EDITORIAL STAFF EDITORIAL BOARD Rafał Krenke, MD, PhD Warsaw, Poland EXECUTIVE EDITOR Franciszek Kokot, MD, PhD Eugeniusz J. Kucharz, MD, PhD Grzegorz Gajos, MD, PhD Katowice, Poland (Co-Chair) Katowice, Poland Roman Jaeschke, MD, MSc STATISTICAL CONSULTANT Jan Kulpa, MD, PhD Hamilton, ON, Canada (Co-Chair) Agnieszka Pac, PhD Kraków, Poland Małgorzata Bała, MD, PhD Jolanta Małyszko, MD, PhD MANAGING EDITOR Kraków, Poland Białystok, Poland Maria Piasecka, PhD MD, PhD Tomasz Brzozowski, Jacek Musiał, MD, PhD MANUSCRIPT EDITING Kraków, Poland Kraków, Poland Małgorzata Kurowska Flavio Coceani, MD Paul O'Byrne, MD, PhD Małgorzata Wiesner-Spyrczyńska Pisa, Italy Hamilton, ON, Canada Deborah Cook, MD, PhD SOCIAL MEDIA EDITOR Grzegorz Opolski, MD, PhD Hamilton, ON, Canada Zbigniew Heleniak, MD, PhD Warsaw, Poland Mark Crowther, MD, MSc, FRCPC Ralf Paschke, MD, PhD DTP Hamilton, ON, Canada Calgary, Canada Tomasz Śmigla Stanisław Czekalski, MD, PhD Marek Sanak, MD, PhD ADDRESS Poznań, Poland Kraków, Poland Cholerzyn 445 Anna Członkowska, MD, PhD Holger Schünemann, MD, PhD 32-060 Liszki, Poland Warsaw, Poland Hamilton, ON, Canada phone: +48 12 293 42 20 fax: +48 12 293 40 10 James Douketis, MD, FRCPC Tomasz Stompór, MD, PhD email: [email protected] Hamilton, ON, Canada Olsztyn, Poland www.mp.pl/paim Józef Drzewoski, MD, PhD Krzysztof Strojek, MD, PhD Łódź, Poland Copyright by Medycyna Praktyczna, Katowice, Poland Kraków 2019 Artur Dziewierz, MD, PhD Michał Tendera, MD, PhD Kraków, Poland Katowice, Poland PUBLISHER Piotr Głuszko, MD, PhD Medycyna Praktyczna Anetta Undas, MD, PhD Warsaw, Poland Kraków, Poland INDEXED IN Gordon Guyatt, MD, PhD Jadwiga Wedzicha, MD, PhD Chemical Abstracts Service (CAS), Hamilton, ON, Canada London, UK Crossref, Database of Abstracts of Andrzej Januszewicz, MD, PhD Reviews of Effects (DARE), EBSCO, Albert W. Wu, MD, PhD Warsaw, Poland EMBASE, GENAMICS, Geneva Baltimore, USA Foundation Free Medical Journals, Barbara Jarząb, MD, PhD Krystyna Zawilska, MD, PhD Index Copernicus (IC), J-Gate, Master Gliwice, Poland Poznań, Poland Journal List, MNiSW, National Library Wiesław W. Jędrzejczak, MD, PhD Irena Zimmermann-Górska, MD, PhD of Medicine (NLM), Polish Medical Warsaw, Poland Poznań, Poland Library (GBL), PubMed/MEDLINE, Irina Kowalska, MD, PhD Science Citation Index Expanded (SCI-Ex), Dorota Zozulińska-Ziółkiewicz, MD, PhD Białystok, Poland SciFinder, Scopus, TUMS Digital Library, Poznań, Poland Web of Science Core Collection

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MONTHLY VOL. 129 (Special Issue 3) 2019

ABSTRACT

PART I GENERAL OVERVIEW OF MAJOR VIRAL INFECTIONS

7 Cytomegalovirus 10 BK virus 14 Epstein–Barr virus 15 Influenza 16 Hepatitis C virus 17 HIV 21 Human papilloma virus

PART II SPECIFIC ISSUES IN MANAGEMENT OF VIRAL INFECTIONS IN TRANSPLANT RECIPIENTS

23 Viruses versus myocarditis and acute coronary syndromes 24 Viruses and kidney transplant eligibility 25 Treatment of hepatitis B virus infection in transplant recipients 27 Viral infections in kidney and upper extremity transplant recipients 28 Histological diagnosis of BK virus and cytomegalovirus infections 29 Viral diarrhea 29 Ground glass opacification

PART III COMMENTARY

35 The art of immunosuppression in liver transplantation: personal reflections based on a 40-year career

ABSTRACT

The 3 leading causes of death in patients after sol‑ Immunosuppressive treatment impairs the im‑ id organ transplantation (SOT) include cardiovas‑ mune function, which renders the patient more cular diseases, malignancies, and infections. Ac‑ susceptible to infections. Furthermore, treat‑ cording to our current understanding, the latter ment of infections in immunocompromised pa‑ play the key role in the pathogenesis of athero‑ tients poses a challenge and SOT. sclerosis. Similarly, infections (mainly viral) are The current publication provides a brief summa‑ implicated in the pathogenesis of at least 20% of ry of the key information provided in 20 lectures known neoplasms. In other words, the implica‑ on viral infections in patients after SOT delivered tions of acute and chronic infectious diseases in during the 9th Practical Transplantology Course in modern medicine, not only transplantology, are Warsaw, Poland on September 15–16, 2017. significant and ever­­‑increasing.

PART I

General overview of major viral infections

Krzysztof Mucha1,2*, Bartosz Foroncewicz1*, Alicja Dębska­‑Ślizień3, Magdalena Durlik4, Ryszard Grenda5, Andrzej Horban6, Piotr Fiedor7, Magdalena Krajewska8, Artur Kwiatkowski7, Jan Lerut1,9, Jacek Małyszko10, Jolanta Małyszko11,12, Piotr Przybyłowski13,14, Krzysztof Zieniewicz15, Michał Ciszek1, Dorota Kamińska9, Maciej Kosieradzki8, Agnieszka Perkowska­‑Ptasińska5, Justyna Czerniawska16, Dominika Dęborska5, Radosław Kwieciński14, Magdalena Kwapisz8, Barbara Moszczuk1, Leszek Pączek1,2 1 Department of Immunology, Transplantology and Internal Diseases, Medical University of Warsaw, Warsaw, Poland 2 Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland 3 Department of Nephrology, Transplantology and Internal Medicine, Gdańsk Medical University, Poland 4 Department of Transplantation Medicine, Nephrology and Internal Diseases, Medical University of Warsaw, Poland 5 Department of Nephrology, Kidney Transplantation and Hypertension, The Children’s Memorial Health Institute, Warsaw, Poland 6 Department for Adult’s Infectious Diseases, Medical University of Warsaw, Poland 7 Department of General and Transplantation Surgery, Medical University of Warsaw, Poland 8 Chair and Department of Nephrology and Transplantation Medicine, Wrocław Medical University, Wrocław, Poland 9 Starzl Unit Abdominal Transplantation, University Hospitals Saint Luc, Université Catholique de Louvain, Brussels, Belgium 10 1st Department of Nephrology and Transplantology with Dialysis Unit, Medical University of Białystok, Białystok, Poland 11 2nd Department of Nephrology and Hypertension with Dialysis Unit, Medical University of Bialystok, Białystok, Poland 12 Department of Nephrology, Dialysis and Internal Diseases, Medical University of Warsaw, Warsaw, Poland 13 1st Chair of General Surgery, Jagiellonian University, Medical College, Kraków, Poland 14 Silesian Center for Heart Diseases, Zabrze, Poland 15 Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland 16 Department of Radiology, Medical University of Warsaw, Poland

Cytomegalovirus infection Immune response to cy- termed “a 40­­‑day fever”, due to an increase of tomegalovirus in solid organ transplant recipient Cy‑ body temperature with the onset on day 40 fol‑ tomegalovirus (CMV) is one of the most common lowing transplantation, present in most cases. opportunistic pathogens in individuals with pri‑ Depending on the transplanted organ, CMV in‑ mary or secondary immunodeficiency, such as fection may present as: a) bronchiolitis obliter‑ organ transplant recipients. Prior to the intro‑ ans syndrome or interstitial pneumonia, some‑ duction of ganciclovir (GCV), which is common‑ times leading to respiratory failure, b) esophagi‑ ly used nowadays, CMV pneumonia caused 50% tis resembling Candida infection, c) colitis with mortality in kidney transplant (KTx) recipients persistent diarrhea, d) heart failure, or e) vanish‑ and over 80% mortality in bone marrow trans‑ ing bile duct syndrome. Furthermore, biochem‑ plant recipients.1,2 With advances of medical sci‑ ical signs of transplanted organ failure are often Correspondence to: ences, detection and treatment of disseminated present, such as elevated serum creatinine levels Krzysztof Mucha, Department of CMV infection have become easier. Currently, di‑ in patients after KTx. Immunology, Transplantology and Internal Diseases Medical University agnosis of CMV infection involves genetic testing of Warsaw, Nowogrodzka 59, along with serology methods. The effect of CMV Risk factors The risk of CMV infection varies be‑ 02-006 Warszawa, Poland, infection on organ transplant recipients, especial‑ tween the organs mostly due to the differences in phone: +48 22 502 16 41, ly the immunomodulatory effect of CMV, has not lymphatic tissue content. With no prophylaxis, email: [email protected]; Bartosz Foroncewicz, Department been fully elucidated. New knowledge should be the highest incidence is seen in lung and pancreas of Immunology, Transplantology applied to developing safer prevention and treat‑ transplant recipients (50%–75% and almost 50%, and Internal Diseases ment standards. respectively). In kidney, liver, or heart transplant Medical University of Warsaw, Nowogrodzka 59, 02-006 Warszawa, recipients, the incidence of CMV infection rang‑ Poland, phone: +48 22 502 16 41, Clinical presentation CMV infection may present es between 10% and 30%, just as it is in alloge‑ email: bartosz.foroncewicz@wum. as flu­­‑like symptoms, with fever, chills, and mus‑ neic bone marrow recipients (30%).3 edu.pl cle aches, as well as leuko- and thrombocytope‑ Seronegative recipients of organs from seropos‑ Conflict of interest: none declared. *KM and BF contributed equally to nia and elevated liver enzyme levels seen in lab‑ itive donors are known to have the highest risk of sections I and II. oratory test results. The condition was initially CMV infection. As mentioned earlier, a primary

PART I General overview of major viral infections 7 infection can have a very severe course; therefore, 30% risk in seropositive individuals. Therefore, it in cases of serological mismatch between the do‑ seems that the CMV infection itself does not in‑ nor and the recipient, prophylaxis based on GCV crease the risk of malignancy but is rather a co‑ should be used. factor in a complex process. This conclusion is Another risk factor is immunosuppression (IS) supported by the report indicating that the inci‑ protocol, in particular induction with antilym‑ dence of malignancies in KTx recipients may be phocyte therapies, for example, antilymphocyte associated with the number of HLA mismatch‑ globulin.4 Everolimus­­‑based IS regimens are con‑ es and CMV mismatch between the donor and sidered to carry a lower risk of infection reacti‑ the recipient.13 vation as compared with those based on, for ex‑ ample, calcineurin inhibitors.5 Immune tolerance CMV infection does not al‑ There are data suggesting that the human leu‑ ways adversely affect patients, as seen, for exam‑ kocyte antigen (HLA) matching status affects ple, in bone marrow transplant recipients. Simi‑ the incidence of CMV infections. Furthermore, larly, the γδ T cells, known to induce operational the degree of HLA matching and reduction of tolerance, were shown to be involved in the late CD8+ T­­‑lymphocyte count are important risk fac‑ acute rejection of liver transplant (LTx), which tors of graft loss due to CMV infection.6 It is also is a new finding. Interestingly, the population of true for children after bone marrow transplant, the γδ T cells increases after primary CMV infec‑ in whom HLA mismatch was associated with in‑ tion, which is potentially associated with a low‑ creased rates of new­­‑onset CMV infection or its er acute rejection rate. This, however, was only reactivation. Further research will help deter‑ confirmed in patients after LTx.14 Favorable char‑ mine whether individual alleles, such as HLA­­‑B44, acteristics of the γδ T cells include their almost significantly modify the risk of CMV infection.7 complete lack of alloreactivity, a very wide spec‑ trum of cancer­­‑associated ligand recognition, or Long­­‑term prognosis Cardiovascular diseases Car‑ acting as a triggering factor for dendritic cell mat‑ diovascular diseases are one of the leading causes uration. Unfortunately, the same cells also trig‑ of mortality in transplant recipients. Patients ger endothelial immune response, which is the ba‑ with known hypertension were shown to be CMV­­ sic mechanism of antibody­­‑mediated rejection in ‑seropositive with higher CMV DNA load twice KTx.15 This means that our current knowledge is as often as healthy recipients.8 In a study assess‑ not sufficient to fully utilize their potential ben‑ ing different risk factors of hypertension, such eficial effect. as age, male sex, hyperlipidemia, body mass in‑ dex, or diabetes, only seropositive CMV status, Prophylaxis Pretransplant CMV serologic status CMV DNA load, and miRNA­­‑UL112 expression in donors (D) and recipients (R) is used for strat‑ significantly increased the risk of hypertension. ifying the overall risk of infection. D+/R– mis‑ match is high, while D±/R+ is a moderate risk Malignancies CMV alters the immune response by factor. R+ status itself is a risk factor for the re‑ producing interleukin (IL)-10 homologue, which activation of latent infection. D–/R– status is “blinds” the immune system. Indirectly, it also not a risk factor provided that blood products, increases the production of vascular endothe‑ administered during the transplant surgery, are lial growth factor, which promotes carcinogen‑ screened for CMV and are leukodepleted.16 Uni‑ esis. Furthermore, inhibiting cyclooxygenase 2 versal prophylaxis with oral valganciclovir (VGCV) involved in signal transduction to vascular en‑ is currently the most common protocol against dothelial growth factor resulted in decreased in‑ CMV infection.16,17 The optimal duration of pro‑ cidence of malignancies in animal models.9 How‑ phylaxis varies between 3 and 12 months, de‑ ever, data on humans are conflicting. On one pending on the risk level and the transplanted hand, a prospective study of CMV­­‑positive pa‑ organ. Its duration should increase along with tients demonstrated a significantly shorter time the risk. The recommendations are presented in from transplantation to the onset of malignan‑ TABLE 1. The incidence of CMV infection in high­­ cy than CMV­­‑negative individuals.10 On the oth‑ ‑risk patients decreases along with the increas‑ er hand, a study was published which not only ing duration of prophylaxis.16 The alternative op‑ failed to confirm such association, but actually tion is a preemptive therapy, based on regular refuted it.11 The association between CMV sta‑ viral load monitoring and early introduction of tus and the risk of posttransplant lymphoprolif‑ anti–CMV therapy in relevant cases. Currently, erative disease (PTLD) has not been unequivocal‑ universal prophylaxis is used more commonly, ly established, and an analysis of over 22 000 pa‑ as a more simple and effective strategy.16 There tients after different transplants did not confirm is also a “hybrid” approach, used mainly in high­­ the association between CMV status and the in‑ ‑risk patients, which includes initial prophylaxis cidence of malignancies.12 Data on bone mar‑ continued for the first 3 to 6 months after trans‑ row recipients makes the analysis of CMV effect plantation, followed by the secondary preemp‑ on carcinogenesis even more complex. The sero‑ tive protocol thereafter. VGCV is typically used negative status of both the donor and the recip‑ at a dose of 900 mg/d; however, there are data to ient is associated with 40% risk of recurrence of confirm the efficacy of half the dose (450 mg/d) in acute myeloid leukemia, as compared with only adult transplant recipients.18 Dosing in children

8 POLISH ARCHIVES OF INTERNAL MEDICINE 2019; 129 (Special Issue 3) TABLE 1 Recommended duration of cytomegalovirus infection prophylaxis, based on ganciclovir (intravenous)/ valganciclovir (oral), depending on risk stratification and transplanted organ17

Status of Duration of prophylaxis Comments D/R risk Kidney Liver Heart Pancreas Lung Islets Intestine D+/R– ≤6 months 3–6 3–6 months 3–6 monthsb Polyclonal induction may prolong a high months ≥6 months 3 months the need for prophylaxis. ≥6 monthsa,b D+/R+ 3 months 3 months 3 months 3 months Polyclonal induction may prolong D–/R+ ≥6 months 3 months the need for prophylaxis. moderate 6 monthsa D–/R– –c –c –c –c Blood products transfused at the time low of transplantation must be screened for CMV and leukodepleted. a In children ≤12 months b Adding anti–CMV antibodies suggested in children c Regular CMV monitoring in children

Abbreviations: CMV, cytomegalovirus; D, donor; R, recipient is determined using a special formula.19 There are virus replication in asymptomatic recipients, vi‑ data on the beneficial effect of IS including mTOR ral testing should be repeated regularly following inhibitors (everolimus) on lowering the risk of transplantation. There are no specific guidelines CMV infection (in combination with regular pro‑ on the threshold value of CMV DNA load for com‑ phylaxis). The underlying mechanism is based on mencing treatment. Considering variable assay the involvement of the mTOR pathway in CMV methodology and difficulties in achieving consis‑ replication.20 Overall, medical anti–CMV prophy‑ tent results that would conform to the 1st Inter‑ laxis is an inevitable part of early posttransplant national Standard by the World Health Organiza‑ management, required in patients at moderate or tion (WHO), a threshold for intervention should high risk of CMV infection. be determined separately for each laboratory. The other strategy is treatment of symptom‑ Treatment Antiviral medications approved by atic CMV infection or CMV disease. In adult KTx the US Food and Drug Agency, which are includ‑ recipients with severe course of CMV disease and ed in the guidelines on treatment of CMV in pa‑ in all children with CMV disease, regardless of its tients after SOT, include: clinical course, treatment with intravenous GCV 1 Gancyclovir (GCV), an intravenous nucleoside is indicated.16,21 GCV or VGCV can be used in adult analogue and its prodrug—oral L­­‑valyl GCV es‑ KTx recipients with CMV disease of a milder clin‑ ter (VGCV). It is phosphorylated by a viral kinase ical course. Treatment should be continued for and cellular kinases to GCV triphosphate, which at least 2 weeks until the symptoms have resolved, competitively inhibits deoxyguanosine triphos‑ and virus eradication has been confirmed in 2 sub‑ phate incorporation into DNA by viral DNA poly‑ sequent assays. During treatment, viral load should merase. As a result, it induces chain termination be monitored every 7 days to assess treatment re‑ or limits chain elongation. sponse. Additionally, kidney function (of the trans‑ 2 foscarnet, an intravenous pyrophosphate an‑ planted kidney in KTx recipients or own kidneys alogue, which inhibits viral DNA polymerase. in recipients of other SOTs) should be monitored, 3 cidofovir, an intravenous nucleotide analogue, so as to adjust the dosage to the current estimat‑ which inhibits viral DNA polymerase in a mecha‑ ed glomerular filtration rate. GCV administered nism similar to the one of GCV. for 2 to 3 weeks clears the virus in 90% of cases. Pharmacological armamentarium of contro‑ The recurrence rate in primary infection is 65%, versial efficacy, considered experimental or ‑al and 20% in seropositive recipients. ternative CMV treatments, include: leflunomide, Another essential element of CMV treatment anti–CMV hyperimmunoglobulin, polyvalent im‑ is adjusting immunosuppressive therapy. Dose munoglobulins, artesunate, and cyclopropavir. reduction or temporary discontinuation of an‑ timetabolites are indicated in patients with con‑ Therapeutic strategies One of the therapeutic firmed, intensive viral replication, leukopenia, strategies in CMV infection is preemptive treat‑ and severe CMV disease. The data on the dos‑ ment, that is, treatment of asymptomatic CMV age of calcineurin inhibitors remain unequivo‑ infection, which is practically started as soon cal. There are case reports to suggest a beneficial as CMV DNA load has been confirmed, before role of mTOR inhibitors on decreasing the inci‑ the onset of any clinical symptoms.16,21 To confirm dence of CMV disease.

PART I General overview of major viral infections 9 TABLE 2 Risk factors for genetic resistance In the first patient, the onset was at 3 months D+/R– serologic status following OHT. The infection was detected during a routine follow­­‑up and the treatment was start‑ Multiple weeks of drug exposure with continued CMV DNA replication ed immediately. Initially, VGCV was administered, Very high CMV DNA load at baseline and with no evidence of response, human immu‑ Subtherapeutic drug concentration due to too low dose and/or malabsorption or noglobulin G containing a high amount of anti‑ impaired drug metabolism body to CMV was administered. CMV reactivation In the second patient, the onset was 2 years fol‑ Thoracic organ transplant lowing OHT and the general practitioner as well as Strong immunosuppression the consultant in an internal diseases ward at the local hospital, did not include CMV infection in Noncompliance the differential diagnosis, considering the clinical presentation. Unfortunately, empirical antibiot‑ Abbreviations: see TABLE 1 ic therapy was started without assessing its po‑ tential interactions with IS, and without assess‑ Over 90% of GCV­­‑resistant CMV isolates con‑ ing blood levels of immunosuppressants. The di‑ tain HCMV UL97 mutations. The HCMV UL97 agnosis was made in our transplant unit, where gene product, a protein kinase, is responsible for the patient was referred to after 3 months of vir‑ the phosphorylation of GCV in HCMV­­‑infected tually symptomatic, ineffective treatment, hav‑ cells. Less frequently, mutations can be found ing suffered from iatrogenic kidney failure along within the UL54- gene, which encodes the viral the way. GCV was used in combination with hu‑ DNA polymerase. Genetic drug resistance occurs man immunoglobulin G containing a high amount in 0.25% to 15.2% of treated SOT recipients, with of antibody to CMV. a mortality rate of 17% to 32%. If not caused by The course of the disease at its advanced stag‑ genetic mutations, GCV resistance may stem from es was severe and similar in both cases, with gas‑ severe immunodeficiency of a recipient or subop‑ troenteritis and bone marrow suppression. Fur‑ timum drug exposure.16,21 Risk factors for genet‑ thermore, patient 1 presented with resistance to ic resistance are presented in TABLE 2. GCV, as well as symptoms of severe foscarnet tox‑ GCV resistance should be suspected in nonre‑ icity, whereas administered anti–CMV antibod‑ sponders, recurrent CMV infection, and/or clin‑ ies were not fully effective, either. In patient 2, ical symptoms of CMV disease during treatment severe gastrointestinal symptoms predominat‑ continued for 6 weeks, especially if risk factors ed, including intestinal obstruction secondary to for resistance have been identified. IS should then paralytic ileus. Despite pp65‑negative­­ test results, be reduced to lowest possible doses and genet‑ the patient’s clinical condition deteriorated, and ic testing for the UL97 mutation should be re‑ he needed hemodiafiltration due to kidney fail‑ quested. If a mutation is confirmed, depending ure. The dose of GCV was reduced for the same on the locus and its effect on effective treatment reason, which caused the recurrence of the active with GCV, the dose may be increased. Alternative‑ infection. Both patients died eventually, which il‑ ly, foscarnet or cidofovir can be used. Unfortu‑ lustrates how dangerous CMV infection can be in nately, the latter option is limited in KTx recip‑ transplant recipients. ients by the risk of nephrotoxicity. In patients To sum up, when planning CMV prophylaxis with multiple drug resistance, immunoglobulin, and/or treatment, the following should be con‑ leflunomide, or artesunate can be used, although sidered: a) transplanted organ; b) CMV status clinical data regarding their efficacy appear con‑ of the donor and the recipient; c) IS protocol; d) troversial. Early data on brincidofovir in SOT re‑ number of HLA mismatches; e) γδ T subpopula‑ cipients did not support its efficacy against CMV tion (if possible); f) CMV strain, and g) individ‑ infection. Currently, clinical trials are pending of ual immune profile of a given patient. Further maribavir or letermovir in SOT recipients. CMV­­ research is needed to fully characterize interac‑ ‑specific ­­‑cellsT are currently evaluated in patients tions between latent CMV infection and human after hematopoietic stem cell transplantation as immune system (FIGURE 1).22 part of clinical research. BK virus Definition and clinical presentation BK Severe refractory cytomegalovirus infection in heart trans- virus (BKV) is a member of the polyomavirus plant recipients There are data supporting the use family. All polyomaviruses are structurally simi‑ of foscarnet in heart transplant recipients with lar, with similar capsid size and high genetic ho‑ confirmed drug resistance. Here, we present 2 mology. The name of the virus originates from case reports of orthotopic heart transplantation the initials of the KTx recipient with ureteral stric‑ (OHT) recipients, both in a serious clinical condi‑ ture, in whom the virus was first isolated from tion at baseline. None of them needed mechani‑ urine in 1971.23 cal ventilation prior to surgery. CMV prophylaxis BKV infection is a relatively common ear‑ was not used either, as both donor and recipient ly complication and an important contribu‑ pairs were seronegative. Typical 3­­‑drug IS proto‑ tor to the dysfunction of the transplanted kid‑ col, based on tacrolimus (TAC), mycophenolate ney. As latent virus is reactivated in uroepithe‑ mofetil (MMF), and glucocorticoids, was used. lial cells, BKV­­‑associated nephropathy (BKVAN)

10 POLISH ARCHIVES OF INTERNAL MEDICINE 2019; 129 (Special Issue 3) time Treatment CLINICAL EFFECT +Immunosuppression Immune-deficiency in recipient Concomitant diseases + +/−

↑↓ T lymphocytes Inborn Prophylaxis RESPONSE CMV strain Cell-mediated immunity CMV gene expression (organ-specific) Differences in: a) b) c) Nonspecific • Monocytes • Dendritic cells Specific • NK cells • Antibodies Summary of factors considered when deciding about the prophylaxis or treatment cytomegalovirus (CMV) infection

Tx FIGURE 1 

PART I General overview of major viral infections 11 TABLE 3 Risk factors for BK virus–associated nephropathy

Donor­‑specific Recipient­‑specific Procedure­‑specific Virus­‑specific • Number of HLA • Older age • Cold ischemia time • Polymorphisms of mismatches • Male sex • Delayed graft function the polyomavirus major capsid protein gene • Deceased donor • Some HLA loci (absence • Graft origin (deceased/ a VP1 and the non­coding • Seropositive donor with of HLAC7 in a donor and/ living donor) control region high BKV­‑specific antibody or recipient triples the risk • Quality and intensity sequences. titer, suggestive of recent of BKV reactivation in of IS treatment (acute exposure a recipient) graft rejection and its • Presence of the virus in • Ureteral injury treatment) the transplanted organ • Diabetes • Ureteral stenting • Female sex • No or low activity of BKV­‑specific T cells (important especially in children due to possible primary infection), but also individual (genetic and epigenetic) differences in response to IS and genetic variability of BKV.

a Animal research demonstrated that virus replication was accelerated in injured kidneys.

b Total immunosuppressive load is the key determinant, although antithymocyte globulin, mycophenolate mofetil, and tacrolimus were also mentioned as important.

Abbreviations: BKV, BK virus; IS, immunosuppression

develops, which affects 5% to 10% of KTx recip‑ Viral load determination has a low predictive ients. The BKVAN‑associated­­ risk of graft loss value. According to the guidelines, urine cytolo‑ within 2 years following virus identification is gy (decoy cells) or urinary VP1‑mRNA­­ titer mea‑ high (15%–50% of cases). Other complications surement may be performed as screening tests. of BKV infection include ureteral stricture seen If positive, a test should be repeated within 4 in KTx recipients and hemorrhagic cystitis seen weeks, while the presence of one of the follow‑ in hematopoietic stem cell transplantation recip‑ ing findings constitutes an indication for kidney ients. Other possible manifestations affect respi‑ biopsy, which confirms the diagnosis: a) urinary ratory, gastrointestinal, and central nervous sys‑ BKV DNA >107 copies/ml; b) urinary V1mRNA tems. BKV is known for its oncogenic effect.24 >6.5 × 105 copies/total mRNA, or c) blood BKV Its replication initiates a cascade of events lead‑ DNA >104 copies/ml. It is recommended to per‑ ing to cell lysis and viruria. The virus replicates form screening at least once a month over the first in the interstitial cells, passes to the tubular ves‑ 3 to 6 months following transplantation and then sels, which clinically manifests as viremia. Later, every 3 months until the end of year 1, plus ev‑ it causes tubulointerstitial injury, which leads to ery time with elevated creatinine levels or acute BKVAN. However, not each virus reactivation graft rejection (or both). leads to this type of nephropathy. Therefore, both The cornerstone of BKV infection and BK‑ viruria and viremia indicate the risk of nephropa‑ VAN therapy is to minimize IS.25 According to thy, yet do not confirm its presence. On the other the 2010 Kidney Disease: Improving Global Out‑ hand, BKV is confirmed in blood samples of most comes guidelines, IS should be reduced with BKV patients with active nephropathy. load over 10 000 copies/ml (107 copies/l). It should Research has demonstrated a number of risk involve halving the MMF dose and reducing cal‑ factors for BKVAN, dividing them into donor-, cineurin inhibitor (CNi) doses, so that the serum recipient-, procedure-, or pathogen­­‑specific, as cyclosporine A (CsA) level does not exceed 60 to presented in TABLE 3. 100 ng/ml and the serum TAC level does not ex‑ It is still unknown whether BKVAN is caused ceed 3 to 5 ng/ml. MMF should be discontinued by the reactivation of a latent infection or wheth‑ in cases of persistent viruria. er it is caused by suprainfection with polyomavi‑ The alternative strategy assumes an initial re‑ ruses transmitted from the donor. Research has duction of the CNi dose by 25% to 50%, followed demonstrated that donor assessment for BKV by reducing the MMF dose by half and further may decrease the risk of BKVAN in KTx recipients. reductions until discontinued. TAC can also be replaced with CsA, which additionally decreases Diagnosis and therapeutic recommendations Cur‑ the MMF level, whereas CNi can be replaced with rently, preventive monitoring of the recipient is mTOR inhibitor. However, this approach has indicated, which is the key in detecting reactiva‑ not been supported by research findings. Simi‑ tion of latent infection and preventing its clini‑ larly, oral prednisone dose should be reduced to cal consequences. The diagnosis of BKV is based 5 mg/d, whereas creatinine levels should be re‑ on serology testing. assessed every 1 to 2 weeks, and viral load, every

12 POLISH ARCHIVES OF INTERNAL MEDICINE 2019; 129 (Special Issue 3) BKV

TNFα TNFαR1 TNFαR2

Human collecting duct epithelial cells

Inflammatory response: • Increased IL-6, IL-8 and RANTES expression siRNA: • Tubular damage TLR1, RIG-I • Interstitial nephritis

FIGURE 2 Tumor necrosis factor (TNF)/TNF receptor (TNFR) system involvement in BK virus (BKV)-associated nephropathy.27 BKV may downregulate TNF­­‑α and upregulate both TNFα­­ R1 and TNFα­­ R2 in human collecting duct epithelial cells. Such a response could be effectively blocked by small interfering RNA (siRNA) to toll­­‑like receptor 1 (TLR1) and retinoic acid inducible gene­­‑I (RIG­­‑I), 2 double­­‑stranded RNA receptors of the innate immune system.28 Abbreviations: IL, interleukin; RANTES, regulated on activation, normal T­­‑cell expressed and secreted

2 to 4 weeks. Regardless of the treatment ap‑ impaired in patients with confirmed BKV replica‑ proach, a rapid reduction of viral load improves tion and infection progressing to BKVAN.30 Im‑ or at least stabilizes the estimated glomerular portantly, allograft function in seronegative re‑ filtration rate. cipients was significantly better than in seropos‑ Despite the risk of increased alloactivation itive ones after effective treatment.31 This obser‑ and acute rejection, such management signif‑ vation strongly suggests that from the perspec‑ icantly decreases the risk of graft loss. Never‑ tive of allograft function it is better to prevent theless, studies with a longer follow­­‑up are still infection than to diagnose and treat. needed to assess the management strategies for To develop effective BKV preventative strate‑ chronic allograft dysfunction (chronic allograft gies, the risk factors should be identified and elim‑ nephropathy). inated. These include, for example, cold ischemia Although antivirals (cidofovir), antibiotics (flu‑ time and KTx from a deceased donor, which can‑ orochinolones), as well as leflunomide and intra‑ not be modified after transplantation. The risk venous immunoglobulins show some antiviral ac‑ of BKVAN increases with male sex and biopsy­­ tivity, their benefit in BKVAN has not been estab‑ ‑confirmed severe interstitial lesions, which can‑ lished yet. At the same time, they are associated not be modified, either. The only known modifi‑ with severe adverse effects. able risk factor is IS. The risk of early BKV infec‑ Future treatment options may include T­­‑cell tion (<6 months following KTx) was shown to in‑ immunotherapy (transfer of BKV­­‑specific T cells), crease the most in patients treated for acute re‑ which has demonstrated promising results in vi‑ jection (hazard ratio [HR], 3.5), with concomitant tro.26 Further research of BKV­­‑specific immune CMV replication (HR, 2.3) and those receiving IS response is necessary, as it may lead to the de‑ induction with T cell–depleting agents (HR, 1.9). velopment of effective treatments and vaccines The risk factors for late BKV infection (>6 months (FIGURE 2).27,28 following KTx) include chronic inflammation, After allograft loss due to BKVAN, retrans‑ repeat transplantation, presensitization, pres‑ plantation is possible unless the virus contin‑ ence of panel reactive antibodies, presence of do‑ ues to replicate. Transplant nephrectomy of al‑ nor specific antibodies, and previous infections.30 lografts lost due to BKVAN does not affect long­­ Undoubtedly, all these risk factors for early and ‑term treatment outcomes.29 late BKV infection are IS­­‑dependent. According to the available literature, it is a cumulative dose Impaired renal allograft function The 2 main end‑ of immunosuppressants rather than individual points in assessing the efficacy of KTx are recipi‑ agents that increases the risk of BKV infection. ent and allograft survival. While there is no signif‑ The main drugs used in KTx recipients are TAC icant effect of BKV infection on recipient surviv‑ and mycophenolic acid (MPA) derivatives. There al, allograft function and survival are significantly is no specific TAC dose suitable for all patients,

PART I General overview of major viral infections 13 and the discrepancies between the daily dose and of action as human IL­­‑10. Additionally, EBV trig‑ serum levels may be significant. There is, howev‑ gers the production of 17 viral miRNA, which af‑ er, a simple arithmetic parameter, referred to as fect cell proliferation and alter their apoptotic po‑ the concentration/dose (C/D) ratio, where D is tential. At the same time, EBV induces a genera‑ a daily dose of TAC, and C is its trough concentra‑ tion of host miRNA (147a and 155), which mod‑ tion measured at 12 hours following the last dose. ulate immune response.34-36 Thus, a patient who needs 10 mg of the drug to achieve a blood level of 10 ng/ml has a C/D ratio Diagnosis Virologic diagnosis is complex and de‑ of 1. Such patients were classified as intermedi‑ pends on the stage of infection. Historically, de‑ ate metabolizers. A C/D ratio exceeding 1 means tecting antibodies against virus­­‑specific antigens that even a small drug dose is sufficient to achieve was the first method to be used. The presence of its target concentration. Such patients are slow IgM antibodies against viral capsid antigen and metabolizers and have low risk of drug‑specific­­ Epstein–Barr nuclear antigens 1, 2 or 3 was to adverse effects. On the other hand, those with confirm active infection, whereas detecting im‑ a C/D ratio below 1 are fast metabolizers, and even munoglobulin G antibodies confirmed past infec‑ though they need high drug doses, they achieve tion without the ability to indicate how long ago low blood concentrations.32 These patients consti‑ the patient was infected. Obviously, antibody titer tute a group at particular risk of TAC nephrotox‑ and its increase mattered, as well. The detection of icity and BKV infection. Therefore, IS conversion the Epstein–Barr nuclear antigen was considered should be considered in each patient with a C/D a confirmation of viral DNA presence in cells.37 ratio below 1.32 It should also be noted that TAC However, serology methods have some seri‑ increases the exposure to MPA. The early phar‑ ous limitations. Antibody production follow‑ macokinetic research from the late 1990s demon‑ ing an exposure to an antigen may take days strated that when combined with TAC instead of or even weeks, which means that if an individ‑ CsA, a half dose of MPA was sufficient to achieve ual is tested directly following infection, then an identical area under the curve in a plot of MPA the virus is actively replicating itself and clinical concentration in blood vs time. This means that symptoms are likely to develop, whereas serol‑ some patients treated with TAC and MPA may be ogy test results remain negative. Immunocom‑ overexposed to MPA and need dose reduction. It promised patients are likely to have lower anti‑ was also demonstrated that high MPA dose upon body levels and their production will be slower. onset of BKV replication is an independent risk Also, in chronic kidney or liver disease there is factor of BKVAN.30 Furthermore, when used in an associated immune dysfunction, and aging al‑ combination with steroids, MPA was associat‑ ters specific antigen‑induced­­ serologic response. ed with significantly higher risk of BKV infec‑ As a result, these patients are poor responders tion and BKVAN than comparable treatment al‑ to both vaccination and infection. Newer diag‑ gorithms based on everolimus and CsA.33 There‑ nostic methods enable direct identification of fore, to minimize the risk of BKV infection, drug viral genetic material. Polymerase chain reac‑ exposure of patients treated with TAC and MPA tion (PCR) is used for detecting viral DNA, and derivatives should be monitored, with dose ad‑ real­­‑time PCR—for quantifying its copies. Clin‑ justments or conversion if feasible and clinical‑ ical samples may include serum (it determines ly justified. the free virus present in circulation), full blood (it determines the virus present in the immune Epstein–Barr virus Virus structure Currently, cells), or tissue specimens. For the latter, the in the name Epstein–Barr virus (EBV) is used in‑ situ hybridization can be used to stain and iden‑ terchangeably with human herpesvirus (HHV)- tify the virus, or alternatively, the technique de‑ 4. The latter originates from the fact that EBV is veloped by Epstein and Barr, including electron the 4th on the list of human herpesviruses which microscopic assessment of the specimens, can contain double DNA strand. EBV is highly infec‑ be applied. These 2 methods, however, are not tious and it enters the B cell using the CD21 com‑ routinely used in clinical diagnosis. Here, the re‑ plement receptor type 2. When viral DNA linear‑ sults of a study on next generation sequencing izes, replication and transcription occur, which should be mentioned, carried out in samples col‑ leads to the lytic phase ending with the break‑ lected from 8240 healthy individuals. The analy‑ down of an infected cell and release of a new gen‑ ses showed that 42% of them contained genet‑ eration of virions. When inside a cell, viral DNA ic material of 94 viruses (including 19 DNA vi‑ becomes a circular, extrachromosomal episome ruses). HHV­­‑4 (ie, EBV) was present in 14.45% and the virus is latent—the cell is infected, but of healthy population.38 its function is fairly stable. It turned out that These findings can be looked upon and inter‑ the virus is capable of manipulating the host im‑ preted differently. When assessed using serol‑ mune system, causing the effect referred to as ogy methods, 70% to 90% of all adults, includ‑ “immune evasion”. Two main mechanisms of this ing 14.5% of all healthy population carry genet‑ effect have been established. Firstly, the EBV ge‑ ic material of EBV in their lymphocytes. Unfor‑ nome contains a gene encoding a protein which tunately, it is impossible to determine the form closely resembles human IL­­‑10. Furthermore, vi‑ in which the virus is present in cells or the per‑ ral IL­­‑10 has an identical biological mechanism centage that undergoes replication.39

14 POLISH ARCHIVES OF INTERNAL MEDICINE 2019; 129 (Special Issue 3) Oncogenesis and other clinical sequelae Fifty years Drug‑induced­­ inhibition of DNA synthesis may ago, Burkitt and Epstein were the first to suggest cause adverse effects. All rapidly dividing cells the possibility of a causal relationship between in‑ quickly “sense” the presence of false adenine de‑ fections and malignancies. Currently, it is thought rivatives, which causes gastrointestinal and bone that 20% of malignancies are caused by only 7 vi‑ marrow adverse effects. Treatment of EBV infec‑ ruses, namely, EBV, human papillomavirus (HPV), tion as described above (ACV is typically used) is human T­­‑lymphotropic virus 1, hepatitis C virus usually effective. However, it only inhibits virus (HCV), hepatitis B virus (HBV), Kaposi’s sarcoma­­ replication rather than eradicates it completely. It ‑associated virus, and Merkel cell polyomavirus.40 should also be noted that such treatment is only Their epidemiology changes dynamically and due slightly effective (or plainly ineffective) in ma‑ to the changes in prevention and treatment strate‑ lignancies. Although the treatment inhibits vi‑ gies of HBV and HCV, the incidence of selected ma‑ rus replication, it does not affect the neoplastic lignancies may decrease. Unfortunately, the above disease itself. In immunocompromised patients, list includes EBV, for which there is currently no the possibility to reduce the dose of IS should al‑ vaccine and the available treatments are only part‑ ways be considered. Such patients may benefit ly effective. According to the WHO, EBV may be re‑ from human immunoglobulin therapy, although sponsible for 200 000 cases of malignancies each the effect will be significantly worse than the one year. Transplant recipients are at risk of PTLD, seen in CMV infection. which is a form of lymphatic malignancy and as such may be linked to viral infection. It should be Influenza Epidemiology Influenza is an acute noted that not all cases of PTLD are associated infectious respiratory disease caused by ortho‑ with EBV, and that EBV­­‑negative cases, albeit very myxoviruses known for their high antigenic vari‑ rare, were also reported.41,42 Currently, increasing‑ ability. There are 3 types of influenza virus (A, B, ly more data points to the involvement of EBV in and C), which are then subclassified according to the development of nasopharyngeal cancer, cer‑ the hemagglutinin (ha) and neuraminidase (n) vical cancer (along with HPV), as well as breast, subtype combinations, which are both immuno‑ prostate, and gastric cancer.43,44 genic surface antigens. The effect of EBV on the immune system causes The main route of transmission is human‑to­­ ­­ additional pathologies. EBV has been implicated ‑human via direct contact or the droplet route. in systemic lupus erythematosus and multiple In temperate climate zones, a seasonal increase sclerosis. In lupus, there are several causal mech‑ in the incidence of influenza is observed between anisms, particularly altered apoptosis of infected November and April. At the same time, every doz‑ B cells. In multiple sclerosis, EBV cooperates with en years highly virulent strains emerge, which another representative of the Herpesviridae fam‑ cause pandemic outbreaks. According to the Pol‑ ily, HHV­­‑6A, inducing abnormal response to my‑ ish National Hygiene Institute, the incidence elin proteins.45 Coinfection with 2 herpesvirus‑ rate of influenza in Poland is 8000 to 10 000 per es, for example, EBV and CMV or EBV and HHV­­ 100 000 population, with the mortality below ‑6 or HHV­­‑7, is common. It should also be noted 0.5% The annual incidence of influenza in trans‑ that the immune evasion is also induced by CMV. plant recipients is 1% to 4%.47 The clinical symp‑ Coinfection alters the course of the disease mak‑ toms manifest after an incubation period of 1 to ing it atypical and more severe, which poses a di‑ 3 days. However, the infection can be transmitted agnostic and therapeutic challenge. onto others from even 1 day before the onset of clinical symptoms until day 3 to 5 of the disease, Treatment The course of disease in immunocom‑ or even for several weeks in immunocompromised petent patients is usually mild and does not re‑ individuals. “Seasonal” influenza is a self­­‑limiting quire specific treatment, so symptomatic treat‑ upper respiratory tract infection. Typical symp‑ ment is used. However, in immunocompromised toms include fever with chills, muscle pain, and patients, the disease can take a dramatic, life­­ nonproductive cough. The recovery takes 1 to 2 ‑threatening course, so it requires intensive treat‑ weeks. Pandemic influenza (AH1N1), on the oth‑ ment. Adenine nucleoside analogues, which in‑ er hand, more often leads to the involvement of sert themselves into the viral genome thus stop‑ the lower respiratory tract and complications, in‑ ping its replication, include acyclovir, GCV, and cluding death. their derivatives Val‑acyclovir­­ and VGCV(offering Due to an impaired lymphocyte function, SOT 3 times better gastrointestinal absorption). recipients on IS are susceptible to a more serious The mechanism of action of ACV involves inhib‑ clinical course. They also present more often with iting protein kinase of the EBK virus (EBV­­‑PK, drug resistance. The risk factors for severe clini‑ encoded by the BGLF­­‑4 gene). Since ACV is a pro‑ cal course include early period after transplanta‑ drug which requires phosphorylation by EBV­­‑PK, tion, high­­‑dose IS, and type of the allograft (lung theoretically only EBV­­‑infected cells can activate allograft recipients are particularly vulnerable).48 it. Practically, though, noninfected cells are also Immunocompromised individuals more often de‑ capable of ACV phosphorylation (and, in turn, velop viral pneumonia (25%-40% of cases), sec‑ activation), but the rate is 100­­‑fold slower than ondary bacterial pneumonia (17% to 68%), or fun‑ in the infected cells. As mentioned above, up to gal pneumonia.48,49 In these patients, the infection date, there is no vaccination available.46 may also present atypically (eg, with isolated fever

PART I General overview of major viral infections 15 TABLE 4 Recommended dosage and duration of influenza antiviral medications for be used in transplant recipients. The vaccine can treatment or chemoprophylaxis (adults) be administered at any time starting at 3 to 6 51 Chemoprophylaxis (after known exposure) months following transplantation. There are no known reports of acute or chronic allograft Oseltamivir 75 mg once daily 10 days rejection triggered by the vaccination. The risk Treatment factors of incomplete immune response to vacci‑ Zanamivir 10 mg twice daily 5 days nation include high doses of IS, early posttrans‑ Oseltamivir ClCr >60 ml/min 75 mg twice daily 5 days plant phase, and recent treatment with antilym‑ ClCr >30–60 ml/min 30 mg twice daily 5 days phocyte globulins. Chemoprophylaxis of infec‑ >10–30 ml/min 30 mg once daily 5 days tions currently involves the use of neuramini‑ dase inhibitors (oseltamivir). Due to the fear of <10 ml/min NA 5 days increasing drug resistance, they cannot be used HD 30 mg After HD as substitutes of vaccinations. Neuraminidase in‑ CAPD 30 mg Single dose hibitors are indicated only in patients with expect‑ Resistant to Zanamivir 10 mg twice daily 5 days ed low­­‑level response to vaccination and contra‑ oseltamivir indications to immunization.51 Once the contact Oseltamivir + 75 mg twice daily + 5 days with influenza virus is confirmed, antiviral treat‑ amantadine 100 mg twice daily ment should be started immediately after the on‑ Oseltamivir + 75 mg twice daily + 5 days set of first clinical symptoms. The dose of neur‑ rimantadine 100 mg twice daily aminidase inhibitors should be adjusted to cre‑ atinine clearance values. M2 inhibitors (amanta‑ Abbreviations: CAPD, continuous ambulatory peritoneal dialysis; ClCr, creatinine dine, rimantadine) have been almost completely clearance; HD, hemodialysis; NA, not available removed from treatment algorithms due to in‑ creasing drug resistance (TABLE 4). Unlike immu‑ or rhinitis with no fever). Gastrointestinal symp‑ nocompetent individuals, transplant recipients toms (nausea, vomiting, diarrhea) may predom‑ benefit from antiviral treatment even if influenza inate in even one­­‑third of patients. Up to 65% symptoms persist for 48 hours. Treatment should to 68% of transplant recipients with influenza be continued until complete virus eradication has require inpatient treatment, of whom 13% to been achieved in the upper and lower respiratory 14% require intensive care.50 The mortality rate in tract (real­­‑time PCR once a week until negative).51 transplant recipients is 4% to 8%, and even 14% If no clinical improvement after 7 to 10 days of in patients with AH1N1 infection.49,50 Other com‑ treatment is observed, testing for pathogenic vari‑ plications of influenza are observed in the respi‑ ant genes should be carried out. When drug resis‑ ratory system (pneumonia, exacerbation of oth‑ tance is confirmed, treatment should be convert‑ er chronic respiratory diseases up to respiratory ed into one of acceptable efficacy.47 failure), cardiovascular system (myocarditis and The need to ensure safety of immunocompro‑ pericarditis, decompensated chronic heart fail‑ mised patients obligates transplant centers to ure), and nervous system (encephalitis, menin‑ undertake actions aiming at limiting influen‑ gitis, Guillain– Barré syndrome, Reye syndrome). za virus transmission at peak season. As part of The need to reduce IS in severe influenza increas‑ such actions, all transplant procedures should es the risk of acute graft rejection. be temporarily suspended, and the patients ad‑ mitted for diagnostic assessment or as elective Detection and prophylaxis Virus isolation, posi‑ admission—discharged. The number of outpa‑ tive antigen assay, viral DNA in a clinical speci‑ tients seen should be reduced to a minimum. Staff men, or specific serologic response are needed members should be sent home immediately af‑ to confirm the diagnosis. The use of serum ‑an ter the onset of the first respiratory symptoms. tibody assay is limited in transplant recipients due to potential failure to trigger the full sero‑ Hepatitis C virus Recent years have witnessed rev‑ logic response. Viral RNA assay is the most effec‑ olutionary changes in the treatment of hepatitis tive diagnostic method. Although high genome C, owing to the introduction of interferon‑free­­ variability may cause false negative results, real­­ therapies based on DAAs. These changes are par‑ ‑time PCR is a preferred diagnostic approach in ticularly important for LTx recipients, in whom immunocompromised patients, in whom molec‑ the efficacy of interferon and ribavirin therapy ular tests offer too low sensitivity.47 Nasopharyn‑ was low and the adverse effects of interferon were geal swabs, sputum, nasopharyngeal or bronchi‑ particularly pronounced. Treatment efficacy mea‑ al aspirate, and pericardial fluid or cerebrospinal sured as sustained virologic response at 24 weeks fluid samples can be used for testing. following treatment completion (SVR24) ranged Prevention of influenza involves annual vac‑ between 12% and 40% for genotype 1 and the in‑ cinations and preventive use of antiviral med‑ cidence of interferon‑induced­­ liver allograft rejec‑ ications. Trivalent seasonal influenza vaccina‑ tion was up to 25%.52 Effective HCV replication tion is recommended in all SOT recipients and depends on the production of viral RNA­­‑encoded transplant candidates, as well as all individuals proteins in ribosomes of infected cells. HCV trans‑ that are in direct contact, including health care lation yields a single polyprotein precursor of ap‑ professionals. Only inactivated vaccines should proximately 3000 amino acid in length, which is

16 POLISH ARCHIVES OF INTERNAL MEDICINE 2019; 129 (Special Issue 3) further cleaved into structural proteins compos‑ patients: activation of HBV infection in patients ing form the newly formed virion (p7, E1, E2, c) with chronic hepatitis B, and the increased risk and nonstructural (NS) proteins, which perform of hepatocellular carcinoma (HCC) recurrence various roles in new viral RNA strand replication in patients with a history of effective HCC treat‑ and forming new virus particles. Primary protein ment. Decreased activity of CD8+ T cells in chron‑ is cleaved by cellular proteases and NS3/4A viral ic hepatitis C is caused by an increased expres‑ protease. The NS5A protein participates in form‑ sion of inhibitory receptors, absence of CD4+ T­­ ing new virus particles, whereas RNA­­‑dependent ‑helper cells, and increased activity of regulatory NS5B polymerase is responsible for new viral RNA T cells. In most patients, effective 12‑week­­ DAA strand replication. treatment leads to reconstitution of HCV­­‑specific Currently available DAAs can be classified into CD8+ T­­‑cell response. It is not associated with in‑ 3 categories, depending on the target viral pro‑ creased activity of CD8+ T cells against other vi‑ tein: NS3/4A protease inhibitors (simeprevir and ruses, which supports a specific effect of HCV paritaprevir, grazoprevir), NS5A polymerase in‑ elimination rather than immunomodulatory ef‑ hibitors (daclatasvir, ledipasvir, ombitasvir, el‑ fect of the administered medications. In chronic basvir, velpatasvir) and NS5B polymerase inhib‑ hepatitis C, natural killer (NK) cells become dys‑ itors (sofosbuvir and dasabuvir). Interferon­­‑free functional and activated. Their functional polar‑ treatment shows very high efficacy with SVR24 ization involving increased cytolytic activity and over 90% in genotype 1 and 4 HCV. The efficacy in decreased interferon‑­­ γ production is associated genotype 2 and 3 HCV is lower; however, the re‑ with chronic exposure to interferon α and may search of new viral protein inhibitors and new make it impossible to eradicate the virus leading therapeutic algorithms is still under way. to chronic hepatitis. DAAs reduce the activation Treatment algorithm depends on a number of NK cells in the liver and peripheral blood, thus of factors, such as HCV genotype, cirrhosis, co‑ decreasing their cytolytic activity and restoring morbidities (especially kidney failure), previous normal phenotype within 8 weeks of treatment, failure of IFN or DAA treatments, and potential with the effect sustained afterwards. Decreased drug interactions. They are discussed in detail in cytolytic activity of NK cells may unlock immune the guidelines published by the Polish Group of regulation of cancer.54,55 Research has confirmed Experts for HCV in 2017.53 Treatment algorithms increased risk of HCC recurrence after DAA treat‑ based on simeprevir, paritaprevir, and elbasvir ment in patients after successful treatment of pri‑ with grazoprevir should not be used in patients mary HCC, including LTx recipients.56,57 However, with decompensated cirrhosis, due to the risk of there is also evidence that the risk of recurrence exacerbating liver failure. In patients with stage 3 may be comparable to the one found in patients chronic kidney disease (glomerular filtration rate previously treated with interferon.58 Apparent‑ >30 ml/min/1.72 m2), DAA dose adjustments are ly, there is no consensus on DAA use in patients not needed. In patients with more advanced kid‑ with a history of HCC. Such patients should be ney failure, elbasvir with grazoprevir, or ombitas‑ closely monitored (magnetic resonance or com‑ vir, paritaprevir, ritonavir combined with dasabu‑ puted tomography imaging are recommended) vir should be used. In patients on renal replace‑ before and after treatment. There have also been ment therapy with genotypes 1 or 4, elbasvir with reports suggesting lower efficacy of interferon­­ grazoprevir is recommended, whereas pegylated ‑free therapies in patients with known HCC me‑ interferon should be used in other genotypes. It tastases identified prior to DAA administration.59 should be noted that ribavirin dose needs adjust‑ Our own experience supports very high effi‑ ment in patients with kidney failure. In LTx recipi‑ cacy of interferon‑free­­ therapy in 110 LTx recipi‑ ents with genotype 1 HCV, regardless of the sever‑ ents with genotype 1 HCV. Treatment failure was ity of fibrosis and decompensation, sofosbuvir and noted in 3 cases only (SVR24 = 97%), including 2 ledipasvir should be used for 12 weeks. In patients cases of extrahepatic HCC metastases found pri‑ with compensated cirrhosis, daclatasvir with so‑ or to treatment, and 1 case of adrenal HCC me‑ fosbuvir can also be used for 12 weeks. Ombitas‑ tastasis found on magnetic resonance imaging vir, paritaprevir, ritonavir combined with dasabu‑ following treatment completion. In 7 patients vir can be used for 24 weeks only in patients with with genotype 3 HCV, sofosbuvir and ribavirin fibrosis Metavir grade F0–F2. In patients after were ineffective in 2 cases (SVR = 71%), includ‑ LTx, DAA should be used in combination with ing 1 case of new HCC lesion seen following treat‑ ribavirin. In genotype 3 HCV, daclatasvir should ment completion. be used for 12 weeks in combination with sofos‑ buvir and ribavirin. Unfortunately, in genotype 3 HIV History of battle against HIV AIDS was first the Polish National Health Fund only reimburses described 38 years ago, in 1981. Gottlieb et al60 the therapy with sofosbuvir and ribavirin, the ef‑ reported cases of pneumocystis pneumonia ficacy of which measured as SVR24 is below 70%. in the New England Journal of Medicine. Over Interferon­­‑free treatments are safe and do not the next year, it became clear that a causative usually cause significant adverse effects. Howev‑ agent was transmitted by sexual intercourse. In er, it seems that rapid inhibition of viral replica‑ 1982, many cases were discovered among blood tion may alter the immune system, which is re‑ recipients. Most of them were adult patients with flected in 2 phenomena observed in DAA­­‑treated hemophilia, but some children were infected, as

PART I General overview of major viral infections 17 well. The next risk group were intravenous drug the patients a chance for longer survival. New users who used nonsterile syringes and needles. gold standard of antiretroviral treatment involves The other identified route of infection was a ver‑ treating everybody as early as possible to achieve tical mother­­‑to­­‑child transmission. undetectable viral load. The goal of care is now In 1980, Robert Gallo et al61 discovered T­­ defined by WHO as 90­­‑90­­‑90, which means that ‑lymphotropic retrovirus, the first virus known 90% of diagnosed patients receive the care, 90% to affect human CD4 cells. They hypothesized that of them are treated with antiretrovirals, and 90% this virus was also responsible for the newly dis‑ of them have undetectable virus. covered syndrome. However, after months of in‑ If a patient with HIV infection is treated ear‑ tensive research all agreed that HIV was identified ly enough, full immune reconstitution is almost in 1983 by Francoise Barre‑Sinoussi­­ and Luc Mon‑ certain. In many developed countries, these pa‑ tagnier from Pasteur Institute in Paris, who were tients are also considered eligible for organ trans‑ awarded Nobel Prize a few years ago, in 2008. plant, should a need arise. The outcomes of trans‑ It became clear that HIV epidemic was a chal‑ plantation in these patients are the same as in lenge for public health systems worldwide. A num‑ an HIV­­‑negative population. ber of organizations initiated vigorous action to find an effective solution. First, the route of in‑ HIV and liver transplantation Until recently, HIV fection was established. A few weeks after HIV infection was considered a significant contrain‑ discovery, routine enzyme‑linked­­ immunosor‑ dication to LTx. HIV­­‑positive patients were not bent assays were manufactured and introduced considered eligible for LTx not only due to active to clinical practice. Donor testing in blood banks and poorly controlled infection. Other concerns reduced the number of transfusion‑transmitted­­ were alcohol or other substance abuse and psy‑ infections to almost zero. Community campaigns chosocial problems, as a result of which successful played the crucial role in combating the epidem‑ treatment after LTx was highly unlikely. Another ic. Individuals above the age of consent were con‑ relevant issue was a suggestion that IS could ac‑ tinuously educated how to avoid HIV infection. celerate HIV/AIDS progression and increase mor‑ A number of harm reduction programs for intra‑ tality. In 1996, HAART was introduced in devel‑ venous drug users were developed in many coun‑ oped countries, which revolutionized treatment tries, demonstrating their effectiveness. approaches and outcomes in HIV­­‑positive pa‑ Public authorities along with researchers and tients to an extent where over 50% of all­­‑cause pharma industry set another important direction. mortality in HIV­­‑positive population are not di‑ Their main effort focused on developing the HIV rectly related to HIV/ AIDS. However, liver dis‑ vaccine. Unfortunately, despite a number of prom‑ eases have become the leading cause of death in ising concepts and a development of almost­­‑ready this population, even exceeding the share of car‑ vaccines, which entered phase III clinical trials, diovascular diseases. Approximately two‑third­­ there is still no vaccine available today. Further‑ of deaths in HIV­­‑positive patients were caused more, there is little chance for the effective vac‑ by chronic HCV infection, followed by 17% of cine to become available in the nearest future. deaths caused by HBV infection and 3% caused The protection rate of an effective vaccine should by HAART­­‑induced liver injury. Other causes of be close to 100%, whereas a prototype HIV vac‑ liver failure include alcoholic fatty liver disease, cine only offers a 50% protection rate. nonalcoholic fatty liver disease and HCC. Over Therefore, medical therapy plays the key role 30% of HIV­­‑positive patients have HCV coin‑ in HIV infection. The first drug, azidothymidine, fection, and the vast majority of deaths in HIV­­ was introduced as monotherapy. A few years later, ‑positive population with advanced liver disease though, its efficacy in monotherapy was shown are caused by HCV.62,63 to be of limited duration, rendering it ineffec‑ Many studies demonstrated that the mortali‑ tive after a couple of years. Additionally, resis‑ ty rates, as well as the incidence of malignancies tance has been shown to result from a set of mu‑ and opportunistic infections, in HIV­­‑positive pa‑ tations, which was another disadvantage of mono‑ tients with T­­‑cell reconstitution after HAART therapy. Fortunately, protease inhibitors, a new‑ are comparable to those seen in HIV­­‑negative er class of antiretroviral drugs, were discovered population. Therefore, LTx is a valuable treat‑ at around the same time. As a result, triple‑drug­­ ment option in this particular group. In the years HAART was introduced in 1994. Also, in 1994, from 2003 to 2011, many reports have been pub‑ the efficacy of antiretroviral therapy in prevent‑ lished on LTx in HIV­­‑positive recipients, most‑ ing vertical transmission of HIV was shown, re‑ ly in the United States, France, Italy, and Spain. ducing the infection rates in children born from The reported patient groups consisted of dozen to HIV­­‑positive mothers from 30% to less than 1%. 60 recipients, with the majority presenting with It was possible owing to numerous grants giv‑ HIV (62%–100%) and HBV (29%–100%) coinfec‑ en for basic science research, which significant‑ tion. The follow­­‑up period ranged between 1 and ly accelerated scientific progress and expanded 6 years, and the survival rate was 48% to 87%. the existing knowledge. Owing to the effort of Considering such promising results, HIV infec‑ researchers working in drug development, new‑ tion was no longer considered a contraindication er treatments were discovered, more effective to LTx. Three groups of criteria for transplant el‑ and much safer than previous generations, giving igibility have been identified, as shown inTABLE 5.

18 POLISH ARCHIVES OF INTERNAL MEDICINE 2019; 129 (Special Issue 3) TABLE 5 Criteria for liver transplant eligibility in human immunodeficiency virus

Stage of liver disease (a hepatologic Stage of HIV infection Social and psychological criteria criterion identical as in HIV­‑positive patients) • Liver failure (HCV, less often acute • Possibility to continue effective, • Positive psychosocial evaluation: and chronic HBV, HCC) safe, and long­‑term antiretroviral assessment of social network • Acute liver failure treatment after LTx support (acceptance, family and friend support) • Decompensated liver disease • Ideally, HIV RNA load (ascites, encephalopathy to be <50 copies/ml • Patients with active psychoactive differentiated with HIV­‑associated • CD4 >100 cells/ml substance dependence are not considered eligible for LTx encephalopathy) • CD4 >200 cells/ml in patients • Bleeding esophageal varices with a history of opportunistic • Stable patients on methadone infection (in Spain) maintenance therapy are • Functional liver impairment (albumin considered eligible for LTx <30 g/l, INR >1.5, bilirubin • CD4 >200 cells/ml (CD4 >450 mmol/l) >100 cells/ml in case of • In some countries, additional requirements have been • HCC (Milan/Mazzaferro criteria) decompensated cirrhosis or portal hypertension) (in Italy) introduced, such as 2­‑year abstinence from heroin and cocaine and 6­‑month abstinence from other psychoactive substances, including alcohol

Abbreviations: HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; INR, international normalized ratio; LTx, liver transplant

In recent years, the reports of successful LTx HIV and kidney transplantation Renal involvement in HIV­­‑positive recipients with long‑term­­ sur‑ is becoming increasingly more prevalent in HIV­­ vival have been published, with primary HCC be‑ ‑positive patients, leading to increased mortality ing the main indication,64 as well as the reports and morbidity. The most common conditions in‑ of LTx from HIV­­‑positive donors to HIV­­‑positive clude acute kidney injury, chronic kidney disease, recipients.65 HIV­­‑associated nephropathy and other glomeru‑ In 2011, in the Department of General, Trans‑ lonephritides as well as complications from tox‑ plant and Liver Surgery, Medical University of icity of antiretroviral and other drugs (FIGURE 3). Warsaw, in cooperation with the Department In aging population of HIV­­‑positive individ‑ of Hepatology and Acquired Immunodeficiency uals, renal involvement could also be associated (Prof. Alicja Wiercińska‑Drapało),­­ a successful with HBV or HVC coinfection, as well as other co‑ emergency LTx was performed in a 20‑year­­ old morbidities, such as diabetes and hypertension. HIV­­‑positive recipient with HBV and end­­‑stage Outcomes of HIV­­‑positive patients changed dra‑ liver failure (encephalopathy and hepatic coma), matically owing to the appropriate antiretrovi‑ which made it the first liver graft transplanted to ral therapy, and patients on renal replacement the HIV­­‑positive recipient in Poland. The patient therapy (dialysis, transplantation) have similar survived for over 1 year despite noncompliance. survival rates to those with other comorbidities, He died due to multiorgan failure, secondary to such as diabetes. Traditionally, HIV infection another sexually transmitted disease. was considered an absolute contraindication to Considering the above information, it seems KTx. It was due to the concern that IS would ac‑ that chronic nature of HIV disease, along celerate AIDS progression and increase mortali‑ with an increasing number of patients with ty. The concern came from the published reports end‑stage­­ liver disease and complications of on some transplant recipients unknowingly in‑ HAART, will likely result in an increasing de‑ fected with HIV, and individuals who received mand for LTx in this population. Assessing pa‑ transplant from HIV­­‑positive donors and then tient eligibility, including virologic, immune, acquired HIV infection. Nowadays, most cen‑ and psychosocial factors, is the key to a safe and ters still exclude patients who test positive for effective transplant. Furthermore, posttrans‑ HIV. However, controlled HIV infection is not plant care is a multidisciplinary challenge and a contraindication to KTx, and these patients effort due to issues related to surgical complica‑ could be effectively managed in units with rel‑ tions, immunosuppressive treatment, HAART, evant expertise and experience. As HAART be‑ and compliance. Long­­‑term results in patients came available, the prognosis of HIV infection with HIV and HCV coinfection are worse than has dramatically improved, making HIV infec‑ in patients with HCV, especially with the same tion a chronic, yet manageable, disease. It also Model for End­­‑Stage Liver Disease scores, al‑ triggered changes to assessment protocols for though newer DAAs will likely improve treat‑ HIV‑positive­­ KTx candidates.66 Several stud‑ ment outcomes. It should also be noted that ies demonstrated excellent outcomes in HIV­­ HIV­­‑positive donors can be considered an al‑ ‑positive subjects who underwent KTx while ternative source of organs for HIV- and HCV­­ on HAART therapy.67,68 One­­‑year survival rates ‑positive recipients. appear comparable between HIV­­‑positive and

PART I General overview of major viral infections 19 IgA nephropathy Unknown Thrombotic microangiopathy GN complexes GN with immune Membrano-proliferative Immune syndrome inflammatory reconstitution disease Anti-GBM Anti-GBM antibodies Deranged Membranous GN immunogenicity synthesis Autoantibody Obstructive nephropathy (crystalluria) Kidney damage in HIV nephritis Interstitial Drugs Tubolopathy - damage chondrial Toxic mito Toxic FSGS disase HIV-dependent Podocyte injury Podocyte Minimal change Renal involvement in HIV Renal

HIVAN FIGURE 3  nephropaty; IgA, immunoglobulin A HIV-associated focal segmental glomerulosclerosis; GBM, glomerular basement membrane; GN, glomerulonephritis; HIVAN, Abbreviations: FSGS,

20 POLISH ARCHIVES OF INTERNAL MEDICINE 2019; 129 (Special Issue 3) FIGURE 4 Anogenital A B lesions in a woman treated with long­­‑term immunosuppression, with a 20­­‑year history of type 1 diabetes; 2 years following kidney transplant from a multiorgan donor. High- grade squamous intraepithelial lesions classified according to the International Society for the Study of Vulvovaginal Disease and International Society of Gynecological HIV‑negative­­ recipients, and the 3‑year­­ surviv‑ with its absorption. Efavirenz, an NNRTI, exerts Pathologists: A - vulvar al rates are significantly lower as compared with a mixed inhibitory and inducing effect on some intraepithelial neoplasia living‑donor­­ or standard‑criteria­­ ‑donor­­ recipi‑ P450 isoenzymes. Antiproliferative drugs, such (usual-type VIN or VIN 3); ents. However, the incidence of acute rejection is as mycophenolate mofetil, may interact with nu‑ B - anal intraepithelial markedly higher in HIV­­‑positive recipients.69 In cleoside analogues, like zidovudine and stavu‑ neoplasia (AIN 3) countries with a high prevalence of HIV, such as dine, limiting their efficacy. On the other hand, South Africa, successful KTx from HIV­­‑positive mycophenolate enhances the effect of abaca‑ donors to HIV­­‑positive recipients has been re‑ vir. Currently, due to low potential for drug ported.70 According to the European Renal Best interactions, raltegravir and dolutegravir are Practice (ERBP) guidelines,71 HIV‑positive­­ kid‑ more frequently used. Antithymocyte globulin, ney transplant candidates should be waitlisted an agent frequently used in induction or to treat if they are compliant with treatment (particular‑ acute rejection, may be associated with marked ly HAART therapy), their CD4+ T­­‑cell counts ex‑ CD4­­‑positive depletion. Therefore, it should be ceed 200/µl, they have been stable over the pre‑ used with caution in this population, and pro‑ vious 3 months, HIV RNA was undetectable over phylaxis against opportunistic infections should the previous 3 months, no opportunistic infec‑ be reinitiated if not used or discontinued ear‑ tions occurred over the previous 6 months, and lier. It is difficult to separate the complications they show no signs of progressive multifocal leu‑ of particular opportunistic infections associat‑ koencephalopathy, chronic intestinal crypto‑ ed with HIV progression from the complications sporidiosis, or lymphoma (grade 1C). Although associated with the IS used for transplantation. the ERBP did not refer to exclusion criteria, it Prophylaxis against opportunistic infections is seems reasonable to exclude patients with a his‑ certainly indicated in patients after transplan‑ tory of opportunistic infections (unless immune tation, as they need lifelong primary and sec‑ reconstitution has occurred), major neoplasms ondary trimethoprim and sulfamethoxazole­­ which might require systemic chemotherapy, or ‑based prophylaxis against Pneumocystis jirove‑ end­­‑stage liver disease. The ERBP also suggest ci (P. jiroveci).74 discussing the most appropriate antiretroviral therapy with the infectious diseases team to an‑ Human papilloma virus The introduction of pri‑ ticipate potential drug interactions after trans‑ mary prevention and continuous monitoring in plantation (ungraded statement). It is of utmost patients with known high‑risk­­ HPV, enabled not importance, since HIV therapy includes a com‑ only early diagnosis and treatment but also pre‑ bination of at least 3 fully active drugs from vention of malignancies in transplant recipients the currently available classes of antiretroviral using long­­‑term immunosuppressive therapy.75,76 agents: nucleoside analogue reverse transcrip‑ HPV belongs to DNA viruses, and protein E6 tase inhibitors (NRTIs), non­­‑NRTIs (NNRTIs), and E7 transformation is directly associated with HIV­­‑protease inhibitors, entry inhibitors, and HPV infection, which may have different presen‑ integrase inhibitors. Protease inhibitors, espe‑ tations (subclinical infection, active clinical stage cially ritonavir, inhibit P450 cytochrome iso‑ and latent stage). Clinically, we typically diagnose enzymes, and one such isoenzyme, CYP3A4, preexisting HPV infection already after trans‑ is critical for the metabolism of calcineurin in‑ plantation, or de novo infection after transplan‑ hibitors.72 It was reported that protease inhib‑ tation, which manifests as Kaposi sarcoma, lym‑ itors increased through levels of cyclosporine, phoma, or skin papillomata including anogenital TAC, and sirolimus, compared with those on region and/or oral cavity (FIGURES 4 and 5). Malig‑ NNRTIs alone or with patients not on antiret‑ nancy may develop at any time following trans‑ roviral therapy, requiring either a dose reduc‑ plantation, with the mean time of 47 months, and tion or an increase in dosing interval.73 As proton constitutes a cause of death in transplant recip‑ pump inhibitors are frequently used in patients ients. The incidence of malignancies at 30 years after transplantation, caution should be exer‑ following transplantation is 75% for skin cancer cised with atanazavir, as these drugs interfere and 33% for other cancers.77,78

PART I General overview of major viral infections 21 FIGURE 5 Lesions in A B C a single-organ–transplant recipient treated with long­­‑term immunosuppression, 6 months following liver transplant from a multiorgan donor. A – scar after liver transplantation; B – low-grade squamous intraepithelial lesion of the vulva (also classified as VIN 1, VIN 2 or mild, moderate dysplasia); C – low-grade anal squamous intraepithelial lesion (also classified as AIN 1 or mild dysplasia)

TABLE 6 Management of human papillomavirus infection in organ / cell transplant recipients on long­‑term immunosuppression

Multidisciplinary care since detection of HPV infection (especially if oncogenic HPV is involved): dentist, dermatologist, general practitioner, gynecologist, and surgeon IS monitoring and changes to treatment algorithm if clinically justified Diagnosis and decision on management option: conservative vs surgical Molecular HPV diagnosis and immunohistochemical evaluation of biopsy specimen or resected lesion If malignancy found: chemotherapy and radiotherapy, and regular follow­‑up Testing sexual partners as a source of infection Choosing optimum management strategy in pregnant women Monitoring of children born from mothers with known HPV infections Immunotherapy as primary HPV prevention to be considered

Abbreviations: HPV, human papillomavirus

Cancer markers are used increasingly often Viruses versus myocarditis and acute coronary syn- at present nowadays in monitoring IS in trans‑ dromes Myocarditis is an inflammation involv‑ plant recipients and in patients treated for high­­ ing cardiomyocytes, interstitium, blood vessels, ‑risk HPV–dependent malignancies. One of such and sometimes also the pericardium. The etiolo‑ markers is tumor protein p53, which plays a role gy cannot be determined in the majority of cas‑ key role in prognosing recurrence or death in es. Apart from de novo infection, reactivation of HPV­­‑positive patients after transplantation on latent infection is also likely. Basic classification long­­‑term IS. Surgical management of basal cell includes acute, giant cell, and eosinophilic myo‑ carcinoma or squamous cell carcinoma with full carditis. Classification by the course of disease histological diagnosis helps determine appropri‑ includes fulminant, acute, and subacute / chron‑ ate treatment and prognosis. Clinical experience ic myocarditis. In 2013, European Heart Journal demonstrated that high expression of p53 corre‑ published the most current position statement lates with increased risk for the recurrence of oral of the European Society of Cardiology on the eti‑ and anogenital cancers.79,80 ology, diagnosis, management, and therapy of Treatment algorithm and multidisciplinary myocarditis.81 medical care not only improved survival in al‑ The diagnosis of myocarditis is based on lograft recipients, but also significantly improved the specific criteria including acute chest pain, and prolonged the allograft function with long­­ rapid progression to heart failure, fatigue, ex‑ ‑term IS, decreasing the risk of many malignan‑ ercise dyspnea, arrhythmia, or even cardiogen‑ cies, directly linked to oncogenic viruses, includ‑ ic shock of unknown origin. The second group ing HPV. The management of HPV­­‑infected trans‑ of criteria include abnormal pattern on elec‑ plant recipients on long‑term­­ IS, requires mul‑ trocardiogram, and abnormalities in diagnos‑ tidisciplinary care of different specialist care tic imaging and laboratory tests. Myocardial bi‑ (TABLE 6). opsy plays the key role in diagnosing myocardi‑ tis and determining its etiology as well as prog‑ nosis. The most common causes of myocarditis

22 POLISH ARCHIVES OF INTERNAL MEDICINE 2019; 129 (Special Issue 3) PART II

Specific issues in management of viral infections in transplant recipients

Krzysztof Mucha1,2*, Bartosz Foroncewicz1*, Alicja Dębska­‑Ślizień3, Magdalena Durlik4, Ryszard Grenda5, Andrzej Horban6, Piotr Fiedor7, Magdalena Krajewska8, Artur Kwiatkowski7, Jan Lerut1,9, Jacek Małyszko10, Jolanta Małyszko11,12, Piotr Przybyłowski13,14, Krzysztof Zieniewicz15, Michał Ciszek1, Dorota Kamińska9, Maciej Kosieradzki8, Agnieszka Perkowska­‑Ptasińska5, Justyna Czerniawska16, Dominika Dęborska5, Radosław Kwieciński14, Magdalena Kwapisz8, Barbara Moszczuk1, Leszek Pączek1,2 1 Department of Immunology, Transplantology and Internal Diseases, Medical University of Warsaw, Warsaw, Poland 2 Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland 3 Department of Nephrology, Transplantology and Internal Medicine, Gdańsk Medical University, Poland 4 Department of Transplantation Medicine, Nephrology and Internal Diseases, Medical University of Warsaw, Poland 5 Department of Nephrology, Kidney Transplantation and Hypertension, The Children’s Memorial Health Institute, Warsaw, Poland 6 Department for Adult’s Infectious Diseases, Medical University of Warsaw, Poland 7 Department of General and Transplantation Surgery, Medical University of Warsaw, Poland 8 Chair and Department of Nephrology and Transplantation Medicine, Wrocław Medical University, Wrocław, Poland 9 Starzl Unit Abdominal Transplantation, University Hospitals Saint Luc, Université Catholique de Louvain, Brussels, Belgium 10 1st Department of Nephrology and Transplantology with Dialysis Unit, Medical University of Białystok, Białystok, Poland 11 2nd Department of Nephrology and Hypertension with Dialysis Unit, Medical University of Bialystok, Białystok, Poland 12 Department of Nephrology, Dialysis and Internal Diseases, Medical University of Warsaw, Warsaw, Poland 13 1st Chair of General Surgery, Jagiellonian University, Medical College, Kraków, Poland 14 Silesian Center for Heart Diseases, Zabrze, Poland 15 Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland 16 Department of Radiology, Medical University of Warsaw, Poland

include viral (both DNA and RNA viruses), bac‑ tumor necrosis factor α (TNF­­‑α), IL­­‑2β, and in‑ terial, fungal, protozoan, and parasitic infec‑ terferon γ. The immune response is followed by tions. Other causes include immune and toxic T­­‑cell influx, reaching the peak between day 7 factors. Over the last 60 years, the profile of vi‑ and 14 of the infection. It is also the phase where ruses responsible for myocarditis has changed the largest damage to the myocardium occurs, as significantly: the share of enteroviruses and ad‑ molecular mimicry mechanisms cause T cells to enoviruses has decreased, while parvovirus B19, damage infected cardiomyocytes.85 Nitric oxide HHV­­‑6, as well as HCV, EBV, and influenza vi‑ also plays an important role in the pathomecha‑ ruses have emerged as the key contributors.82 It nism of myocarditis. In myocarditis, the expres‑ Correspondence to: should be noted that from 0.4% to 13% of adults sion of induced nitric oxide synthase is upregu‑ Krzysztof Mucha, Department of hospitalized with confirmed influenza infec‑ lated by TNF­­‑α and IL­­‑1β originating from both Immunology, Transplantology and Internal Diseases Medical University tion develop myocarditis, and as many as 68% inflammatory cells and myocytes. This increas‑ of Warsaw, Nowogrodzka 59, of myocarditis cases secondary to influenza are es the production of NO and toxic peroxynitrite, 02-006 Warszawa, Poland, seen in adults below 40 years of age.83 causing oxidative stress that leads to apoptosis phone: +48 22 502 16 41, Acute myocarditis is a dangerous condition, and necrosis as well as impairs myocardial func‑ email: [email protected]; Bartosz Foroncewicz, Department which may lead to chronic cardiac failure in 25% tion. Treatment of myocarditis is limited to symp‑ of Immunology, Transplantology of cases. The acute phase may also lead to death tomatic options available for heart failure and ar‑ and Internal Diseases or severe dilated cardiomyopathy in 12% to 25% rhythmia or involves implantation of implant‑ Medical University of Warsaw, 84 Nowogrodzka 59, 02-006 Warszawa, of cases. The immune mechanism is the key con‑ able cardioverter­­‑defibrillators. Antiviral drugs Poland, phone: +48 22 502 16 41, tributor to myocardial damage due to myocardi‑ are currently in clinical trials. email: bartosz.foroncewicz@wum. tis. The NK cells, which exert cardioprotective ef‑ According to current definitions, acute coro‑ edu.pl fect by inhibiting virus replication, are the first nary syndromes (ACSs) can be classified into ST­­ Conflict of interest: none declared. *KM and BF contributed equally to to reach the infected myocardium. The next im‑ ‑segment elevation myocardial infarction ACS (in sections I and II. mune stage involves cytokine production: IL­­‑1β, which the blockage of the coronary artery causes

PART II Specific issues in management of viral infections in transplant recipients 23 the blood flow to stop, thus leading to myocar‑ patients on renal replacement therapy. Vaccina‑ dial necrosis) and non–ST­­‑segment elevation tions should be administered prior to transplan‑ (NSTEMI) ACS (unstable angina [UA] / NSTE‑ tation, which is an absolute necessity in case of MI). UA / NSTEMI is referred to as a clinical syn‑ attenuated vaccines. The most common of them drome caused by a new or persistent, yet increas‑ are measles, mumps, rubella, and varicella zoster ing, blood flow reduction in the coronary artery vaccines. A 4‑week­­ interval between attenuated (UA), which leads in some patients to myocardial vaccine administration and transplantation is in‑ necrosis presenting as elevated blood levels of ne‑ dicated. There are no vaccines available for CMV, crosis markers, without signs of new ST­­‑segment EBV, HCV, HSV, and BKV. elevation on electrocardiogram.86 The key viruses implicated in ACS include HCV, Viral infections in kidney transplant candidates Hep- HIV, and CMV. However, it should be noted that atitis B and hepatitis C virus Although HBV and parvovirus B19 is the most common etiological HCV infections are not contraindication to KTx, factor of acute myocarditis presenting as ACS with HBV- and HCV­­‑positive recipients are at higher generalized ST­­‑segment elevation. HIV leads to risk of posttransplant complications. Therefore, a faster and more aggressive development of cor‑ each patient eligible for KTx should undergo vi‑ onary atherosclerosis in affected patients, both rology testing prior to the procedure. directly by inducing permanent inflammation Currently, HBV and HCV infections are increas‑ and coagulation disorders and indirectly through ingly less problematic due to availability of effec‑ adverse effects of antiretroviral agents and high‑ tive HBV vaccines and effective treatment of HCV. er risk of coronary artery disease (CAD) in HIV­­ Anti–HBs antibody titer should be reassessed every ‑positive population.87 HCV infection, on the oth‑ 6 months and a decision of potential booster vac‑ er hand, causes chronic, smoldering inflamma‑ cine should be guided by its results. In nonimmu‑ tion, which along with dyslipidemia, hepatic ste‑ nized patients, anti–HBc antibody titers should also atosis, and insulin resistance increase the risk of be determined. In patients positive for anti–HBc CAD, which is typically already more advanced on antibodies, HBV DNA load should be determined. diagnosis. The adverse effects of antiviral agents Obviously, transplant candidates positive for should also be considered in this context, as it HBV or HCV (or both) should be treated prefera‑ is with antiretrovirals used in HIV­­‑positive pa‑ bly prior to transplantation, although the results tients. Additionally, HCV increases the risk of of HBV treatment are usually unsatisfactory. On stroke by 27%. Among all HHVs, only CMV has the other hand, owing to the availability of effec‑ been confirmed to increase the risk of CAD and tive antiviral treatment, HCV has virtually been ACS.88 CMV infection is also a key contributor to eradicated in affected patients. HCV­­‑infected pa‑ ACS in patients after OHT.89,90 It affects the devel‑ tients should be treated prior to transplantation, opment of graft vascular disease associated with as most direct­­‑acting antivirals (DAAs) used for chronic graft rejection, thus decreasing survival. HCV treatment interfere with IS, especially with calcineurin inhibitors. Patients without serologic Viruses and kidney transplant eligibility General and virologic features of HBV or HCV infections recommendations Patients awaiting KTx should (or both), should be tested for the presence of be free of infections. Active acute infection is HBsAg, HCV RNA, and anti–HBc and anti–HCV an absolute contraindication to a transplant sur‑ antibodies every 6 months. gery. Patients with chronic infections may only be considered eligible after the infection is re‑ Human herpes virus 8 HHV­­‑8 infection is usually solved or well‑controlled­­ with treatment. There‑ a reactivation of a latent infection. It is respon‑ fore, each patient on a transplant waiting list sible for Kaposi sarcoma in transplant recipients. should be monitored for chronic infections and Some guidelines—especially in endemic coun‑ should undergo the following virologic tests: tries—provide for routine anti–HHV­­‑8 antibody HCV PCR, HCV genotype, hepatitis B surface testing in potential transplant recipients. (HBs) antigen (HBsAg), HBV DNA, as well as antibody titers against CMV, EBV, HIV, HCV, Human papilloma virus A significant number of and HBV (HBs and hepatitis B core [HBc]).91,92 If transplant recipients develop papillae (warts) clinically indicated, antibody titers against her‑ on the skin and in the genital area, which are not pes simplex virus (HSV), Varicella zoster virus cancerous but are prone to malignant transforma‑ (VZV), HPV, and West Nile virus should be de‑ tion. Their presence increases the risk of cervical, termined along with serology testing for HHV­­ vulval, rectal, and skin cancer. Therefore, vacci‑ ‑8 and BKV. Additionally, both the donor and nating transplant candidates without anti–HPV the recipient should be tested for CMV and BKV antibodies seems clinically justified, especially in directly prior to transplantation, so that their young women.92 However, there are no guidelines, serological status is known. It is essential for not even in the development stage, on prevent‑ choosing the optimal IS protocol and determines ing HPV infections in male transplant recipients. potential need for CMV prophylaxis. Vaccinations are a means for preventing in‑ Herpes simplex virus 1 and 2 Both HSV infection fections.93 A good example is HBV vaccination, and its reactivation in allograft recipients are which virtually eliminated new cases of HBV in common. The reactivation typically occurs within

24 POLISH ARCHIVES OF INTERNAL MEDICINE 2019; 129 (Special Issue 3) the first month following transplantation. Apart histology close to normal), and during this pe‑ from insignificant mucositis, HSV may also cause riod such patients are positive for hepatitis B e­­ severe infections, such as encephalitis. On enroll‑ ‑antigen (HBeAg) and HBsAg. The second phase ment on a transplant waiting list, potential recip‑ is immune clearance of infection (the immune ients are not routinely tested for the presence of system recognizes the virus and attempts to clear anti–HSV antibodies. However, some centers in it from the liver, which results in ALT flares and the United States test their patients for the pres‑ a decrease of HBV­­‑DNA load). Subsequently, most ence of anti–HSV­­‑2 antibodies. patients remain in the immune control or non‑ replicative phase, and they are negative for both Human polyomaviruses BK and JC BKV is not rou‑ HBeAg and HBsAg, and also positive for anti– tinely tested when assessing patient eligibility for HBe, anti–HBs, and anti–HBc antibodies. How‑ transplantation, except in those who need anoth‑ ever, most patients with end­­‑stage renal disease er transplant and lost the first kidney allograft remain in the so called inactive carrier phase with due to BKV infection. Repeat transplantation is normal ALT levels and either low or undetectable possible in such patients. However, it should be HBV­­‑DNA due to the attrition of the immune sys‑ performed at least 6 months following a complete tem. They remain positive HBsAg­­‑positive and discontinuation of IS, when BKV is not present in HBeAg‑negative,­­ although some patients may the blood and only low viruria is allowed.92 Graft proceed to clear HBsAg and be negative for HBsAg removal does not prevent future BKV infection. and positive for anti–HBc antibodies, and some‑ However, it should be considered if IS cannot be times even positive for anti–HBs antibodies. Do discontinued (double transplant) or with persis‑ the patients ever get rid of the HBV? The traces tent high virus load.92 JC virus is only a rare cause of HBV­­‑DNA (cccDNA, covalently closed circular of nephropathy. Due to its special affinity to ner‑ DNA) insert themselves in an episomal form, sim‑ vous tissue, it usually causes progressive multifo‑ ilar to chromosomal DNA of the host, into the nu‑ cal leukoencephalopathy. When cured, and the pa‑ clei of hepatocytes and remain there as long as tient is eligible for another transplant, the risk of the cell survives, probably surviving the mito‑ reactivation should always be considered. There‑ sis and transferring to daughter cells. Therefore, fore, such patients should be tested for JC virus it is immune control rather than clearance that before and after transplant.92 takes place in chronic HBV infection, even in pa‑ tients with the so called resolved HBV. However, Varicella zoster virus About 90% of transplant re‑ the problem starts when IS is achieved with T­­‑cell cipients test positive for anti–VZV antibodies. inhibition, because there is less control of viral Reactivation after transplant usually presents as replication, which facilitates HBV reactivation re‑ shingles, and in seronegative recipients as chick‑ sulting in a dramatic increase of viral load. With enpox, often following a severe clinical course. Se‑ downregulation of IS, immune reconstitution oc‑ rologic assessment of recipients for VZV is usu‑ curs. T cells “wake up”, recognize the abundance ally recommended. If seronegative, they should of HBV and while clearing HBV from the liver, be immunized when on dialysis.91,92 As only live they simultaneously destroy hepatocytes. This attenuated vaccines are available, they cannot be leads to flares of hepatitis, which may result in administered after transplant.93 liver failure and patient death even despite con‑ tinued antiviral therapy. HIV HIV is discussed in greater detail in the sub‑ Depending on the HBV profile at baseline, sequent part of this paper. Here, we only pres‑ HBV reactivation is defined as: 1) a marked in‑ ent basic information on the eligibility of HIV­­ crease in HBV replication or a new onset of HBV­­ ‑positive patients for transplantation. HIV in‑ ‑DNA in a HBsAg­­‑positive individual or 2) a re‑ fection does not constitute a contraindication to verse seroconversion defined as a reappearance transplantation if the patient meets the following of HBsAg and HBV­­‑DNA in a previously HBsAg­­ criteria:94 1) CD4 count greater than 200 cells/μl ‑negative patient, without detectable HBV­­‑DNA over the last 6 months; 2) undetectable HIV viral load. The main causes of reactivation include can‑ load (<50 copies of HIV­­‑1 RNA/ml) over the last cer chemotherapy, immune modulation for auto‑ 6 months; 3) documented, regular highly active immune conditions (use of TNF inhibitors in in‑ antiretroviral therapy (HAART) over the last 6 flammatory bowel disease or rheumatoid arthri‑ months; 4) no signs or symptoms of acquired im‑ tis), HIV, solid organ transplantation (kidney, mune deficiency syndrome (AIDS); 5) available heart, lung), bone marrow transplantation, and antiretroviral treatment after transplantation. antiviral HBV therapy. The key risk factors for re‑ Anti–HIV antibody titer should be determined activation can be classified broadly into the 3 cat‑ in potential transplant recipients every 6 months. egories of host­­‑related factors, virus­­‑related fac‑ tors, and type or degree of IS. Host­­‑related factors Treatment of hepatitis B virus infection in transplant include male sex, older age, presence of cirrho‑ recipients The majority of general population sis, and type of disease needing IS (eg, lympho‑ with chronic HBV infections undergo the so called ma). Virus­­‑related factors associated with an in‑ immune­­‑tolerant phase of infection (very high creased risk of reactivation include high base‑ HBV­­‑DNA load, no immune response to the vi‑ line HBV­­‑DNA levels, HBeAg positivity, chronic rus, alanine transaminase (ALT) levels and liver hepatitis B, non­­‑A HBV genotype, treatment of

PART II Specific issues in management of viral infections in transplant recipients 25 coinfected patients with antivirals such as DAAs likely to occur up to 1 to 2 years after the last dose for HCV, and non‑B­­ antiretroviral therapy for of rituximab. Therefore, anti–HBV prophylaxis HIV. The assessment of host- and virus­­‑related can be continued for up to 2 years after the last risk factors should be important caveats to help dose of rituximab in all exposed patients. decide whether to initiate preventative therapy The European Association for the Study of before initiating IS. To properly assess the risk the Liver 2017 Clinical Practice Guidelines on of reactivation, the following serological mark‑ the management of HBV in renal transplant re‑ ers should be tested: HBsAg, anti–HBc antibody, cipients recommend entecavir or tenofovir as anti–HBs antibody, and HBV­­‑DNA in all HBsAg­­ prophylaxis or treatment. Lamivudine is not con‑ ‑positive patients. The risk of HBV reactivation sidered the drug of choice because it has a low‑ can be divided into high (>10%), moderate (1%– er genetic barrier to resistance; especially when 10%), and low (<1%) based on the type of immu‑ administered for over 12 months. HBV serology, nosuppressive therapy stratified by the HBV se‑ including HBsAg and anti–HBs antibody levels, rology. The risk is considered high to moderate should be monitored after transplantation. Vac‑ in patients positive for anti–HBc but negative for cination pre- and posttransplantation is also rec‑ anti–HBs antibodies, whether HBsAg‑positive­­ or ommended in all patients, including those with HBsAg­­‑negative. It is lower in patients negative resolved hepatitis B, with the aim to maintain‑ for HBsAg and positive for anti–HBc anti–HBs ing HBsAb level above 100 U/l. HBsAb is an im‑ antibodies. The risk of reactivation is high in all portant natural antibody to prevent HBV infec‑ patients treated with B cell–depleting agents, in‑ tion; it may also sufficiently prevent HBV reacti‑ cluding rituximab, and may be high or moderate vation in occult HBV carriers after KTx. in those treated with high doses of steroid and After vaccination, more patients become calcineurin inhibitors. HBsAb­­‑positive, which reduces the risk for HBV In many patients, exposure to immunosuppres‑ reactivation or HBV reinfection after KTx. Al‑ sive therapy early in HBV reactivation, induces though the efficacy of vaccination is lower in im‑ the asymptomatic phase, which provides a window munosuppressed patients, a booster dose may of opportunity to initiate treatment. In HBsAg­­ induce an anamnestic response in patients with ‑positive patients, this asymptomatic phase is char‑ a history of HBV infection and decreasing HB‑ acterized by a rapid increase in HBV­­‑DNA, followed sAb levels, so vaccination may prove useful in by a rapid increase in ALT levels. In HBsAg‑negative­­ a reasonable proportion of such patients. In pa‑ patients, this asymptomatic phase is characterized tients who do not exhibit an anti–HBs antibody by the reappearance of HBsAg, and then a sudden response, monitoring viral serology remains man‑ increase in HBV­­‑DNA, followed by an increase in datory to detect reactivation. ALT levels. Taking the above into consideration, In summary, it should be emphasized that prophylaxis should be ideally started 2 to 4 weeks the need for prophylaxis or treatment of HBV before the initiation of immunosuppressive ther‑ infection depends on viral and host factors, as well apy and maintained for at least 6 to 12 months af‑ as the risk of HBV reactivation based on the type ter the last dose of the therapy. of immunosuppressive therapy. The recommendations for the management of hepatitis B reactivation are as follows (FIGURE 6): Viral infections in kidney and upper extremity trans- antiviral therapy should be started in patients plant recipients Human adenovirus infections In with chronic hepatitis B (HBsAg‑positive,­­ HBV­­ patients on IS, adenovirus may cause hemorrhag‑ ‑DNA level of ≥2000 IU/ml, increased ALT lev‑ ic cystitis and—less often—other organ involve‑ els). Inactive HBV carriers (HBsAg‑positive,­­ ment, typically within the first 3 months follow‑ HBV­­‑DNA <2000 IU/ml, normal ALT levels) ing transplantation.95 exposed to high- and moderate‑risk­­ immuno‑ suppressive therapy should undergo prophylax‑ Case report 1 A 45­­‑year­­‑old man previously is. Inactive HBsAg carriers exposed to low­­‑risk treated with hemodialysis received a kidney al‑ immunosuppressive therapy, as well as HBsAg­­ lograft from a deceased donor. The IS regimen ‑negative and anti–HBc­­‑positive patients, should included TAC, MMF, and glucocorticoids. On day be monitored (ALT and HBsAg, plus addition‑ 10 following transplantation, the patient pre‑ ally HBV‑DNA­­ in HBsAg‑positive­­ individuals). sented with dysuria, hematuria, and pain with‑ HBsAg­­‑negative and anti–HBc­­‑positive patients in the bladder area which required opioid anal‑ exposed to high‑risk­­ regimens should receive gesics. The decision was made to remove the ure‑ routine prophylaxis. teral catheter (on day 19 following transplan‑ HBsAg­­‑negative, anti–HBc­­‑positive and anti– tation), which did not improve the symptoms. HBs­­‑positive patients have a lower risk of reac‑ Urinalysis demonstrated red blood cells and mac‑ tivation than those without anti–HBs antibod‑ roscopic hematuria. On day 25 following trans‑ ies. When exposed to moderate risk of reactiva‑ plantation, adenovirus infection was confirmed tion, anti–HBV prophylaxis should be consid‑ with viruria of 1.27×106 copies/ml, and viremia ered in these patients. Alternatively, they can be of 1.65×105 copies/ml. monitored (serum ALT and HBsAg levels) every 3 MMF dose was reduced and GCV was admin‑ months until 6 months after the last dose of im‑ istered for 14 days. The viral load in blood be‑ munosuppressive therapy. HBV reactivation is came undetectable with the significantly reduced

26 POLISH ARCHIVES OF INTERNAL MEDICINE 2019; 129 (Special Issue 3) Evaluation of the risk of reactivation (reverse seroconversion) (HBsAg, anti-HBc; vaccinate if anti-HBs-negative or <100 UI/ml)

HBsAg-positive HBsAg-negative Anti-HBc-positive Anti-HBs-positive or -negative

HBV-DNA Inactive carriers ≥2000 U/ml, >ALT HBV-DNA <2000 U/ml, nALT High Moderate Low risk risk risk

Treat High Moderate Low hepatitis risk risk risk

Prophylaxis

Monitoring: HBsAg, ALT, HBV-DNA

FIGURE 6 Algorithm for management of hepatitis B reactivation (modified from Loomba and Liang. Gastroenterology. 2017; 152: 1297-1309.)

Abbreviations: ALT, alanine transaminase; anit-HBc, antibody to hepatitis B core antigen; anti-HBs, antibody to hepatitis B surface antigen; HBV, hepatitis B virus; HBsAg, hepatitis B surface antigen

viruria (2.3×105 copies/ml). After the comple‑ Parvovirus B19 infection In SOT recipients, par‑ tion of intravenous treatment, VGCV prophylax‑ vovirus B19 infection leads to anemia and retic‑ is was continued until the end of month 6 follow‑ ulocytopenia in 99% of cases. Other symptoms ing transplantation. At 3- and 6­­‑month follow­­ may include fever, joint pain, rash, leukopenia, ‑up, viruria or clinical symptoms did not recur, thrombocytopenia, as well as chronic or acute al‑ and the function of the allograft was stable with lograft dysfunction. The treatment involves im‑ a serum creatinine level of 1.5 mg/dl. munosuppressant dose reduction and intrave‑ nous immunoglobulins.96 Case report 2 A 62‑year­­ ‑old­­ male KTx recipient presented to the emergency department at 24 Case report A 45‑year­­ ‑old­­ woman with a long month following transplantation with fever history of IS due to focal segmental glomerulo‑ (40ºC), hematuria, and dysuria. He was on chronic sclerosis received KTx from a deceased donor. IS with TAC, MMF, and glucocorticoids. Diagnos‑ The kidney immediately assumed its function, and tic imaging (abdominal ultrasound and comput‑ the early postoperative course was uneventful. IS ed tomography) was requested due to significant included induction with basiliximab, followed by hematuria, and massive interstitial nephritis of TAC, MMF, and glucocorticoids. Six weeks follow‑ the allograft was diagnosed. Cystoscopic exami‑ ing TAC, she was admitted to our department on nation demonstrated blood­­‑stained urine leaking an emergency basis due to anemia, stenocardia, from the allograft, along with hyperemia and in‑ and exercise dyspnea. The follow­­‑up hemoglobin flamed mucosal membranes of the bladder. Urine level was 7.4 g/dl; leukoreduced red blood cell cultures were negative; however, adenovirus was (RBC) unit were administered and MMF dose was detected in blood (3.28×102 copies/ml) and urine reduced. The patient was readmitted 3 weeks lat‑ (3.35×106 copies/ml) samples. MMF was tempo‑ er due to significant anemia and leukopenia (he‑ rarily discontinued. The patient was started on moglobin, 6.9 g/dl; white blood cell count, 2.74 GCV (for 18 days) and VGCV was continued. Such K/µl). The graft function was normal. Virology treatment resolved clinical symptoms and cleared testing confirmed very high blood B19 parvovirus the virus from the blood and urine. The patient levels (>107 copies/ml). Leukoreduced RBC unit was restarted on MMF 3 months later. Follow­­ and 10 g of intravenous immunoglobulin were ad‑ ‑up assessment at 12 months and 3 years did not ministered and MMF was discontinued. Another demonstrate reactivation of infection. 3 weeks later, the patient was hospitalized again

PART II Specific issues in management of viral infections in transplant recipients 27 FIGURE 7 Vesicular lesions of varicella zoster virus infection on the sole of the patient’s foot.

due to urinary tract infection caused by K. pneu‑ microscopically detectable lesions in transplant‑ moniae. Along with antibiotics, she was admin‑ ed kidneys, the in situ hybridization techniques istered 20 g of intravenous immunoglobulin and confirmed the CMV presence within the tubular 3 packs of leukoreduced packed red blood cells. epithelium of about 40% of kidney allografts.98 The parvovirus B19 viral load still remained high Classic microscopic manifestation of CMV in‑ (>107 copies/ml). Additionally, TAC was switched fection includes cytopathy affecting epitheli‑ to CsA. Later, the patient experienced similar inci‑ um, less often endothelium (FIGURES 7 and 8), and dents of urinary tract infection and anemia twice (the least often) inflammatory mononuclears.99 at 1‑month­­ interval. From month 7 following Among CMV­­‑induced cellular changes, the most the onset of symptoms, anemia was controlled, characteristic are the oval inclusions, situated viral load was undetectable, and the function of centrally within the nucleus, with darker center the allograft kidney was normal. and bright, crescent­­‑shaped periphery (thus re‑ sembling an “owl’s eye” appearance). Apart from Varicella zoster virus infections VZV causes the oc‑ those intranuclear inclusions, tiny basophilic cy‑ currence of serous blisters and vessicles on an er‑ toplasmic inclusions can also be seen in some cas‑ ythematous base within the involved segment of es. Along with cytopathy, cellular inflammatory the nervous system. In immunocompetent in‑ response may be present, sometimes with the for‑ dividuals, the face, torso and chest are typical‑ mation of epithelial granulomas or tiny parenchy‑ ly affected. In SOT recipients, the infection can mal abscesses. Due to the nonspecific morpholo‑ be diffuse.97 gy of interstitial inflammatory infiltrate the di‑ agnostic differential must include an acute tu‑ Case report A 40­­‑year old male upper extremity bulointerstitial rejection. Apart from CMV ear‑ allograft recipient presented to the emergency de‑ ly nuclear protein, CMV mRNA, or CMV protein partment with severe pain in his right hip and sacral revealed by immunohistochemical or in situ hy‑ bone. The symptoms, which were not associated bridization assays of help may be immunomor‑ with other clinical symptoms or abnormal laborato‑ phological evaluation of major histocompatibility ry test parameters, left him immobile and he need‑ complex class II antigens (HLA­­‑DR). The demon‑ ed opioid analgesia. For 74 months following upper stration of HLA­­‑DR expression on the surface of extremity transplant, the patient was on long­­‑term tubular epithelium is suggestive of allograft rejec‑ IS based on TAC, MMF, and glucocorticoids. The re‑ tion. There have been reports indicating potential sults of abdominal ultrasound, chest X‑ray,­­ lumbo‑ involvement of CMV in the post­­‑transplantation sacral spinal X‑ray,­­ and hip X­­‑ray were insignificant. thrombotic microangiopathy, that could be trig‑ After 3 days following admission, the linear vessicu‑ gered by CMV­­‑induced production of anticardio‑ lar lesions on the sole of the patient’s foot were no‑ lipin antibodies. In rare cases, CMV infection can ticed, consistent with VZV infection (FIGURE 7). ACV lead to acute glomerulopathy (FIGURES 8 and 9).100 treatment was started, initially intravenously, fol‑ The only method to confirm BKV­­‑associated ne‑ lowed by oral formulation (for a total of 17 days), phropathy is a core needle biopsy of the kidney. and the dose of MMF was reduced. The treatment However, it should be noted that the infection­­ led to gradual symptom resolution. ‑related lesions are focal, which increases the risk of sampling error if only tiny, single tissue frag‑ Histological diagnosis of BK virus and cytomegalovi- ments from the superficial renal cortex are col‑ rus infections Even though CMV rarely causes lected during the biopsy.101 BKVAN is diagnosed

28 POLISH ARCHIVES OF INTERNAL MEDICINE 2019; 129 (Special Issue 3) FIGURE 8 Acute based on virus replication in tubular epithelial cytomegalovirus cells and/or the Bowman’s capsule epithelium glomerulopathy (acid which may be revealed by immunohistochemis‑ fuchsin orange G try or in situ hybridization methods. A character‑ staining). Cytopathic istic, but not always present feature that accom‑ lesions (hypertrophy and panies virus replication, is the presence of intra‑ nuclear enlargement) in nuclear inclusion in the tubular, as well as pari‑ endothelial cells. etal (Bowman’s capsule) epithelial cells (FIGURE 10). In early stages of the infection, the only man‑ ifestation of virus replication may be necrosis of single tubular epithelial cells.102 In some cas‑ es, tiny focal areas of polymorphic inflammato‑ ry infiltration or fibrosis can be present within the interstitium, often only within the medulla. FIGURE 9 Acute At early stages of BKVAN, intranuclear viral in‑ cytomegalovirus (CMV) clusions may be unnoticeable; which makes a di‑ glomerulopathy, CMV agnosis fully dependant on viral antigen detec‑ nuclear viral inclusions in tion (FIGURE 11) in tubular or glomerular parietal endothelial cells epithelial cells. Another sign of BKV­­‑associated (immunohistochemical nephropathy is the presence of virion clusters staining with anti–CMV forming structures that may be visualized in urine antibodies). samples by electron microscopy. Late‑stage­­ BK‑ VAN is characteristically manifested by the de‑ generation and necrosis of infected epithelial cells as well as tubulointerstitial nephritis and tubulointerstitial scarring. Along with the pres‑ ence of lymphocytes and—less often—neutro‑ phils, another feature of BKVAN is a significant concentration of plasma cells in the interstitium; FIGURE 10 some of which may also invade tubular epitheli‑ BK virus–associated um. In some cases, the described lesions may be nephropathy; concomitant with less specific morphologic ab‑ intraepithelial viral normalities such as pseudo crescents formation inclusions and acute (associated with BKV­­‑induced damage and pro‑ tubular necrosis (HE) liferation of the parietal glomerular epithelium), as well as immune complexes deposition within tubular basal membranes.103 The coexistence of BKV intraepithelial repli‑ cation with endarteritis, capillarities (glomeru‑ lar and/or peritubular) or microscopic signs of complement activation within the allograft tis‑ sue implicates the recognition of concomitant BKVAN and acute rejection. Due to identical mor‑ phologic presentation in the interstitial compart‑ ment, differentiation between isolated BKVAN and BKVAN superimposed on acute tubulointer‑ stitial rejection is much more challenging. How‑ ever, the distinction between these two clinical FIGURE 11 situations has the key significance, due to differ‑ BK virus–associated ent management algorithms. nephropathy. Nuclear viral inclusions in tubular Viral diarrhea Gastrointestinal symptoms are epithelium marked by present in 40% to 70% of transplant recipients. brown coloration in They are typically ascertained from the history. the immunohistochemical According to the United Network for Organ Shar‑ reaction with anti­­‑SV40 ing data, 11.5%, 17.5%, and 22.6% of KTx recipi‑ antibody. ents experience diarrhea within 1, 2, and 3 years after transplantation, respectively.104 WHO de‑ fines diarrhea as the passage of 3 or more loose or liquid stools per day, whereas persistent diarrhea lasts for over 1 month. Diarrhea in transplant re‑ cipients causes increased morbidity, need for inpa‑ tient treatment, acute kidney injury due to dehy‑ dration, variable exposure to immunosuppresants

PART II Specific issues in management of viral infections in transplant recipients 29 causing nephrotoxicity or acute rejection, and course. The incubation period lasts 2 to 4 days, impaired survival and quality of life. Diarrhea in the onset is acute, and the symptoms include fe‑ transplant recipients can have an infectious or ver, vomiting, and watery diarrhea lasting 3 to 8 noninfectious etiology. Infectious diarrhea can days. The virus remains present in the stool for 1 be caused by bacteria, viruses, fungi, and para‑ to 3 weeks. The infection usually develops in re‑ sites, whereas noninfectious one can be induced cipients of intestinal or liver transplant and in by immunosuppressants, other medications, and children recipients. The treatment is symptom‑ comorbidities, such as graft versus host disease, atic. The attenuated vaccine is available yet con‑ PTLD, inflammatory bowel disease, colon cancer, traindicated in transplant recipients. and malabsorption syndrome.105 Among 7 DNA groups (A­­‑G) of adenovirus‑ Among viruses, CMV, norovirus, rotavirus, es, groups F (AdV 40 and 41) and G (AdV 52) sapovirus, and adenovirus are the most com‑ are known to cause gastroenteritis, manifesting mon causes of diarrhea in transplant recipients. as fever, vomiting, and diarrhea. The infection CMV is responsible for 5% to 20% of diarrhea in in transplant recipients may develop as a reac‑ transplant recipients. Clinically, such infection tivation of a latent infection or donor­­‑derived presents as gastroenteritis with symptoms from infection. The infection usually develops with‑ the entire gastrointestinal tract (esophagus, stom‑ in the first few months following transplanta‑ ach, small intestine, and colon). The diagnosis of tion, often with an involvement of an entire al‑ gastrointestinal CMV disease should be based on lograft. If diarrhea is the only symptom, the treat‑ viral load testing (preferably using quantitative ment should be symptomatic. If involvement of PCR assay) and histological confirmation of in‑ at least 2 organs is confirmed, antiviral treatment fected cells (preferably immunohistochemistry with cidofovir, ribavirin, or brincidofovir should or in situ hybridization). It should be noted that be attempted. the viral load may be undetectable in about 15% of cases of gastrointestinal CMV disease. Gastro‑ Ground glass opacification “Ground glass opaci‑ intestinal CMV disease should be treated in line fication (GGO)” is a descriptive term used in ra‑ with the general guidelines on CMV treatment diology, referring to an area of increased attenu‑ (GCV is the first­­‑line treatment). However, some ation in the lung on computed tomography with patients may need longer treatment.106 Other vi‑ preserved bronchial and vascular markings.109 ruses can be detected in stool samples using mo‑ It is a nonspecific sign with a wide etiology in‑ lecular biology assays. Modern diagnostic tech‑ cluding pathologies with alveolar or interlobu‑ niques significantly increased the detection of vi‑ lar septal involvement. It is seen when the alveoli ral diarrhea (from 23% to 72%), and demonstrat‑ are incompletely filled with transudate, exudate, ed that a significant percentage (39%) of diarrhea blood, or cellular infiltration, or when the pulmo‑ have a mixed etiology. Multiplex PCR platforms nary interstitium thickens as a result of fibrosis, are capable of multiple matrix amplification dur‑ edema, or cellular infiltration. The described le‑ ing a single polymerase chain reaction, which can sions can be chronic or acute. In transplant recip‑ detect over 20 pathogens in a stool sample with‑ ients (but not only), clinical information regard‑ in 1 hour.107 ing the patient’s immune status, nature, and du‑ Norovirus (single‑stranded­­ RNA virus) causes ration of symptoms, smoking status and comor‑ outbreaks of acute diarrhea resolving after 2 to 3 bidities are the key to accurate differential di‑ days in immunocompetent individuals. In trans‑ agnosis. Viral, bacterial, and fungal infections, plant recipients, norovirus is responsible for 17% malignancies and drug­­‑induced abnormalities to 26% of diarrhea, which can be acute or chronic, may all present as GGO. and the virus is excreted in stool for a relatively One of significant pathologies seen in trans‑ long time. Almost 80% of hospitalized patients plant recipients is angioinvasive aspergillosis, present with acute kidney injury reversible after which typically manifests as consolidated nod‑ rehydration therapy. In transplant recipients, ules surrounded by the GGO forming a crescent the course is usually 2­­‑stage, with acute symp‑ shape (halo sign)110 (FIGURE 12) Although GGO can toms followed by a cycle consisting of a period of be seen in other pathologies (eg, granulomato‑ normal stools and a period of abnormal stools. sis with polyangiitis, malignancies, or viral in‑ Clinical observation supports the adverse effect fections), in antibiotic­­‑resistant cases, it is con‑ of chronic noroviral diarrhea on the function of sidered pathognomonic for Aspergillus fumigatus kidney allograft. Treatment is usually symptom‑ infection.111 Treatment and improving immune atic, and there have been attempts to reduce IS status of a patient results in separation of necrot‑ and use oral or intravenous human immunoglob‑ ic parenchyma from healthy parenchyma, which ulins as well as antiparasitic nitazoxanide. There presents as the “air crescent sign.”112 is no available vaccine.108 Sapovirus (identified Other pathologies present in transplant recip‑ during an outbreak of gastroenteritis in Sapporo ients include CMV and P. jiroveci infections. Ra‑ in 1982) causes milder diarrhea than norovirus. diographic features of CMV infection (just as it The symptoms resolve within 7 days and treat‑ is with other viruses) are nonspecific and typi‑ ment should be symptomatic. cally involve bilateral blot­­‑like or confluent ar‑ Rotavirus infections (1%-15% of all posttrans‑ eas of GGO, tiny nodules, and alveolar consol‑ plant diarrhea cases) have the most severe clinical idation113,114 (FIGURE 13). Radiographic features of

30 POLISH ARCHIVES OF INTERNAL MEDICINE 2019; 129 (Special Issue 3) a CNI­­‑based regimen: A systematic review and meta­­‑analysis of random- FIGURE 12 Halo sign in ized, controlled trials. Clin J Am Soc Nephrol. 2017; 12: 1321-1336. angioinvasive pulmonary 6 Gatault P, Halimi JM, Forconi C, et al. CMV infection in the donor and in- aspergillosis creased kidney graft loss: impact of full HLA­­‑I mismatch and posttransplan- tation CD8(+) cell reduction. Am J Transplant. 2013;13: 2119-2129. 7 Futohi F, Saber A, Nemati E, et al. Human leukocyte antigen alleles and cytomegalovirus infection after renal transplantation. Nephrourol Mon. 2015; 7: e31635. 8 Li S, Zhu J, Zhang W, et al. Signature microRNA expression profile of es- sential hypertension and its novel link to human cytomegalovirus infection. Circulation. 2011; 124: 175-184. 9 Maussang D, Langemeijer E, Fitzsimons CP, et al. 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Cytomegalovirus and cancer Cytomegalovirus infection after kidney transplantation: Role of the human leukocyte antigen system? manifested by bilateral Transpl Infect Dis. 2017; 19.doi: 10.1111/tid.12631. ground glass opacity 14 Bachelet T, Merville P, Dechanet­­‑Merville J, Couzi L. cytomegalovirus­­ areas on computed ‑induced gammadelta T cells during rejection: an ambivalent T cell. Am J Transplant. 2016; 16: 368-369. tomography 15 Couzi L, Manook M, Perera R, et al. Difference in outcomes after antibody­­‑mediated rejection between abo­­‑incompatible and positive cross­­ ‑match transplantations. Transpl Int. 2015; 28: 1205-1215. 16 Kotton C, Kumar D, Caliendo A, et al. on behalf of The Transplantation Society International CMV Consensus Group. Updated international consen- sus guidelines on the management of cytomegalovirus in solid organ trans- plantation. Transplantation. 2013; 96: 333-360. 17 Hodson E, Ladhani M, Webster A, et al. Anitiviral medications for pre- venting cytomegalovirus disease in solid organ transplants recipients. Co- chrane Database Syst Rev. 2013; 2: CD003774. 18 Gabardi S, Asipienko N, Fleming J, et al. Evaluation of low­­‑versus high­­ P. jiroveci infection also include GGO, forming ‑dose valganciclovir for prevention of cy tomegalovirus disease in high­­‑risk a pattern of reticular opacities caused by inter‑ renal transplant recipients. Transplantation. 2015; 99: 1499-1505. lobular septal thickening. Clinical features of P. 19 Cameron B, Kennedy S, Rawlinson W, Mackie F. The efficacy of valgan- ciclovir for prevention of infections with cytomegalovirus and Epstein­­‑Barr jiroveci infection include pneumatocele (which— virus after kidney transplantation. Pediatr Transplant. 2017: 21: e12816. if ruptured—may lead to pneumothorax), pe‑ 20 Radtke J, Dietze N, Spetzler VN, et al. 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Sta- nal transplant recipients receiving an mTOR inhibitor­­‑based regimen versus bilization of renal function after the first year of follow­­‑up in kidney

PART II Specific issues in management of viral infections in transplant recipients 31 transplant recipients treated for significant BK polyomavirus infection or 60 Gottlieb MS, Schroff R, Schanker HM, et al. Pneumocystis carinii pneu- BK polyomavirus­­‑associated nephropathy. Transpl Infect Dis. 2017; 19. doi: monia and mucosal candidiasis in previously healthy homosexual men: ev- 10.1111/tid.12681. idence of a new acquired cellular immunodeficiency. N Engl J Med. 1981; 32 Thölking G, Schmidt C, Koch R, et al. Influence of tacrolimus metab- 305: 1425-1431. olism rate on BKV infection after kidney transplantation. Sci Rep. 2016; 6: 61 Poiesz BJ, Ruscetti FW, Gazdar AF et al. Detection and isolation of 32273. type C retrovirus particles from fresh and cultured lymphocytes of a pa- 33 van Doesum WB, Gard L, Bemelman FJ, et al. Incidence and outcome tient with cutaneous T­­‑cell lymphoma. 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Human immunodeficiency virus 2015; 390: 211-240. infection does not worsen prognosis of liver transplantation for hepatocellu- 36 Piedade D, Azevedo­­‑Pereira JM. The role of microRNAs in the patho- lar carcinoma. Hepatology. 2016; 63: 488-498. genesis of herpesvirus infection. Viruses. 2016; 8: 156. 65 Hathorn E, Smit E, Elsharkawy AM, et al. HIV­­‑positive­­‑to­­‑HIV­­‑positive 37 Maylin S, Feghoul L, Salmona M, et al. Evaluation the Architect EBV liver transplantation. N Engl J Med. 2016; 375: 1807-1809. VCA IgM, VCA IgG and EBNA­­‑1 IgG chemiliminescent immunoassays 66 Gómez V, Fernández A, Galeano C, et al. Renal transplantation in HIV­­ to assess EBV serostatus prior transplantation. J Med Virol. 2017; 89: ‑infected patients: experience at a tertiary hospital in Spain and review of 2003-2010. the literature. Transplant Proc 2013; 45:1255. 38 Moustafa A, Xie Ch, Kirkness E, et al. The blood DNA virome in 8000 67 Qiu J, Terasaki PI, Waki K, et al. HIV­­‑positive renal recipients can humans. PlosPathogens. 2017; 13: e1006292. achieve survival rates similar to those of HIV­­‑negative patients. Transplan- 39 Roy SG, Robertson ES, Saha A. Epigenetic impact on EBV associated tation 2006; 81: 1658. B­­‑cell lymhogenesis. Biomoleculars. 2016; 6: 46. 68 Roland ME, Barin B, Carlson L, et al. HIV­­‑infected liver and kidney 40 Le J, Durand ChM, Agha I, Brennan DC. Ebstein­­‑Barr virus and renal transplant recipients: 1- and 3­­‑year outcomes. Am J Transplant 2008; 8: transplannation. Transplant Rev. 2017; 31: 55-60. 355. 41 Teiken K, Kreipe H, Maecker­­‑Kolhoff B, Hussein K. Variant of classical 69 Stock PG, Barin B, Murphy B, et al. Outcomes of kidney transplantation high grade PTLD: post­­‑transplant EBV­­‑negative T cell lymphoblastic leukae- in HIV­­‑infected recipients. N Engl J Med 2010; 363: 2004. mia after solid organ transplantation. Ann Hematol. 2017; 96: 1403-1405. 70 Muller E, Kahn D, Mendelson M. 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Oncol Res Treat. 2017; 40: 334-340. experience. Transplant Proc. 2016; 48: 2315-2318. 79 Zhang D, Zhang W, Liu W, et al. Human papillomavirus infection in- 51 Kumar D, Morris M, Kotton CN, et al. Guidance on novel influenza A/ creases the chemoradiation response of esophageal squamous cell carcino- H1N1 in solid organ transplant recipients. Am J Transplant. 2010; 10: 18-25. ma based on P53 mutation. Radiother Oncol. 2017; 124: 155-160. 52 Berenguer M. Systematic review of the treatment of established re- 80 Zhang L, Epstein JB, Poh CF, et al. Comparison of HPV infection, p53 current hepatitis C with pegylated interferon in combination with ribavirin. J mutation and allelic losses in post­­‑transplant and non­­‑posttransplant oral Hepatol. 2008; 49: 274-287. squamous cell carcinomas. J Oral Pathol Med. 2002; 31: 134-141. 53 Polish Group of Experts for HCV, Halota W, Flisiak R, Juszczyk J, et al. 81 Caforio AL, Pankuweit S, Arbustini E, et al. 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PART II Specific issues in management of viral infections in transplant recipients 33

PART III COMMENTARY

The art of immunosuppression in liver transplantation: personal reflections based on a 40­­‑year career

Jan Lerut1, Samuele Iesari2 1 Universite Catholique Louvain Brussels, Belgium, Former Head of Starzl Abdominal Transplant Unit 2 DISCAB, University of L’Aquila, L’Aquila, Italy

Introduction Since the introduction of liver trans‑ Although the immunopriviledged status of a liv‑ plantation (LTx) in clinical practice by Th. E. Starzl er was proven a long ago, both in the laboratory and in 1963, major progress has been made in short­­ in clinical practice, clinicians were pushed by nu‑ ‑term outcomes. Indeed, organ procurement and merous industry driven studies to use increasingly preservation techniques, transplant surgery itself stronger IS schemes in order to virtually eliminate and perioperative care have all improved substan‑ ACR. With more experience, a curious constella‑ tially. Despite this progress, long‑term­­ survival tion has become noticeable that the incidence of rates remained almost unchanged, which can be ACR remained similar despite using much stronger easily noticed when comparing the survival rates CNi­­‑based IS schemes. It was only trough a better over the two last decades, having first eliminat‑ understanding and uniformization of transplant ed the early mortality (6‑month­­ post­­‑LTx) data. pathology (cf. Banff classification and classification This is explained by the fact that many recipients of antibody mediated or humoral rejection) that die—most of them with a functioning graft— the rejection process became considered a physi‑ due to cardiovascular, infectious and oncologic ological event inherent to the mixing of the donor (de novo tumor formation) complications, all of and recipient immune systems (cf. chimerism). It them linked directly or indirectly to the life‑long­­ was understood that this interaction should be al‑ intake of noxious immunosuppressants. With 85 lowed to take place under the umbrella of an ide‑ to 90% of recipients surviving the early post­­‑LTx ally individualized IS rather than forcefully sup‑ period, the transplant community should focus pressed. Both experimental and clinical studies on these complications and thus on the quality of SOT confirmed the importance of this interac‑ of life of liver allograft recipients. A thorough re‑ tion, providing an explanation so as to why recip‑ flection about the use of immunosuppressants is, ients who had a controlled ACR may have a signif‑ therefore, more than welcome in the beginning icantly better long­­‑term outcome. of this millennium (TABLE 1) Along with an obvious immunologic advan‑ Fifty years ago, clinicians developed immuno‑ tage, a number of other reasons support mini‑ suppression (IS) schemes, which aimed at eliminat‑ mal IS schemes such as high risk of cardiovas‑ ing acute cellular rejection (ACR) of liver allograft cular (20%), oncologic (10 to 20%) or infectious at any cost. It all started in the early 1960’s with complications, kidney failure (20%) and metabolic the “secret cocktail” of steroids and azathioprine. syndrome (40%). All these complications signifi‑ This rather simplistic IS scheme enabled stable 25% cantly impact on long­­‑term survival rates, some survival, despite almost unsurmountable technical of them becoming relevant only after 10 years. and peri‑operative­­ problems at that time. Later on, Every effort should, therefore, be undertaken to Correspondence to: antilymphatic sera were added to this cocktail aim‑ counteract such evolution. Reducing the immuno‑ Prof. Jan Lerut, MD, PhD, ing essentially at reducing numerous physical and suppressive burden should nowadays be the pri‑ FACS, Institut de Recherche Clinique, Université catholique psychological side effects of chronic steroid intake. ority of every transplant center. Louvain, Avenue Hippocrate The introduction of calcineurin inhibitors (CNi) 55, 1200 Woluwé-Saint-Lambert, in the early 1980s, first cyclosporine A and later How to proceed to fulfil all these requirements? IS Brussels, Belgium, on tacrolimus, represented a major breakthrough reduction should start by avoiding or eliminat‑ phone: +32 475 859504, email: [email protected] paving the way for selective IS resulting in a 80% ing steroids, which are the most noxious of all Conflict of interest: none declared. survival of both patients and grafts. immunosuppresants. Whereas eliminating CNi

PART III COMMENTARY Immunosuppresion in liver transplantation 35 TABLE 1 Dogmas (or fixed beliefs) on immunosuppression (IS) to be reversed in liver such as acute (cellular and/ or humoral) rejec‑ transplantation tion or renal insufficiency, a combined end­­‑point Every moderate or severe (Banff score >6) rejection needs to be treated. should rather be assumed comprising patient and graft survival, as well as the incidence of chronic Multidrug antirejection therapy is better than monodrug calcineurin inhibitor–based IS. rejection. It also implies developing a long­­‑term Steroid containing IS is better than steroid free IS. strategy for protocol liver biopsy. Mycophenolate mofetil is more effective than azathioprine. Many publications, even in the highest im‑ m­‑Tor inhibition–based IS is better than calcineurin inhibitor minimization in relation to pact factor transplantation journals, omitted renal sparing. the comparison of immunosupressive schemes m­‑Tor inhibition–based IS improves results of transplantation for hepatocellular with the real standard of care. This strategy has cancer. hampered major improvements in relation to long­­ ‑term patient outcomes over the last two decades. It is now the task of all transplant professionals to has been shown to be a risky undertaking, ste‑ take up this challenge seriuosly and to embark on roid withdrawal or avoidance has been proven to well designed, investigator­­‑driven studies. be feasible and safe, since the seminal paper by A plea should also be made to reorganize trans‑ Padburg et al. After a long period of hesitation, plantation clinics in order to centralize care pro‑ IS without long­­‑term (ie, months) steroid use has vided for transplant recipients, often presenting become a common practice, especially in Europe. with numerous comorbidities. Such centralization If the liver tests remain stable, one can take one will not only contribute to improved efficiency; it more step towards subtherapeutic monotherapy. will also be of utmost importance in the expand‑ The next step of the minimization philosophy is ing field of transplant oncology. Indeed, widen‑ to go for a monodrug CNi­­‑based therapy. At long­­ ing the inclusion criteria of primary and second‑ ‑term, IS monotherapy can consist of either CNi ary liver tumors implies a very good interaction or an antimetabolite, depending on potential neu‑ between immunology and oncology in order to ro- and especially nephrotoxicity. The subthera‑ achieve a maximum possible reduction of tumor peutic monotherapy IS strategy again has been recurrence. Evidently, the minimization approach proven to be feasible as well as safe. These three is also of importance in reducing the risk for bac‑ steps have without any doubt led to a marked im‑ terial fungal as well as viral diseases. provement in the quality of life of the patients as well as an improved renal profile. Conclusion Despite major progress in early out‑ Consequently, the question should be put for‑ comes, long­­‑term outcomes after liver transplan‑ ward whether it is desirable to further walk down tation remain compromised by the development the road towards clinical operational tolerance of many side‑effects­­ linked to the chronic use (COT). The COT road has undoubtedly been vi‑ of immunosuppressants. Based on the immu‑ olated frequently by the IS studies, those poor‑ noprivileged status of liver allograft, the trans‑ ly designed or even excessive, and by numerous plantology community should wholeheartedly changes to IS care of a given recipient. Indeed, one support immunosuppressive minimization pro‑ should opt for a continuity of care and vision in tocols. Good and consistent results can only be the follow­­‑up of transplant recipients, a condition obtained by standardization and uniformization very frequently lacking in daily clinical practice. of liver transplant clinics. Part of the success will Each change in the assumptions of the IS plan depend on the set up of well‑performing,­­ outpa‑ of an individual patient inevitably disrupts their tient liver biopsy clinics. tolerogenic process. Just like it is seen in mod‑ ern traveling, a destination (a city or region) can REFERENCES be reached using different means of transporta‑ 1 Starzl TE. 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36 POLISH ARCHIVES OF INTERNAL MEDICINE 2019; 129 (Special Issue 3)