Screening test
Sensitivity (%)
Specificity (%)
PPV (%)
NPV (%)
BK viremiaa
100
96
50
100
BK viruriab
100
92
31
100
Decoy cellsc
25
84
5
97
Urinary capsid protein (VP1)d
93.8
93.9
Haufen cellse
100
99
97
100
It is not clear whether the use of immunosuppression therapy is associated with mutations, deletions, or rearrangements in the NCCR region of polyomaviruses which leads to aggressive disease from these dormant viruses [41].
Due to spontaneous deletions, rearrangements, and amplifications in the polyoma NCCR regions, different quasi-species have been identified. Architectural rearrangements in the NCCRs of BKV do not appear to be a prerequisite for development of hemorrhagic cystitis in hematopoietic stem cell transplant recipients [42]. Analysis of BKV TCR sequences at times demonstrated substitution or insertion, but no specific pattern has been recognized that could be responsible for the aggressiveness of this virus in a cohort of kidney transplant recipients induced with basiliximab [43]. Moreover, it might be clinically useful to know whether specific BKV subtypes or rearrangements could be linked to a particular disease state such as polyomavirus-associated nephropathy or hemorrhagic cystitis in renal or bone marrow transplant patients, respectively.
Advances in Immunosuppression Therapy as a Risk Factor for Polyomaviral Disease
Cyclosporine vs. Tacrolimus: Risk Factors for BKPyV Reactivation
While BKV nephropathy was relatively rare in the cyclosporine era, increased use of tacrolimus- and mycophenolic acid (MPA)-based therapy has been associated with a resurgence of this disease [29, 44, 45]. A recently published study (RCT) lends some support to the long-held notion that following induction with basiliximab and maintenance IS therapy with CsA-MPA resulted in lower incidence as well lesser degree of BK viremia compared to the use of tacrolimus-MPA combination therapy [46]. However, these short-term results may not portend a benefit for long-term graft function and graft survival.
Quadruple IS Therapy
During the past decade, acute T cell-mediated rejection has decreased to as low as 20 % as the majority of centers use quadruple immunosuppression including induction therapy with depleting antibodies [47]. This accomplishment, however, has been confounded by increasing trends in post-transplant infections, particularly increased incidence of BKPyV reactivation syndrome in the post-transplant period. Although no universal pattern of its emergence has been recognized, reports for the past decade suggest that polyomaviral reactivation develops in 30–40 % of recipients of kidney transplant and 5–10 % of heart, lung, and pancreas transplants. It can progress to the development of polyomaviral-associated nephropathy (PyVAN) in approximately 1–10 % of post-transplant population. PyVAN develops as a consequence of BKV reactivation in more than 95 % of cases and less than 5 % of cases are attributed to reactivation of JC virus, but none so far reported due to SV40.
Before the year 2000, PyVAN was usually diagnosed after the onset of allograft dysfunction and was associated with very high allograft attrition rate (50–70 %) [48].
Polyomaviral-Associated Nephropathy
Histopathological evaluation of allograft biopsies in recipients of kidney transplants demonstrated that interstitial nephritis is the leading lesion due to BKPyV or JCPyV reactivation [38, 44, 49].
Diagnosis of polyomavirus nephropathy (PyVAN) is established on the evaluation of biopsy specimens. The histological diagnosis is confirmed by the presence of staining for SV40 antibodies that cross-react with BKPyV or JCPyV due to more than 70 % genomic overlap [49]. Histological changes include renal tubular damage, interstitial fibrosis, and inflammatory reactions in the presence of SV40 antigen positive staining by immunohistochemistry or immunohybridization techniques. Additionally, PyV DNA can be demonstrated in the allograft biopsy specimens [50]. Drachenberg et al. have described various stages of PVAN, allowing to stratify the degree of allograft damage and helping in determining the prognosis of the allograft survival. However, during early stages of the PyV reactivation, histology could be normal, and hence it is of limited sensitivity in the early stage of disease [51, 52].
The definitive diagnosis of PyVAN requires a renal biopsy, ideally containing two cores of cortex and medulla obtained with a 15-gauge needle. Diagnostic confirmation of PyVAN can easily be achieved by immunohistochemistry using commercially available antibodies to detect the simian virus 40 T antigen or the BKV T antigen. In addition to immunohistochemistry, in situ hybridization and electron microscopy can be used to confirm the diagnosis of PyVAN [38, 49, 53, 54], and fluorescein in situ hybridization (FISH) is considered to be a sensitive marker for the detection of polyomavirus [55]. However, they can only serve as confirmatory adjunct diagnostic tools in cases when PyVAN is already suspected histologically. Since BKV affects the kidney in a random, multifocal manner, false-negative biopsy results may occur, especially in an early stage of disease.
Morphologically, PyVAN is characterized by viral replication in tubular epithelial cells showing typical intranuclear viral inclusion bodies of different phenotypes [51]. Viral cytopathic changes are often seen in small groups of cells located in distinct nephrons. The renal medulla is preferentially affected during the early stages of the disease before viral replication spreads to the renal cortex and cytopathic changes become apparent in proximal tubules [38, 49, 56]. The main feature of the polyomavirus inclusions is the presence of enlarged nuclei with smudgy, ground-glass, basophilic inclusions that completely replace the nuclear chromatin. The electron microscopy analysis shows clusters of intranuclear, rounded, electron-dense virions measuring 40–45 nm in diameter and arranged in parallel linear arrays inside the infected tubular epithelial cells. PyVAN shows varying degrees of tubular epithelial cell injury ranging from occasional intranuclear viral inclusion bodies to widespread tubular epithelial cell necrosis with denudation of basement membranes. The interstitium is typically infiltrated by mononuclear leukocytes with active tubulitis, and this form of tubulointerstitial nephritis closely mimics acute cellular rejection [51, 57].
A histological grading system has been proposed in 2004 to correlate the extent of tissue damage with clinical graft outcome [51, 57]. The histological PVAN-A pattern is characterized by mild to moderate viral cytopathogenic changes accompanied by only minimal interstitial inflammation, fibrosis, and tubular atrophy (≤10 %). In PVAN-B, cytopathogenic changes vary from moderate to extensive, together with mild (11–25 %), moderate (26–50 %), and severe (>50 %) interstitial inflammation, the latter designating the subtypes PVAN-B1, PVAN-B2, and PVAN-B3, respectively. Tubular atrophy and interstitial fibrosis are minimal, mild (11–25 %), and moderate (26–50 %) in PVAN-B1, PVAN-B2, and PVAN-B3, respectively. In PVAN-C, severe interstitial fibrosis and tubular atrophy (>50 %) indicate irreversible chronic allograft damage associated with variable degrees of (residual) interstitial inflammation and viral cytopathogenic alterations.
A revised classification schema that includes three stages was proposed in the report of the 2009 Banff meeting: stage A (early changes, without tubular epithelial cell necrosis), stage B (active nephropathy with virally induced tubular necrosis), and stage C (late sclerosing changes) [58].
This pathological classification is reliable from the viewpoint of interobserver reproducibility; however, its clinical significance is less clear with only stage C showing a significantly poorer prognosis compared with stages A and B in a clinicopathological study [51, 52, 57–59]. Further prospective analyses are necessary.
Concomitant diagnosis of acute allograft rejection in the presence of PyVAN should be considered if one finds endarteritis, fibrinoid vascular necrosis, glomerulitis, or C4d deposits along peritubular capillaries [38, 58, 60, 61].
Risk Factors for Progression in BKPyN
Different studies demonstrated that very high viral load, treatment with tacrolimus vs. cyclosporine or mTOR inhibitors, delayed diagnosis, and slow rate of decay in viremia after modifications in baseline immunosuppression therapy are predictors of poor outcome following the diagnosis of PyVAN [63].
Treatment Strategies Following Detection of PyV Reactivation Syndrome After Organ Transplantation
Reduction or modification of baseline immunosuppression therapy continues to remain the mainstay of treatment for patients with different types of polyomaviral reactivation in solid organ transplant recipients. This is particularly well studied now for BKPyV viremia with or without the onset of BK viral nephritis [64–66].
Preemptive reduction in immunosuppression therapy is most effective in presumptive PVAN as defined by surrogate markers (i.e., high BKV viremia) [45]. In this setting, preservation of allograft function remains the most important outcome.
It is believed that reduction in the intensity of IS therapy allows the recovery of BKV-specific T cell immunity, though the time needed for the immunological recovery remains unknown; certainly during that period, cytopathic changes in the allograft may continue to progress. Despite remarkable progress in our understanding of the natural history of polyomaviral reactivation during the past decade, important challenges remain, such as the rare patient with PVAN refractory to any intervention intervention, the newly recognized the newly recognized association of PVAN with urogenital tumors [67, 68] and now recently developed evidence of Merkel cell canner of the skin.
There are no specific guidelines for reduction in IS therapy after detecting BK viremia. Due to the lack of standardized tools to measure the level and magnitude of IS at the point-of-care makes it difficult to individualize this strategy; obviously, the concerns are that (a) too little reduction may trigger further replication and increase the magnitude of viremia, (b) too much reduction in IS therapy is a risk factor of the development of T cell- as well as B cell-mediated organ rejection, and (c) too rapid reduction in IS therapy could result in immune reconstitution syndrome (IRS) which per se is a risk factor for the development of organ transplant rejection or worsening viral infection [69].
Small case series, mostly retrospective in design, showed that elimination of one agent or reduction in the doses of the all three IS agents was associated with similar outcomes for graft failure as well as acute rejection [70].
In addition to modifications of baseline IS therapy, which has not been standardized (as different centers use different approaches to modify the baseline IS therapy), the use of other adjunctive therapies, such as the use of leflunomide, cidofovir, fluoroquinolones, intravenous immunoglobulins (IVIgs), and immunomodulatory immunotherapy, has been studied. These adjunctive therapies in the absence of well-defined clinical studies continue to remain elusive in their efficacy for the treatment of polyomaviral reactivation syndromes.
Adjunctive Therapies Following HPyV Reactivation Syndrome
Leflunomide
The immunomodulatory drug leflunomide is used for the treatment of rheumatoid arthritis. It has been used off-label in patients with PyVAN, yet its antiviral mechanism is not very well established other than it has the ability to induce the depletion of pyrimidine in the virion as well as host cell. Bernhoff et al. using PRTEC (proximal tubular epithelial cells) showed that LEF-A (leflunomide metabolite) at 10 μg/mL reduced the extracellular BKV load by 90 %. This level of leflunomide, however, was associated with marked degree of cytostatic effects [73].
Leflunomide was used in 17 patients with biopsy-confirmed BKPvN, and after discontinuing mycophenolate mofetil, patients who had blood levels of A77 1726 (metabolite of leflunomide) above 40 μg/mL above 40Ug/ml had a significant decrease in the plasma viral load [74]. However, the long-term graft outcome and drug-related toxicity were not reported.
Evaluation of T cell functions (intralymphocyte cytokine expression for IL-2 and TNF-alpha), T cell activation (transferring receptor (CD71) and IL-2 alpha-chain (CD25) expression), and T cell proliferation after initiating treatment with leflunomide did not demonstrate any changes in T cell function despite potential benefit of treatment in the form of decrease in viral load with the use of leflunomide-based therapy following discontinuation of mycophenolate mofetil [75]. Other studies have demonstrated limited efficacy and increased potential of side effects with leflunomide use in recipients of kidney transplants [75, 76].
Pharmacodynamic study by Krisl et al. correlated blood A77 1726 concentration of leflunomide and BK viral load reduction (n = 52) in comparison to similar degree of BK viral disease without the use of leflunomide (n = 24) and demonstrated that the use of leflunomide did not reduce BKPy viremia [77].
A recent literature review by Wu and Harris [78] regarding the off-label use of leflunomide for refractory BKPyAN showed there were a total of two in vitro culture studies, five case reports/series, two retrospective cohort studies, and three prospective observational trials which had used leflunomide as an adjunctive therapy along with reduction in maintenance IS therapy. This analysis suggested that leflunomide at target blood concentrations of around 40 mg/L reduces BK viremia/viruria. It is indeed associated with dose-limiting adverse events.
The use of leflunomide should include careful monitoring of blood cell counts, hepatic functions, and drug concentrations to prevent the drug-related adverse events. Due to the lack of controlled randomized trials, however, the use of leflunomide as first-line treatment should not be routinely recommended.
The clinical correlation between leflunomide levels and its efficacy in clearing viremia remains debatable. But the toxicity profile such as anemia, hemolysis, thrombotic microangiopathy, and neuropathy remains a major concern especially at leflunomide at target blood concentrations of greater than 40 mg/L levels [79].
Cidofovir
Cidofovir is a nucleoside analogue, has been demonstrated to inhibit BKV replication in vitro, and has been explored in observational studies in the treatment of refractory BKPyAN. However, its efficacy has never been demonstrated in randomized controlled trials. Several case reports have demonstrated that treatment with low-dose cidofovir can ameliorate BK viremia/viruria along with recovery of graft function particularly if BKPyVAN continues to progress despite modification and reduction in the intensity of baseline IS therapy [80].
Recent analysis by probabilistic modeling demonstrated that treatment with cidofovir in combination with immunosuppression reduction can lead to cost savings and improved graft survival, BKPyAN, and improved health outcomes in patients with BKPyVAN [81].
A small series of pediatric patients, age range from 5 to 21 years, were treated with cidofovir (0.25–1 mg/kg/dose) every 2–3 week. Total number of cidofovir doses ranged from 1 to 18 (mean 8) for a total of eight patients after confirming the diagnosis of BKPyAN with clearance of viremia as well as preservation of allograft function [82].
Different studies have reported that cidofovir dose ranges from 0.25 to 1 mg/kg every 1–3 weeks, depending on renal function [80, 83]. The treatment duration ranged from 6 weeks to 6 months and is usually monitored by temporal trends in viremia and viruria [68].
A recent systematic review identified 21 publications reporting the use of cidofovir for the treatment of BKPyVAN; most of these were in the form of case reports or small series. The efficacy of cidofovir therapy could not be assessed in 17 of these publications because of lack of surrogate end points or long-term follow-up data or because it was used with concomitant reduction of immunosuppressive drugs; hence, it was concluded that cidofovir alone may not lead to beneficial effect on BK viremia [84].
Clearly, there is an absolute lack of comparative effectiveness studies in the treatment of BK viral disease; therefore, risks associated with the use of cidofovir should be carefully evaluated [85].
Fluoroquinolones
Fluoroquinolones have the ability to inhibit BK DNA topoisomerases II and IV as well as large T-antigen (LT-ag) helicase and DNA gyrase activities. The effects of ofloxacin and levofloxacin on BKPyV replication were analyzed in vitro on renal proximal tubular epithelial cells. BK replication was arrested in a dose-dependent manner and without complete eradication of the infection. The use of these agents has the potential to abrogate the cell injury by decreasing the viral load. However, safety and efficacy including the doses of the drug to achieve in vivo therapeutic concentration akin to in vitro levels remain to be established [86].
Patients who had been exposed to levofloxacin or ciprofloxacin for more than a month in the immediate post-transplant period were less likely to develop BK reactivation syndrome during the first post-transplant year compared to those without such exposure [87]. Another study demonstrated that the use of ciprofloxacin prophylaxis during first 30 days after transplantation leads to a lower rate of BKV infection at 3 months but not at 12 months [88].
The long-term effectiveness and optimal duration and type of fluoroquinolone for prophylaxis against BKV reactivation remain unknown. Antipolyomaviral activity of different fluoroquinolones is currently under investigation [89].
Intravenous Immunoglobulin Therapy
IVIg therapy has been used for the rescue therapy of those patients who failed to show declining trend in viremia following modification of IS therapy [90]. Efficacy and safety of IVIg therapy in polyomaviral disease remain unknown; it is possible that amelioration of viremia with the use of IVIg therapy could be related to immunomodulatory effects of such therapy [91].
In vitro studies show that human IVIgs at concentrations within the range 10–100 μg/mL cause 95.8–98.7 % inhibition of BKV DNA loads after 7 days in cell cultures, provided that the IVIgs and BKV are co-incubated for at least 2 h prior to infection [91–93]. However, clinical experience with IVIgs in PyVAN is limited with sparse evidence of any benefit [94]. In the absence of controlled studies, the high costs associated with adjuvant IVIg treatment make it even a less attractive option [95].
In summary: Detailed systematic review of the therapeutic modalities used in the prevention and treatment of BKPyV disease [96] that included published reports in MEDLINE, EMBASE, and Cochrane databases (1950–2008) as well as published abstracts from the American Transplant Congress (2005–2008) identified more than 500 publications, and review of these published reports did not suggest that addition of cidofovir, leflunomide, IVIg, or ciprofloxacin had a benefit on death-censored graft failure compared to IS reduction alone.
PyV-Specific Immunotherapy
All five BKV antigens are immunogenic and elicit T cell elicit T cell responses of varying degrees in different patients. Using novel approach of a mixture of overlapping peptide pools encompassing all five BKV antigens (viral protein [VP] 1, VP2, VP3, large tumor antigen, and small tumor antigen). Patients who had rapid clearance of BK viremia had polyfunctional T cells polyfunctional T-Cells such as interferon gamma-and IL-2 producing CD4-positive T cells [97]. This observation is particularly important as it may allow to develop polyomaviral immunotherapy.
Immunotherapy by adoptive transfer of cellular effectors can help to abrogate the clinical symptoms associated with opportunistic infections in the post-transplant period. Such therapy has been demonstrated to control some virus-related diseases in transplant recipients, particularly Epstein–Barr virus and cytomegalovirus. Infusion of BKV-specific T cells may potentially reconstitute functional BKV immunity and reduce clinical complications of BKV infection. After monocyte-derived dendritic cells were pulsed with a peptide pool of all the five BKV proteins VP1, VP2, VP3, large T antigen, and small T antigen, it resulted in the generation of BKV-specific T cells, can be used to induce adaptive immunity against the BKV-specific T cells, that can be a goal-directed immunotherapy particularly in patients who develop BKPyVAN as well as acute allograft rejection [98]. It is not used in the realms of clinical practice as yet.
Monitoring of IS Therapy Using Cylex Immune Cell Function Assay
Recently, the Cylex immune cell function assay (ICFA) (ImmuKnow; Cylex, Inc., Columbia, MD) was approved by the U.S. Food and Drug Administration (FDA) to measure global immune response in solid organ transplant patients receiving immunosuppressive therapy.
Current monitoring systems of immunosuppression in solid organ transplant recipients are typically focused on prevention of clinical toxicities of immunosuppressive drugs. We lack the ability to determine the optimal level of immunosuppression at individual basis. It is being postulated that ImmuKnow assay results can reveal either overimmunosuppression with individuals at risk of infection or bone marrow suppression or underimmunosuppression with individuals at risk of organ rejection.
The Cylex ImmuKnow test (Cylex, Columbia, MD) measures immune cell function (ICF) and is based on the amount of adenosine triphosphate (ATP) released when T cells are stimulated by phytohemagglutinin. Low levels of ICFA have been associated with BK viremia in small sample studies [99, 100]; these observations support the notion that overimmunosuppression could be a major risk factor for polyoma viral reactivation syndrome. Similarly, very low values on ICF test correlated with viruria in kidney transplant recipients [101].
Allograft Rejection Vs. Polyomaviral Nephritis on Histological Examination
BKPyVAN along with graft dysfunction often times produces a daunting task of identifying the concomitant presence of T cell-mediated acute rejection. It is being postulated that IS modification or reduction should be undertaken only when the presence of concomitant rejection has been excluded. However, in the presence of significant inflammatory reaction in the biopsy specimen, it becomes a very challenging task for the renal pathologist as well as for the clinician. Studies have suggested that histological features of acute cellular rejection as well as polyoma nephritis could be very similar as demonstrated by immunohistological analysis and gene expression profile [102].
Similarly, Masutani et al. [103] reported single-center retrospective study of the natural history of polyomaviruria in a cohort of patients when more than 80 % were induced with single-dose alemtuzumab, followed by tacrolimus-based monotherapy along with early steroid discontinuation in 70 % of the cohort. Viruria developed in 43 %, and combination of viruria and viremia was noted in 10 %. Nearly 21 % developed biopsy-proven BKPyV-associated nephropathy. Surprisingly, patients with persistent viruria had very high acute rejection rate (36.7 %) compared to 28 % in those without viruria. However, the grade of rejection was not elaborated. Treatment refractory rejection was more common in patients with viruria vs. without viruria (36.2 % vs. 19.6 %).
Masutani et al. [103] as well others have demonstrated that during BKPyV reactivation there is an increased upregulation of plethora of inflammatory markers including interleukin (IL)-6, IL-3, and granzyme b in the urine [104, 105]. In the presence of BKPyV reactivation, at times it could be difficult to differentiate inflammatory changes that could accompany the viral-induced CD8+ cell response in the graft and different grades of T cell-mediated rejection [102]. However, the use of other techniques such as immunophenotyping of the allograft biopsy may yield helpful information for clinical decision making [60].
Genomic biomarkers in the near future may help to make this distinction without ambiguity, since treatment of concomitant T cell-mediated rejection could practically lead to more immunosuppression, hence fostering BKPyV replication, thus a vicious cycle.
Type of Polyoma Viral Reactivation in the Post-transplant Period
Is It BKPyV or JC PyV Reactivation?
Several studies have demonstrated that JCPyV viral reactivation can happen in the recipients of kidney and other organ transplants. JC reactivation is less common than BK viral reactivation, usually has a benign clinical course, and responds briskly to modification of IS therapy, without jeopardizing the graft survival [62, 106].
Urinary shedding of BKPyV and JCPyV (viruria) was studied in a small but a longitudinal study of 41 kidney and 33 liver transplant recipients. Polyomaviral shedding was more common in liver than kidney recipients. Among these, JCV was more common in liver recipients, and JCV viral loads were much higher than those of BK viruria in both the liver and kidney recipients [106]. The role of JC viruria in recipients of kidney transplants is more often associated with better outcomes than either BK or combination of BK and JC viruria [62].
HLA Mismatch and HPyV Disease
Risk of HLA mismtach (HLA-MM) and HLA mismatch (MM) and BKPyV disease, Drachenberg et al. correlated the relationship of HLA mismatch (MM) and BKPyN and graft loss; those with higher degrees of HLA-MM with polyoma disease were at increased risk for graft loss compared to those with lower degrees of HLA-MM [107]. The exact impact of this correlation has not been well established, but raises an intriguing question, if HLA-MM [108, 109] and ABO incompatibility [110] may be associated with more severe form of BK disease as a consequence of more intense IS therapy or is it that HLA-MM exposes tubular cells to immune damage by innate immunity and thereby tubular epithelial cell injury triggers intense BKPy viral replication and intense epithelial cell inflammation [111]. The association of HLA-MM and the development of BK- or JCPyV need more evaluation.
Retransplantation and Role of Transplant Nephrectomy Following Graft Failure Due to BKPyN
Retransplantation following graft loss due to BKPyV disease remains a cause for concern due to the anxiety related to the potential possibility of recurrence of PyV disease in the new graft. Retrospective study compiled data on adult patients undergoing repeat transplantation after previous loss of allograft to PyBKVN from six US centers. A total of 31 patients underwent retransplantation after a median of 6 months after failure of the first allograft, 10 of these underwent preemptive retransplantation. Twenty-six patients had documented clearance of viremia. Only 13 underwent transplant nephrectomy before the retransplantation. Following repeat transplant, 11 (35 %) had BKV replication in urine and plasma with two patients experiencing BKVN. Seven patients developed acute rejection [112].
Other reports also support the notion that retransplantation can be successfully performed following loss of allograft due to PyV disease but with a caution that such patients should have undetectable or very low viremia/viruria at the time of retransplantation. Viremia should be monitored more frequently in the post-transplant period [113, 114].
Nonrenal Solid Organ Transplantation and BKPyV Disease
BKPyV replication may occur anytime in the post-transplant period; recent studies have demonstrated that a trend peaks during the first 3–6 months post-transplantation, though it is not unusual to develop late reactivation past first year after transplantation. On the contrary, BKPyV reactivation in recipients of other solid organ transplants usually develops in the later years after transplantation.
The overall frequency of BKV viruria, in non-kidney SOT recipients, is variable at rates, and even in those SOT recipients such as lung recipients, the frequency of activation is far lower than recipients of kidney transplants [117]. Studies in recipients of other solid organ transplants such as the liver, heart, and pancreas alone demonstrated a lack of correlation between viremia, viruria, and renal dysfunction [118–121]. Therefore, general screening is not recommended. Biopsy-confirmed PyV disease affecting the native kidneys is based on a few case reports [106, 122, 123].
In summary, BK or JC viruria may develop in more than 10 % of recipients with nonrenal solid organ transplantation (NRSOT); its impact on the development of renal dysfunction in such patients is far from proven [124]. Hence screening for PyV reactivation should be limited to those who have new-onset renal dysfunction following SOT.
Other Systemic Diseases Associated with HPyV Reactivation
Progressive Multifocal Leukoencephalopathy
It is a demyelinating disease of the central nervous system caused by the neurotropic human polyomavirus (JCPyV) that results in lytic infection of oligodendrocytes. PML was first described as a complication of lymphoproliferative disorders more than 50 years ago and emerged as a major complication of HIV infection in the 1970s [4].
Despite the ubiquity of this virus, PML is rare and always seen in association with an underlying immunosuppressive state, such as HIV infection, autoimmune diseases, cancer, and organ transplantation. JCV remains quiescent in the kidneys as well as oligodendrocytes, where it displays a stable archetypal noncoding control region (NCCR). Conversely, rearranged JCV NCCRs, including tandem repeat patterns found in the brain of PML patients, have been associated with neurovirulence. The specific sites and specific sites and mechanisms of JCV NCCR transformation remain yet to be explored. PML has been reported among the heart, kidney, and liver transplant recipients, but its true incidence in these patient groups is not known [125, 126].
Skin Manifestations
Trichodysplasia Spinulosa
Trichodysplasia spinulosa (TS) is a skin disease due to TSPyV reactivation. It is characterized by (1) history of organ transplantation and/or drug-induced immunosuppression, (2) eruptive follicular papules with spiny excrescences concentrated in the central face with spread to trunk and extremities, and (3) alopecia of varying degrees.
The histopathologic findings are distinctive and include distended hair follicles containing sheets of eosinophilic cells and the presence of viral inclusions on ultrastructural examination, along with molecular confirmation of polyomavirus in the lesions of trichodysplasia spinulosa [129]. Treatment includes supportive therapy along with the general principle of reduction in maintenance IS therapy and careful monitoring of allograft function and skin lesions.
Merkel Cell Skin Cancer (Merkel Cell Cancer)
Merkel cell cancer (MCC) in the immunocompromised host is invariably due to reactivation of MCPyV [6, 106]. MCC arises most often on sun-exposed areas and is more common in fair-skinned people, but not uncommon in other colored people especially if immunocompromised.
It derives its name from the similarity of these cancer cells to normal Merkel cells in the skin that were first described over 100 years ago by Friedrich Sigmund Merkel. MCC in the immunocompromised host is more often due to MCPyV infection [130]. It is now diagnosed more easily due to the availability of special stain (CK20) that differentiates it from other types of skin cancers.
Merkel cell carcinoma usually appears as a firm, painless lesion on a sun-exposed area. These tumors are typically red, blue, or skin-colored and vary greatly in size at the time of first presentation. The major challenge of MCC is that it oftentime presents with spread to local lymph nodes; therefore, sentinel node biopsy is an essential part of diagnosis and management.
Treatment is mostly along the principles that include reduction in the intensity of IS therapy, surgical excision of the primary lesion along with any nodes that are involved with MCC, radiation therapy, as well as chemotherapy if nodes are positive. Overall, the 5-year survival rate is about 60 %, though it can be higher if MCC is diagnosed before local invasion.
BKPyV-Associated Hemophagocytic Syndrome
Hemophagocytic syndrome is a rare symptom complex that can develop due to PyV reactivation. Constellation of signs and symptoms of hemophagocytic syndrome includes fever of unknown origin, pancytopenia, and increased levels of lactate dehydrogenase, ferritin, triglycerides, and alanine aminotransferase in the setting of negative bacterial or viral etiology. Several case series of hemophagocytic syndrome due to PyV reactivation have been described by several authors [131, 132]. Early diagnosis is critical since management is simply supportive in combination with early withdrawal of IS therapy and careful monitoring for allograft rejection. If recognized early, it is often associated with resolution of symptoms with prompt discontinuation of IS therapy.
BKPyV-Associated Multisystem Disease
Single case report illustrates that reactivation of HPyV can result in systemic illness, leading to multiorgan failure. During the epidemic of AIDS, BKPyV reactivation was demonstrated with the development of nephritis, retinitis, as well as meningoencephalitis [133, 134]. Additionally, BKPyV reactivation was associated with development of life-threatening pneumonia following bone marrow transplantation [135]. Although tissue tropism is well defined for different types of polyomavirus, a recent report of endothelial invasion with BKPyV illustrates that polyomaviruses in the immunocompromised host could lead to fatal dissemination [136]. Whether changes in tissue tropism is due to mutational changes in BKPyV remains to be proven.
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