Accordingly, risk-adapted consultation, screening, and intervention are currently recommended for these respective patients.

Kidney transplantation

The key steps of BKPyV reactivation to nephropathy have been described in detail, but they were mostly derived from adult patients after kidney transplantation. These include the following:

• 1.

  Low-level viruria in approximately 5% to 10% of patients with residual urine production before kidney transplantation

• 2.

  High-level replication with urine BKPyV loads greater than 10 million copies/mL and decoy cell shedding in 20% to 50% of patients after transplantation

• 3.

  Detection of BKPyV DNA in plasma in 10% to 40% of patients after transplantation

• 4.

  Histologically proven BKPyV-associated nephropathy with little inflammation and baseline allograft function (PyVAN-A)

• 5.

  Increasing allograft damage due to BKPyV replication and inflammation decreasing kidney allograft function (PyVAN-B1, -B2, -B3); and

• 6.

  Irreversible fibrosis and tubular atrophy causing decline in allograft function (PyVAN-C).

Accordingly, screening for high-level viruria and/or DNAemia using nucleic acid testing (NAT) is recommended to identify patients with persistent DNAemia who would benefit from preemptive reduction in immunosuppression.

Most of the literature describing BKPyV infection replication and disease in children has been published in the past decade. In a prospective clinical and laboratory study from 2002 to 2005 in Italy, Ginevri and colleagues followed up with 62 children who received basiliximab and standard maintenance triple therapy with a calcineurin inhibitor, mycophenolate mofetil, and corticosteroids. Only 3 of the 62 patients received induction that included antithymocyte globulin. Blood and urine samples were collected at months 1, 3, 6, 9, 12, 18, 24, 36, and 48 after transplant for NAT testing (458 samples, average of 7 samples per patient after transplant). The cumulative risk of viruria was 64% (95% confidence interval 53% to 78%) and that of DNAemia was 22% (95% confidence interval 13% to 35%), and was first detected at a median of 3 months (range 1 to 24 months for viruria and 1 to 18 months for DNAemia) after transplant. Using a protocol to reduce immunosuppression, no cases of BKPyV-associated nephropathy occurred in this series.

Risk factors for BKPyV replication after kidney transplant have included the depth and type of immunosuppression, including the use of antithymocyte globulin for induction or rejection treatment and the level of exposure to tacrolimus and mycophenolate mofetil. Other reported risk factors include human leukocyte antigen (HLA) mismatches, deceased donation, older age, male gender, donor antibody high/recipient antibody low, and ureteral stents. In their analysis of 313 children receiving a kidney transplant in Europe, Höcker and colleagues reported the cumulative incidence of DNAemia and biopsy-proven nephropathy after kidney transplant ( Fig. 23.1 ). In a multivariate model, they found that a higher degree of immunosuppression (odds ratio [OR] 1.3, P < .01), tacrolimus use (vs. cyclosporine) (OR 3.6 P < .01), younger recipient age (OR 1.1 per year, P < .001), and obstructive uropathy (OR 12.4, P < .01) were associated with higher risk of BKPyV infection.

The serostatus of the donor and recipient may also contribute to posttransplant BKPyV risk. Ali and colleagues conducted a retrospective analysis of pediatric kidney transplant patients at their center in Canada from 1986 to 2007. All patients had follow-up for at least 1 year after transplant. Using an enzyme-linked immunosorbent assay to detect IgG against the BKPyV Vp1 virus-like particle, the authors tested stored blood samples from donors and recipients. An antibody titer of 1:2560 or less was categorized as a low titer and a titer of 1:10,240 or more was defined as a high titer. Of the 94 included transplant recipients, 34% had low anti-BKPyV IgG serostatus and 66% had high serostatus before transplant. Consistent with published reports for healthy children, pretransplant antibody titers were higher with increasing age, especially after the age of 6 years. Blood was also available to test 40 donors, 73% of whom had antibody titers in the high anti-BKPyV IgG serostatus group. Recipients with a low serostatus had a significantly higher risk of BKPyV DNAemia in the first year after transplant. The highest risk of BKPyV DNAemia was found in children with high donor serostatus and low recipient serostatus. Although BKPyV-specific IgG mediate part of the antiviral immune response, a higher antibody status may be a surrogate of recent exposure or reactivation, and hence reflect a higher tissue BKPyV load in the allograft that cannot be countered by sufficient immune effector functions in the recipient with low BKPyV-specific immunity evidenced by low antibody titers. Although the numbers were small, BKPyV DNAemia occurred in 4 of 7 (57%) transplants from a high donor serostatus to a low serostatus recipient, in none of the 3 transplants in which both the donor and the recipient had low serostatus, and in only 1 of 26 (4%) transplants in which the recipient had high serostatus before transplant. Unlike CMV and Epstein-Barr virus (EBV), it is not standard to test for donor and recipient antibodies against BKPyV before kidney transplant in children or adults. This may change, however, as more research becomes available on the functional and surrogate role of antibody titers and specificities in donor-recipient pairs, and may help to better determine the posttransplant risk of uncontrolled BKPyV replication and disease.

This notion may be extended to differences in BKPyV subtype antibody titers. BKPyV can be divided into four major subtypes (I, II, III, and IV) and each subtype can be further divided in subgroups yielding a total of 12 different categories of BKPyV strains. BKPyV subtype I is found in patients worldwide, whereas subtype IV is found in patients mostly from East Asia and Europe. Subtypes II and III are rarely reported. Subtypes II, III, and IV and subgroups Ib1 and Ib2 are also known to be distinct serotypes. Thus a subtype mismatch arising from transplanting of a donor graft harboring BKPyV subtype IV into a recipient with antibody titers to Ib may be followed by preferential replication of the donor BKPyV subtype. Momynaliev and colleagues examined BKPyV subtypes among 6 pediatric kidney transplant recipients and 10 adult controls at their center in Russia from 2008 to 2009. They found that 66% of the identified BKPyV isolates were Ib2 and 24% were IVc2. More research is needed to determine the role of BKPyV genotypes and serotypes in children with respect to posttransplant high-level viruria, DNAemia, and disease, and the risk-benefit of BKPyV mitigation and graft survival through informed screening and organ allocation.

Nonrenal solid organ transplantation

Few studies have examined the risk of BKPyV replication in children after nonrenal SOT with most of the literature limited to cross-sectional analyses of patients who were several years after transplant, when the risk of BKPyV replication events is presumably lower. In a study of 59 pediatric liver transplant recipients in Israel by Amir and colleagues, blood and urine samples were tested at a single time point at least 1 month after transplant and retested if they were positive. At a median of 5 years after liver transplant, 9 of 59 (15.3%) had viruria, and 1 of 59 patients (1.7%) had low-level DNAemia. In all 9 of the patients with viruria, BKPyV replication was transient and there was no longer evidence of DNAemia or viruria by their next clinic visit 5 months later. In Germany, Brinkert and colleagues tested 100 pediatric liver transplant recipients for BKPyV and JCPyV in urine, and plasma was tested only if the initial urine result was positive above 100,000 copies/mL. Of the 100 included patients in this cross-sectional analysis, 15 (15%) had isolated BKPyV viruria at a median of 6 years after transplant, but no DNAemia was identified.

In contrast to liver transplantation, recipients of thoracic transplants (heart and lung) typically receive higher doses of immunosuppression to prevent rejection, placing them at greater risk for infectious disease events. Ducharme-Smith and colleagues conducted a cross-sectional analysis of pediatric heart transplant recipients in the United States by collecting urine samples at regular clinic appointments. Since 2006, urine testing was performed only in patients with a history of chronic kidney disease and all patients were screened starting in 2012. Blood testing for BKPyV DNA was performed only if urine testing was positive. Of the 83 patients screened for viruria at a median of 3.3 years after transplant, 28 (34%) had viruria. Of these 28 patients, 7 had test results for DNAemia (representing 8% DNAemia among the total study population). In multivariate analysis, patients in whom BKPyV viruria developed were significantly more likely to have evidence of EBV detection in the blood. In a follow-up study, the authors prospectively collected urine and blood samples from 10 consecutive pediatric heart transplant recipients from 2013 to 2015. Samples were collected before transplant and at 1 week and months 3, 6, 9, 12, and 15 after transplant. Quantitative blood and urine NAT was only performed if the result of the initial qualitative urine NAT was positive. The 10 subjects had follow up for 15 months after transplant, during which time viruria developed in 2 of 10 and 1 of 10 (10%) had DNAemia.

Several reviews have summarized the literature describing cases in adults and children with BKPyV replication after heart or lung transplant. ^, In adults after heart transplant, studies have reported a viruria risk of 19% and a DNAemia risk of 5%. After lung transplant, 33% of recipients have been found to have viruria, with less data available on the risk of DNAemia. No studies have systematically examined the risk of BKPyV replication after pediatric lung transplant or in children with cancer. As summarized in later text, there are mainly case reports of BKPyV nephropathy in children after nonrenal SOT, especially in those receiving heart or lung transplants. However, the exact risk of nephropathy in the native kidneys of children with SOT remains unknown.