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Epidemiology and Outcomes of Early-Onset and Late-Onset Adenovirus Infections in Kidney Transplant Recipients

Epidemiology and Outcomes of Early-Onset and Late-Onset Adenovirus Infections in Kidney... Downloaded from https://academic.oup.com/ofid/article-abstract/6/12/ofz489/5625281 by DeepDyve user on 06 December 2019 Open Forum Infectious Diseases MAJOR ARTICLE Epidemiology and Outcomes of Early-Onset and Late-Onset Adenovirus Infections in Kidney Transplant Recipients 1,2 2,3 4 4 2,5 1 Jackrapong Bruminhent, Suchin Worawichawong, Chutatip Tongsook, Ekawat Pasomsub, Sarinya Boongird, and Siriorn P. Watcharananan 1 2 Division of Infectious Diseases, Department of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand, Excellence Center of Organ Transplantation, Faculty 3 4 of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand, Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand, Division of Virology, Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand, and Division of Nephrology, Department of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand Objective. Adenovirus (ADV) infection aer k ft idney transplantation (KT) causes significant morbidity. Patient characteristics and outcomes of ADV infection in KT recipients were investigated. Method. All adult KT recipients with ADV infection between January 2015 and June 2019 were included. ADV infection/dis- ease was defined as detection of ADV DNA in clinical specimens/plus symptoms. Clinical and laboratory findings, treatments, and outcomes were assessed. Results. Adenovirus infection was diagnosed in 24 of 751 (3.2%) KT recipients. Twenty (83%) were male with a median age of 47 years (interquartile range [IQR], 36–58). Fifteen (63%) underwent deceased donor KT, and 13 (54%) received induction therapy. Twenty-one (88%) and 4 (17%) patients developed hemorrhagic cystitis and disseminated disease, respectively. There were equal distributions of early-onset (EOI) (≤3  months) and late-onset (LOI) (>3  months) infections. Patients who were diagnosed with 3 3 EOI had lower median absolute lymphocyte counts compared with those with LOI (735/mm [IQR, 543–1123] vs 1122/mm [IQR, 784–1344], P = .04). All achieved resolution aer r ft eduction of their immunosuppression regimen and 13 (54%) received cidofovir therapy. Eighteen (75%) developed allograft dysfunction, of which 67% were transient. One (4%) underwent nephrectomy for al- lograft failure and 1 (4%) died (non-ADV–related). Patients with EOI were more likely to receive cidofovir therapy (75% vs 33%, P = .04) and develop other opportunistic infections (75% vs 8%, P < .001). Conclusions. Adenovirus infection aer KT t ft ypically involves a genitourinary system and transiently impairs an allograft func- tion. Those who developed early infection tend to have more lymphopenia, coinfection, and receive antiviral therapy. Keywords: absolute lymphocyte count; cidofovir; cytomegalovirus; hemorrhagic cystitis; human adenovirus; lymphopenia. INTRODUCTION pneumonitis, hepatitis, and gastroenteritis, which occasionally result in severe disseminated infection affecting multiple organs Adenovirus (ADV) is a nonenveloped double-stranded DNA [2]. Only a few published reports mention the epidemiology of virus that can cause a wide variety of clinical symptoms in hu- ADV infection in adult KT recipients. Our team retrospectively mans. Adenovirus infection usually is asymptomatic or mild reviewed the incidence of ADV infection in adult KT recipients, in immunocompetent individuals, but it can cause substantial and it was approximately 4.9% [3, 4]. As well as clinical and morbidity in immunocompromised individuals [1]. In kidney histopathological findings, nucleic acid amplification testing transplant (KT) patients, ADV can cause localized and invasive (NAAT) has been utilized for the diagnosis and monitoring of end-organ diseases, including hemorrhagic cystitis, nephritis, ADV infection after KT [2]. Virus-specific immune monitoring has recently been explored in the management of solid organ transplant (SOT) recipients [5, 6]. A  low absolute lymphocyte Received 13 August 2019; editorial decision 6 November 2019; accepted 11 November 2019. count (ALC) is associated with early ADV infection resulting in Correspondence: Jackrapong Bruminhent, MD, Division of Infectious Diseases, Department of Medicine and the Excellence Center of Organ Transplantation, Faculty of significant morbidity after KT [3]. In a recent study, the restora- Medicine Ramathibodi Hospital, Mahidol University, 270 Rama VI Rd., Ratchathewi, Bangkok, tion of ALC and ADV-specific T-cell immunity was correlated 10400, Thailand. Email: jbruminhent@gmail.com with viral clearance in KT recipients [7]. The management of Open Forum Infectious Diseases © The Author(s) 2019. Published by Oxford University Press on behalf of Infectious Diseases ADV infection in SOT recipients mainly involves the reduction Society of America. This is an Open Access article distributed under the terms of the Creative of their immunosuppression regimen combined with cidofovir Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/ by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any therapy. For the last few years, NAAT and cidofovir have been medium, provided the original work is not altered or transformed in any way, and that the accessible more at our transplant center. In the present study, we work is properly cited. For commercial re-use, please contact journals.permissions@oup.com DOI: 10.1093/ofid/ofz489 investigated the incidence of ADV infection after KT, aspects of Adenovirus Infection in Kidney Transplant • ofid • 1 Downloaded from https://academic.oup.com/ofid/article-abstract/6/12/ofz489/5625281 by DeepDyve user on 06 December 2019 its epidemiology, diagnosis, and management, and patient out- recorded, as were treatment details. Intravenous (IV) cidofovir comes during the study period. Severe or disseminated ADV at a dose of 5  mg/kg, 1  mg/kg 3 times weekly, or 0.5  mg/kg 3 infection can require cidofovir therapy, but clinicians may hes- times weekly (those with creatinine clearance <50  mL/min) itate to administer it to KT recipients in view of potential drug- and IV immunoglobulin (IVIG) therapy at doses ranging from related nephrotoxicity. Herein, we report our experiences in the 0.5–2.0  g/kg was prescribed based on current guidelines [8]. management of ADV infection in KT recipients using cidofovir, Outcomes were recorded, including clinical and virological res- in terms of clinical and virological resolutions, adverse reac- olution, patient survival, allograft function, and opportunistic tions, allograft outcomes, and rates of rejection after therapy. infection other than ADV. Allograft function was calculated as the estimated glomerular filtration rate as determined via ei- METHODS ther the Cockcroft‐Gault Formula, the Modification of Diet in Renal Disease Study Equation, or the Chronic Kidney Disease All adult KT recipients diagnosed with ADV infection between Epidemiology Collaboration equation. Transient allograft dys- January 2015 and June 2019 at a single transplant center in function was defined as any estimated glomerular filtration rate Bangkok, Thailand, were included in the present study. At our (eGFR) reduction compared to baseline that subsequently re- center, trimethoprim/sulfamethoxazole for pneumocystis pro- turned to baseline after the resolution of infection. Allograft phylaxis, acyclovir for herpes simplex virus prophylaxis, and failure and loss was defined as an irreversible estimated glo- isoniazid for latent tuberculous infection therapy (regardless of merular filtration rate reduction requiring chronic hemodial- status) were prescribed in all patients. Surveillance testing for ysis and/or retransplantation. The Institutional Review Board cytomegalovirus (CMV) infection was performed due to a high of the Faculty of Medicine of Ramathibodi Hospital, Mahidol prevalence of CMV-seropositive recipients, except for those re- University, Bangkok, Thailand, approved the study protocol quiring antithymocyte globulin induction therapy when (val) and waived the requirement to obtain any informed consent. ganciclovir prophylaxis was implemented. Instead, surveillance for ADV infection was not performed routinely. Only patients Statistical Analyses clinically suspected of ADV infection or exhibiting a consistent Patient demographic data and clinical characteristics were as- etiology underwent investigation, and other pathogens that sessed via descriptive analysis. Categorical data were described were potentially responsible for their symptoms were excluded as absolute and relative frequencies, and continuous data were in the patients included in the study. Adenovirus infection was described as medians with interquartile ranges (IQRs). Clinical defined as detection of ADV by NAAT in plasma or organ- and laboratory findings, treatments, and outcomes in those specific specimens. Adenovirus disease was defined as ADV with EOI and LOI were compared via the Mann-Whitney test infection combined with at least 1 specific organ symptom. and χ test for continuous and categorical data, respectively. P Disseminated ADV disease was defined as ADV disease with values <.05 determined via a 2-tailed test were considered sta- the involvement of at least 2 specific organs. Early (EOI) and tistically significant. Statistical analyses were performed with late (LOI) onset ADV infection was defined as the occurrence Stata statistical software (version 15, StataCorp, LLC, College within and after 3 months, respectively. Adenovirus DNA loads Station, TX). in plasma and urine specimens were measured via quantitative real-time polymerase chain reaction (PCR) assays (Adenovirus RESULTS R-Gene US Real-Time PCR kit, bioMérieux, Marcy l’Etoile, France, from January 2015 until August 2018, and Adenovirus Epidemiology and Demographic Data ELITe MGB Kit, ELITech Group SpA, Turin, Italy, thereafter). During the study period, 751 KTs were performed at our trans- Adenovirus DNA load was reported as log10 copies/mL with plant center, and of these, 24 (3.2%) patients subsequently were limits of quantification of 2.0–6.0 log10 copies/mL for the diagnosed with ADV infection. Each and overall patient char- R-Gene kit and 2.4–6.0 log10 copies/mL for the ELITe MGB kit. acteristics are shown in Table 1 and 2, respectively. Twenty Adenovirus DNA in respiratory specimens was measured via (83%) patients were male and the median age was 47 years (IQR qualitative PCR assays (xTAG Respiratory Viral Panel, Luminex 36–58  years). Twenty-three (96%) patients received their first Corporation, Austin, TX). Imaging and histopathologic ana- KT, and 15 patients (63%) received an allograft from a deceased lyses were performed as appropriate based on clinical indica- donor. The most common etiology of end-stage renal disease tions. Plasma ADV DNA loads were determined at the time of was unknown (67%). Thirteen patients (54%) received induc- diagnosis and twice weekly after treatment until no ADV DNA tion therapy, including 12 (50%) who received antithymocyte load was detected in 2 consecutive tests. Clinical resolution globulin (ATG) and 1 (4%) who received interleukin-2 receptor was defined as resolution of all symptoms. Virological reso- antagonist. The majority was followed by maintenance therapy, lution was defined as undetectable ADV DNA load in plasma including tacrolimus (75%), mycophenolate mofetil (83%), or urine on 2 consecutive occasions. Demographic, clinical, and prednisolone (100%). All donors and recipients were se- laboratory, and virological data pertaining to all patients were ropositive for CMV; hence, preemptive CMV monitoring was 2 • ofid • Bruminhent et al Downloaded from https://academic.oup.com/ofid/article-abstract/6/12/ofz489/5625281 by DeepDyve user on 06 December 2019 Table 1. Baseline Characteristics of 24 Kidney Transplant Recipients shortness of breath (8%), reduced allograft function (8%), and testicular pain (8%). Urinalysis results included pyuria (n = 7), Characteristics, n (%) N = 24 microscopic hematuria (n  =  8), and proteinuria (n  =  10). Age (median, IQR; years) 47 (36–58) Twenty-two (92%) patients had a detectable plasma ADV DNA Male sex 20 (83) load. Among those, the median initial plasma ADV load was 5.3 Etiologies of end-stage renal disease log copies/mL (IQR, 3.5–6.0 log copies/mL), then it increased - Diabetic nephropathy 2 (8) to a median peak plasma ADV load of 5.5 log copies/mL (IQR, - IgA nephritis 3 (13) - Lupus nephritis 2 (8) 5.3–6.0 log copies/mL). Twenty (83%) patients had detectable - Chronic glomerulonephritis 1 (4) ADV DNA in urine and the majority (85%) had a urine ADV - Unknown etiology 16 (67) load of 6.0 log copies/mL or more. Two (17%) had detectable Deceased-donor kidney transplantation 15 (63) ADV DNA in respiratory specimens. At diagnosis, the median Immunosuppressive regimens total white blood cell count was 6255/mm (IQR, 4208–10498/ Induction therapy 3 3 mm ) and the median ALC was 883/mm (IQR, 704–1398/ - None 11 (46) - Antithymocyte globulin 1 (4) mm ). Probable ADV pneumonitis was diagnosed via the de- - Interleukin-2 receptor antagonist 12 (50) tection of ADV DNA from bronchoalveolar lavage fluid via Maintenance therapy PCR, histopathology revealed no viral cytopathic change, and - Tacrolimus 18 (75) ADV in situ hybridization was not detected. Adenovirus inter- - Cyclosporine 6 (25) stitial nephritis was defined as the detection of viral cytopathic - Mycophenolate mofetil 20 (83) - Mycophenolate sodium 3 (13) changes in tubular cells; ADV in situ hybridization was detected - Everolimus 1 (4) in 1 patient (proven) and it was inconclusive in another. In 2 - Prednisolone 24 (100) patients, a diagnosis of probable epididymo-orchitis was sup- Abbreviations: ADV, adenovirus; Ig, immunoglobulin; IQR, interquartile range. ported by compatible symptoms, Doppler ultrasonography, and detectable ADV DNA in urine without histopathological confirmation that was deemed to be invasive. Clinical, radio- undertaken after KT in the majority of cases. One patient un- logical, and histopathological findings of representative patients derwent a second KT requiring ATG induction therapy and who were diagnosed with hemorrhagic cystitis, pneumonitis, received IV ganciclovir prophylaxis during admission and sub- epididymo-orchitis, and interstitial nephritis are shown in sequently was switched to preemptive approaches for 3 months Figure 1. after KT. Trimethoprim/sulfamethoxazole for pneumocystis Patients who were diagnosed with LOI were slightly more prophylaxis, acyclovir for herpes simplex virus prophylaxis, frequent to present with hemorrhagic cystitis compared to EOI and isoniazid for latent tuberculous infection therapy were pre- (100% vs 75%, P = .06) Table 3. Patients who were diagnosed scribed in all patients. with EOI were more likely to be febrile compared with those with LOI, but this was not statistically significant (83% vs 58%, Diagnosis of Adenovirus Infection P  =  .18). Patients with EOI had lower median absolute lym- The distribution of ADV infection onset after KT included 7 (29%) phocyte counts (ALCs) than those with LOI (735/mm [IQR, patients who developed infection within 1 month after KT, 5 (21%) 543–1123] vs 1122/mm [IQR, 784–1344], P = .04). There was between 1 and 3  months, and 12 (50%) after 1  year. There were no different in median peak plasma and urine ADV DNA load equal distributions of patients diagnosed with EOI and LOI. Seven between 2 groups. (29%) and 17 (71%) patients developed infection during a wet season (June to October) and a dry season (November to May), Management respectively. Among 7 patients (no respiratory symptoms) who underwent an investigation for possible route of acquisition, naso- After diagnosis the immunosuppression regimen was reduced pharyngeal (NP) swab for ADV PCR was detectable in 2 (29%) pa- in all patients. Mycophenolic acid was discontinued. The me- tients. Among the LOI group, there was no patients who developed dian dose reduction of mycophenolate mofetil was 1.5 g (IQR, rejection within 3 months prior to ADV infection. 1.25–1.50 g). Calcineurin inhibitors were reduced to maintained e Th infections were classified as asymptomatic ADV trough levels of 3–5 ng/mL in patients who were on tacrolimus (4%), ADV disease (4%), hemorrhagic cystitis (88%), upper and 50–100  ng/mL in patients who were on cyclosporine. respiratory tract infection (4%), lower respiratory tract Prednisolone was maintained as tolerated, to a median dose of infection (8%), gastroenteritis (4%), hepatitis (8%), interstitial 7.5  mg/day (IQR, 5–15  mg/day). Thirteen (54%) patients re- nephritis (8%), epididymo-orchitis (8%), and disseminated dis- ceived IV cidofovir with prehydration and posthydration with ease (17%). Initial presentations included dysuria (83%), gross 1  L of 0.9% normal saline solution, and, of those patients, 10 hematuria (83%), fever (46%), sore throat/runny nose (4%), (77%) received oral probenecid with dosing of a total of 4 g oral Adenovirus Infection in Kidney Transplant • ofid • 3 Downloaded from https://academic.oup.com/ofid/article-abstract/6/12/ofz489/5625281 by DeepDyve user on 06 December 2019 4 • ofid • Bruminhent et al Table 2. Patient Characteristics, Management, and Outcomes in 24 Kidney Transplant Recipients Diagnosed With Adenovirus Infection Mainte- Plasma/urine Age Type Induction nance Onset After Peak ADV DNA Load Clinical Outcome/Other Allograft Patient (Years) Sex of KT Regimen Regimens KT (Months) Diagnosis (Log Copies/mL) Cidofovir IVIG Infections Outcome Survived 1 37 M LRKT IL2RA TAC 0.50 ADV-associated 5.4/ > 6.0 Yes, 3 mg/kg/wk (divided Yes, 0.5 g/kg Resolved Transient allograft Yes Everolimus hemorrhagic cystitis as 3 times a wk) at wk 0 at week 1 dysfunction Pred without oral probenecid 2 45 M DDKT IL2RA TAC 0.50 Disseminated ADV > 6.0/> 6.0 Yes, 1.5–3.0 mg/kg/wk (di- Yes, 2 g/kg (in Resolved/ Transient allograft Yes MMF disease (hemor- vided as 3 times a 5 divided asymptomatic CMV dysfunction Pred rhagic cystitis, right wk) at wk 0,1 with oral doses daily) infection epididymo-orchitis) probenecid 3 38 F DDKT IL2RA TAC 0.50 ADV-associated 4.2/> 6.0 Yes, 1.5–3.0 mg/kg/wk (di- No Resolved Transient allograft Yes MMF hemorrhagic cystitis vided as 3 times a dysfunction Pred wk) at wk 0,1 with oral probenecid 4 58 M LRKT IL2RA CsA 0.75 ADV-associated > 6.0/> 6.0 Yes, 5 mg/kg/wk at wk 0,1 No Resolved/ Allograft dysfunc- Yes MMF hemorrhagic cystitis with oral probenecid asymptomatic CMV tion Pred infection 5 42 M LRKT IL2RA TAC 1 Asymptomatic ADV 3.6/4.6 No No Resolved/asymptomatic No allograft Yes MMF infection CMV infection dysfunction Pred 6 34 F Re-DDKT ATG TAC 1 ADV-associated > 6.0/> 6.0 Yes, 1.5 mg/kg/wk (divided as Yes, 2.8 g/ Resolved, human Allograft failure, Yes MMF hemorrhagic cystitis, 3 times a wk) at wk 0,1,2 kg (in 7 parainfluenza URI, acute antibody- Pred ADV interstitial with oral probenecid divided E. coli UTI mediated and nephritis doses daily) T-cell–mediated rejection/graft loss 7 60 M LRKT None CsA 1 ADV pneumonitis < LLOQ/not detected No No Organizing pneumonia, Transient allograft No (non- MMF resolved/asympto- dysfunction ADV – Pred matic CMV infection related) 8 56 M LRKT None CsA 1.50 ADV-associated 5.1/> 6.0 No No Resolved Transient allograft Yes MMF hemorrhagic cystitis dysfunction Pred 9 42 M LRKT IL2RA CsA 1.50 ADV-associated > 6.0/> 6.0 Yes, 5 mg/kg/wk at wk 0,1 No Resolved/ESBL- Allograft dysfunc- Yes MMF hemorrhagic cystitis without oral probenecid producing E. coli UTI tion, acute Pred T-cell–mediated rejection 10 36 M DDKT IL2RA TAC 2 Disseminated ADV > 6.0/> 6.0 Yes, 3 mg/kg/wk (divided as 3 Yes, 2 g/kg (in Resolved/asymptomatic Transient allograft Yes MMF disease (hemor- times a wk) at wk 0,1 with 5 divided CMV infection dysfunction Pred rhagic cystitis, left oral probenecid doses daily) epididymo-orchitis, pneumonitis, hepatitis) 11 59 F DDKT IL2RA TAC 2 ADV-associated 5.7/> 6.0 Yes, 5 mg/kg/wk at wk 0,1 No Resolved/Enterococcus No allograft Yes MMF hemorrhagic cystitis with oral probenecid spp. UTI, BKVAN dysfunction Pred 12 30 M LRKT None CsA 3 ADV syndrome 5.5/N/A Yes, 5 mg/kg/wk at wk 0, 1, 3, No Resolved/asymptomatic No allograft Yes MMF (fever with leukopenia) 5 with oral probenecid CMV infection dysfunction Pred Downloaded from https://academic.oup.com/ofid/article-abstract/6/12/ofz489/5625281 by DeepDyve user on 06 December 2019 Adenovirus Infection in Kidney Transplant • ofid • 5 Table 2. Continued Mainte- Plasma/urine Age Type Induction nance Onset After Peak ADV DNA Load Clinical Outcome/Other Allograft Patient (Years) Sex of KT Regimen Regimens KT (Months) Diagnosis (Log Copies/mL) Cidofovir IVIG Infections Outcome Survived 13 53 M DDKT IL2RA TAC 12 ADV-associated 5.4/> 6.0 Yes, 3 mg/kg/wk (divided as Yes, 2 g/kg (in Resolved Allograft Yes MMF hemorrhagic cystitis, 3 times a wk) at wk 0,1 5 divided dysfunction Pred ADV interstitial without oral probenecid doses daily) nephritis 14 55 F DDKT None TAC 16 ADV-associated > 6.0/5.0 Yes, 3 mg/kg/wk (divided as 3 No Resolved No allograft Yes MMF hemorrhagic cystitis times a wk) at wk 0, then dysfunction Pred 5 mg/kg/wk at wk 1, 3, 5 without oral probenecid 15 29 M LRKT None TAC 15 Disseminated ADV > 6.0/> 6.0 Yes, 5 mg/kg/wk at wk 0,1 No Resolved Transient allograft Yes MMF disease (hemor- with oral probenecid dysfunction Pred rhagic cystitis, hep- atitis) 16 43 M DDKT None CsA 22 Disseminated disease 5.7/> 6.0 No Yes, 1 g/kg (in Resolved/CMV Transient allograft Yes MMF (hemorrhagic 3 divided syndrome, BKVAN dysfunction Pred cystitis, doses daily) gastroenteritis, upper respiratory tract infection) 17 49 M DDKT IL2RA TAC 22 ADV-associated < LLOQ/5.6 No No Resolved Transient allograft Yes MMF hemorrhagic cystitis dysfunction Pred 18 62 M DDKT None TAC 27 ADV-associated 5.3/> 6.0 Yes, 3 mg/kg/wk (divided as No Resolved No allograft Yes MPS hemorrhagic cystitis 3 times a wk) at wk 0 with dysfunction Pred oral probenecid 19 59 M DDKT None TAC 36 ADV-associated > 6.0/> 6.0 No No Resolved Transient allograft Yes MMF hemorrhagic cystitis dysfunction Pred 20 54 M DDKT IL2RA TAC 39 ADV-associated 5.0/> 6.0 No No Resolved Allograft Yes MPS hemorrhagic cystitis dysfunction Pred 21 57 M DDKT None TAC 40 ADV-associated > 6.0/> 6.0 No No Resolved No allograft Yes MMF hemorrhagic cystitis dysfunction Pred 22 67 M DDKT None TAC 47 ADV-associated 3.9/> 6.0 No No Resolved Transient allograft Yes MPS hemorrhagic cystitis dysfunction Pred 23 24 M LRKT None TAC 59 ADV-associated 5.1/> 6.0 No No Resolved Transient allograft Yes MMF hemorrhagic cystitis dysfunction Pred 24 34 M DDKT IL2RA TAC 63 ADV-associated 5.3/> 6.0 No No Resolved Allograft Yes MMF hemorrhagic cystitis dysfunction, Pred acute T-cell–medi- ated rejection Abbreviations: ADV, adenovirus; ALC, absolute lymphocyte count; ATG, antithymocyte globulin; BKVAN, BK polyomavirus-associated nephropathy; CMV, cytomegalovirus; CsA, cyclosporine; DDKT, deceased-donor kidney transplantation; DNA, deoxyribo- nucleic acid; ESBL, extended-spectrum beta-lactamase; F, female; IL2RA, interleukin-2 receptor antagonist; IVIG, intravenous immunoglobulin; LLOQ, lower limit of quantification; M, male; MMF, mycophenolate mofetil; MPS, mycophenolate sodium; LRKT, living-related kidney transplantation; N/A, not applicable; Pred, prednisolone; TAC, tacrolimus; UTI, urinary tract infection; wk, week. Downloaded from https://academic.oup.com/ofid/article-abstract/6/12/ofz489/5625281 by DeepDyve user on 06 December 2019 Outcome probenecid,with 2 g 3 hours prior to infusion, 1 g 2 hours after infusion, and 1 g 8 hours after infusion. The details of cidofovir In all patients, the median time from diagnosis to clinical reso- dosing are shown in Table 2. Five patients received weekly IV lution of 9 days (IQR, 5–13 days) was significantly shorter than cidofovir at a dose of 5  mg/kg, 5 patients received 1  mg/kg 3 virological resolution of 46 days (IQR, 30–60 days) (P < .001). times per week, and 3 patients received 0.5 mg/kg 3 times per Infection completely resolved without complications in 23 pa- week (those with creatinine clearance <50 mL/min) for 2 con- tients (96%). One patient was diagnosed with probable ADV secutive weeks followed by every other week until clinical and pneumonitis that was subsequently complicated by organizing viral clearance in most cases. Different doses of cidofovir was pneumonia requiring a tapered course of prednisolone therapy. selected on clinician preference based on the doses that were re- Recurrence with low-level ADV DNAemia that was not clini- commended by an international guideline. Patients diagnosed cally significant occurred in 1 patient (4%) after the resumption with EOI were more likely to receive IV cidofovir therapy (75% of immunosuppressant. Ten patients (42%) developed oppor- vs 33%, P = .04) compared with those who diagnosed with LOI. tunistic infections other than ADV, including CMV (including Among 13 patients who received IV cidofovir, the creatinine in- asymptomatic CMV infection; n=6), CMV syndrome (n=1), creased in 9 (69%) patients after therapy and 5 (38%) returned BK polyomavirus-associated nephropathy (n=2), human para- to baseline. Allograft dysfunction occurred more frequently influenza virus upper respiratory tract infection (n=1), uri- in patients who received IV cidofovir therapy compared with nary tract infection with Enterococcus spp. (n=1), Escherichia those withheld from therapy (38% vs 18%, P  =  .66) as well as coli (n=1), and extended-spectrum beta-lactamase-producing those received once weekly (40%) compared with thrice-weekly E.  coli (n=1). Patients diagnosed with EOI were more likely to regimen (40% vs 25%, P = .57), though the trends were not sta- develop opportunistic infection other than ADV (75% vs 8%, tistically significant. No patients developed uveitis, significant P  <  .001), including CMV coinfection (50% vs 8%, P  =  .03), neutropenia, anemia, or proteinuria, or adverse reactions to compared with those diagnosed with LOI. probenecid, including fever, rash, headache, or nausea. Eighteen (75%) patients developed allograft dysfunction, and Six (25%) patients received IVIG at doses ranging from 0.5– 67% of these were transient. Three (13%) patients developed 2.0 g/kg as adjunctive therapy. Aer r ft esolution, all patients were acute T-cell–mediated allograft rejection aer ft therapy, and 1 restarted gradually on mycophenolic acid closed to baseline (4%) of them developed concurrent antibody-mediated rejec- dosing. Calcineurin inhibitors were kept at appropriate trough tion. One patient (4%) underwent nephrectomy for allogra ft levels and low dose prednisolone was maintained. failure and 1 (4%) died from a non-ADV–related cause. A B CD Figure 1. Clinical, Radiographic, and Histopathology Findings in Kidney Transplant Recipients Diagnosed With Adenovirus Infection A, Gross hematuria. B, computed to- mography of the chest showed newly developed patchy ground glass opacities with overlying consolidation opacity as well as several scattering solid nodules in both lungs. C, Doppler ultrasonography of the testes showed relatively enlarged size and increased vascularity of the right testis without mass or abnormal echogenicity. D, histopa- thology findings of the renal allograft biopsy showed lymphoplasmacytic infiltration in the interstitium with tubular injury and focal tubulitis. (P AS X 400). 6 • ofid • Bruminhent et al Downloaded from https://academic.oup.com/ofid/article-abstract/6/12/ofz489/5625281 by DeepDyve user on 06 December 2019 Table 3. Clinical, Laboratory, Management, and Outcome Data Derived From 24 Kidney Transplant Recipients Who Were Diagnosed with Early and Late Onset ADV Infection Early onset Late onset (n = 12) (n = 12) P value ADV infection, n (%) - Asymptomatic infection 1 (8) 0 .30 - Hemorrhagic cystitis 9 (75) 12 (100) .06 - Interstitial nephritis 1 (8) 1 (8) >.999 - Hepatitis 1 (8) 1 (8) >.999 - Upper respiratory tract infection 0 1 (8) .30 - Pneumonitis 2 (17) 0 .14 - Gastroenteritis 0 1 (8) .30 - Epididymo-orchitis 2 (17) 0 .14 - ADV syndrome 1 (8) 0 .30 - Disseminated infection 2 (17) 2 (17) >.999 Clinical presentations, n (%) - Fever 10 (83) 7 (58) .18 - Dysuria 9 (75) 11 (92) .27 - Gross hematuria 9 (75) 11 (92) .27 - Testicular pain 2 (17) 0 .14 - Shortness of breath 2 (17) 0 .14 Laboratory findings at diagnosis, median (IQR) - Total white blood cell count (cells/mm ) 7670 6050 .37 (4013–10658) (4208–7423) - Absolute lymphocyte count (cells/mm ) 735 1122 .04 (543–1122) (784–1344) - Peak urine ADV DNA load (log10 copies/mL) 6.0 (6.0–6.0) 6 (6.0–6.0) >.999 - Peak plasma ADV DNA load (log10 copies/mL) 5.7 (5.1–6.0) 5.4 (5.1–6.0) .70 Treatment, n (%) - Cidofovir 9 (75) 4 (33) .04 - Intravenous immunoglobulin 4 (25) 2 (17) .35 Outcome, n (%) - Time to virological resolution (median, IQR; days) 56 (35–60) 43 (28–52) .24 - Time to clinical resolution (median, IQR; days) 10 (5–17) 6 (5–11) .30 - Opportunistic infection other than ADV 9 (75) 1 (8) <.001 - Cytomegalovirus coinfection 6 (50) 1 (8) .03 - Normal allograft function 3 (25) 3 (25) 1.00 - Transient allograft dysfunction 6 (50) 6 (50) 1.00 - Allograft dysfunction 2 (17) 3 (25) .62 - Allograft failure 1 (8) 0 .30 - Acute T-cell–mediated rejection 2 (17) 1 (8) .54 - Antibody-mediated rejection 1 (8) 0 .30 - Hemodialysis required after transplantation 1 (8) 0 .30 - Mortality (non-ADV–related) 1 (8) 0 .30 Abbreviations: ADV, adenovirus; DNA, deoxyribonucleic acid; IQR, interquartile range; RBC, red blood cell. DISCUSSION at diagnosis, opportunistic infection (other than ADV), and receive cidofovir therapy. Although reduction of the immuno- Herein, we have reported the most recent and comprehensive suppression regimen combined with IV cidofovir evidently can data on the epidemiology, clinical characteristics, manage- achieve a favorable clinical and virological outcome, transient ment, and outcomes of ADV infection in KT recipients from allograft dysfunction remains a substantial consideration. a retrospectively analyzed cohort at a single transplant center. Kidney transplant recipients have been considered to be at The genitourinary tract was the most commonly involved low to moderate risk of ADV infection compared with those system, followed by some unusual presentations rarely seen who undergo liver or thoracic organ transplantation, likely due in clinical practice. Nucleic acid amplification testing with or to less intense immunosuppression [9]. A  large cohort study without histopathological testing is the main diagnostic tool of KT performed previously at our center provided an oppor- used to achieve a diagnosis. Patients who developed ADV in- tunity to investigate this uncommon infection aer KT ft . The fection early posttransplant seem to have more lymphopenia Adenovirus Infection in Kidney Transplant • ofid • 7 Downloaded from https://academic.oup.com/ofid/article-abstract/6/12/ofz489/5625281 by DeepDyve user on 06 December 2019 prevalence of ADV infection in KT recipients were decreased study [13]) due to the recent increased availability of the slightly during 2 periods of time approximately a decade apart, medication at our institution. Cidofovir was considered to 4.9% from 2007 to 2010 [3], and 3.2% during the current study be cost-prohibitive in our resource-limited setting. Some period of 2015 to 2019. Time to diagnosis varied similarly in the patients were able to complete the induction phase but not 2 studies, ranging widely from a few months to years aer KT ft the maintenance phase as recommended in the aforemen- [3]. Although ADV infection can occur all year round without tioned guideline [8]. However, both early clinical and viro- seasonal variability [10], the majority of ADV infection in our logical improvement in those patients would be less likely cohort occurred during the wet season. Kidney transplant re- to require further treatment. The combination of an anti- cipients with ADV infection can present with symptoms ran- ADV agent and optimized immunosuppression has been ging from absent or mild to severe disseminated disease [8]. shown to improve clinical and virological outcomes, and the e p Th resent cohort was concordant with previous studies with strategy reportedly facilitates more rapid clinical resolution regard to similar initial presentations and organ involvement of although it takes approximately 2  months to achieve viro- ADV infection with hemorrhagic cystitis in the majority of pa- logical clearance. The present patients tolerated IV cidofovir tients. Nanmoku et al [11] recently reported a high incidence well, without hematological or ocular toxicities. We found of ADV genitourinary tract infection (4.5%) in their cohort. In those who received IV cidofovir were more likely to develop contrast, we also detected uncommon presentations of ADV in- allograft dysfunction. However, the majority of the patients fection that are somewhat unique and specific to immunocom- developed transient increases in serum creatinine, which is promised patients, such as pneumonitis, epididymo-orchitis, known to be derived from multifactorial etiologies, including and interstitial nephritis, due to the availability of NAAT and cidofovir exposure, but the incidence of permanent damage immunohistochemical testing at our institution, in which clin- in this context is reportedly low [14]. Patients diagnosed icians who are managing these patients should be aware of. In with EOI were more likely to receive IV cidofovir therapy; the present study, median initial and peak ADV loads were both this could be explained by the complexity of the infection >5 log copies/mL, which is greater than they were in a previous during a period with more intense immunosuppression. We study [3]. found less allograft dysfunction had occurred in those who Observations in the present study were concordant with our received a once-weekly regimen compared with the thrice- previous study in which patients with early infection (onset weekly regimen (40% vs 25%) and a true explanation for this within 3 months aer KT) t ft hat was more severe tended to have different outcome has been elucidating. However, we did not lower ALCs at weeks 1 and 3 than patients with late infections observe other significant complications apart from nephro- [3]. In the present cohort, half of the patients developed ADV toxicity in our cohort. infection within 3 months post-KT, and these patients exhibited Although a few patients did not receive oral probenecid (be- variable ALCs. Nierenberg et al [12] reported that lymphopenia cause a high urine drug concentration was achieved in order to (<500 cells/mm ) measured prior to transplantation is a poten- treat ADV genitourinary tract infection), the allograft outcome tial tool for predicting opportunistic infection aer li ft ver trans- was acceptable. This may have been due to aggressive IV saline plantation. Absolute lymphocyte count indirectly represents hydration concomitantly with cidofovir therapy. However, it is impairment of nonspecific cell-mediated immunity (CMI) important to monitor renal function closely (including protein- in these patients. Our team recently reported low nonspecific uria) both before and during treatment. CMI as indicated by the total lymphocyte count and lympho- Anti-ADV agents were implemented in the majority of + + cyte subset proportions (CD4 and CD8 T-cells), as well as the current patients who were diagnosed with ADV dis- ADV-specific CMI in patients diagnosed with ADV infection, ease, facilitating evaluation of the efficacy of these agents. wherein this immunity was later restored aer r ft esolution [7]. Cidofovir with and without IVIG has been reported to be ef- Because there is no commercial assay available for measuring fective in some SOT, including KT recipients diagnosed with ADV-specific immunity in clinical practice, we encourage the disseminated disease [15, 16]. The true efficacy of cidofovir use of a practical and simple tool to at least stratify and predict and/or IVIG is difficult to assess based on outcome, because those who may develop severe infection. all patients underwent reduction of their immunosuppres- Although no ideal management strategy for ADV infec- sion regimen. Because there has been no randomized con- tion has been established, all patients underwent reduc- trol trial of cidofovir and IVIG to support efficacy, a current tion of their immunosuppression regimen as recommended guideline suggested considering those agents for severe or in a current guideline [8], including discontinuation of disseminated ADV disease and hypogammaglobulinemia, re- mycophenolate, maintenance of low calcineurin inhibitor spectively [8]. trough level, and the lowest dose of prednisolone tolerated Apart from antiviral agents and adjunctive therapies, it has [2] in the present study. More than half of the patients re- been reported that ADV-specific immunity is related to ADV ceived IV cidofovir (compared with a quarter in a previous clearance in KT recipients [5, 7]. Allograft rejection may occur 8 • ofid • Bruminhent et al Downloaded from https://academic.oup.com/ofid/article-abstract/6/12/ofz489/5625281 by DeepDyve user on 06 December 2019 Sinee Disthabanchong, Atiporn Ingsathit, Arkom Nongnuch, Montira as a consequence of reduction of an immunosuppressive reg- Assanatham, and Punlop Wiwattanathum. imen. Therefore, 1 goal is to balance immunosuppression Author contributions. J.B. and S.P.W. conceptualizatized this work. J.B., during infection and maintain the allograft by resuming im- S.W., and C.T. performed data collection. J.B. analyzed the data and com- posed the original draft of the manuscript. This manuscript was revised and munosuppression as soon as the infection is controlled. A  fu- edited by J.B., S.W., C.T., E.P., S.B., and S.P.W. ture study measuring specific ADV-specific immunity in order Financial support. None reported. to facilitate optimal management in this setting is encouraged. Potential conifl cts of interest. All authors: No reported conflicts of in- Although KT recipients with disseminated disease are at a high terest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to risk of mortality, there were no cases of disseminated disease- the content of the manuscript have been disclosed. associated mortality in the present study. That was likely due to early diagnosis, prompt reduction of an immunosuppressive regimen, and vigilant management [6]. References 1. Bruminhent  J, Watcharananan  SP. Adenovirus beyond “pink eye”. J Infect Dis e Th current study had some limitations. er Th e is an inherent Antimicrob Agents 2018; 35:191–4. possibility of bias due to the retrospective nature of the study. 2. Florescu DF, Stohs EJ. Approach to infection and disease due to adenoviruses in e t Th rue incidence of ADV infection likely was underestimated solid organ transplantation. Curr Opin Infect Dis 2019; 32:300–6. 3. Watcharananan  SP, Avery  R, Ingsathit  A, et  al. Adenovirus disease after kidney due to a lack of preemptive ADV load monitoring, which would transplantation: course of infection and outcome in relation to blood viral load have facilitated the diagnosis of asymptomatic ADV infection. and immune recovery. Am J Transplant 2011; 11:1308–14. 4. Watcharananan  SP, Junchotikul  P, Srichanrusmi  C, et  al. Adenovirus infection Such preemptive ADV load monitoring currently is not advo- after kidney transplantation in Thailand: seasonal distribution and potential cated, and, in Humar et al [17], half of the patients developed route of acquisition. Transplant Proc 2010; 42:4091–3. 5. Sester M, Leboeuf C, Schmidt T, Hirsch HH. The “ABC” of virus-specific T cell transient and self-limiting reactivation without clinical sig- immunity in solid organ transplantation. Am J Transplant 2016; 16:1697–706. nificance. Accordingly, preemptive monitoring is not recom- 6. Florescu  MC, Miles  CD, Florescu  DF. What do we know about adenovirus in renal transplantation? Nephrol Dial Transplant 2013; 28:2003–10. mended in the aforementioned guidelines [8]. Additionally, 7. Bruminhent  J, Apiwattanakul  N, Hongeng  S, Kantachuvesiri S, Watcharananan approximately one-third of patients had CMV coinfection, a SP. Absolute lymphocyte count and human adenovirus-specific T-cell immune restoration of human adenovirus infection after kidney transplantation. J Med sole effect of each pathogen that contributes to the idea that the Virol 2019; 91:1432–9. symptoms could be limited. An immunomodulatory effect of 8. Florescu  DF, Schaenman  JM; AST Infectious Diseases Community of Practice. CMV infection is known to place patients at risk of infection Adenovirus in solid organ transplant recipients: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin from another opportunistic pathogen [18]. Last, because the Transplant 2019; e13527. rarity of the disease could limit a sample size, independent risk 9. Florescu DF, Kwon JY, Dumitru I. Adenovirus infections in heart transplantation. Cardiol Rev 2013; 21:203–6. factors analyzed from multivariate analysis to investigate from 10. Ison  MG. Adenovirus infections in transplant recipients. Clin Infect Dis 2006; this small cohort would not be allowed. 43:331–9. 11. Nanmoku K, Ishikawa N, Kurosawa A, et al. Clinical characteristics and outcomes During recent years, ADV has remained a relatively uncommon of adenovirus infection of the urinary tract after renal transplantation. Transpl pathogen that can cause genitourinary tract infection in adult Infect Dis 2016; 18:234–9. 12. Nierenberg  NE, Poutsiaka  DD, Chow  JK, et  al. Pretransplant lymphopenia is a KT recipients. Low ALC at the time of diagnosis may predict novel prognostic factor in cytomegalovirus and noncytomegalovirus invasive in- an increased risk of ADV infection in KT recipients early post fections after liver transplantation. Liver Transpl 2014; 20:1497–507. 13. Bruminhent  J, Rotjanapan  P, Watcharananan  SP. Epidemiology and outcome of KT. Effective management is facilitated by early diagnosis and is ganciclovir-resistant cytomegalovirus infection after solid organ transplantation: a assisted by readily available NAAT, supportive care, and reduc- single transplant center experience in Thailand. Transplant Proc 2017; 49:1048–52. tion of immunosuppression. This combination evidently can 14. Neofytos D, Ojha A, Mookerjee B, et al. Treatment of adenovirus disease in stem cell transplant recipients with cidofovir. Biol Blood Marrow Transplant 2007; 13:74–81. achieve favorable clinical and virological outcomes. Although 15. Saquib R, Melton LB, Chandrakantan A, et al. Disseminated adenovirus infection transient worsening of allograft function may occur, it is not in renal transplant recipients: the role of cidofovir and intravenous immunoglob- ulin. Transpl Infect Dis 2010; 12:77–83. associated with high mortality. 16. Bruminhent J, Athas DM, Hess BD, Flomenberg P. Disseminated adenovirus dis- ease in heart transplant recipient presenting with conjunctivitis. Transpl Infect Dis 2015; 17:125–8. Acknowledgments 17. Humar A, Kumar D, Mazzulli T, et al; PV16000 Study Group. A surveillance study We thank Darunee Chotiprasitsakul, Nantanee Rungpethwong, of adenovirus infection in adult solid organ transplant recipients. Am J Transplant Subencha Pinsai, and Charat Thongprayoon for their helpful participa- 2005; 5:2555–9. tion in discussions. We also thank the Ramathibodi Kidney Transplant 18. Razonable RR, Humar A. Cytomegalovirus in solid organ transplant recipients- Cohort Study team: Vasant Sumethkul, Somnuek Domrongkitchaiporn, Guidelines of the American Society of Transplantation Infectious Diseases Surasak Kantachuvesiri, Bunyong Phakdeekitcharoen, Chagriya Kitiyakara, Community of Practice. Clin Transplant 2019; 33:e13512. Adenovirus Infection in Kidney Transplant • ofid • 9 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Open Forum Infectious Diseases Oxford University Press

Epidemiology and Outcomes of Early-Onset and Late-Onset Adenovirus Infections in Kidney Transplant Recipients

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Abstract

Downloaded from https://academic.oup.com/ofid/article-abstract/6/12/ofz489/5625281 by DeepDyve user on 06 December 2019 Open Forum Infectious Diseases MAJOR ARTICLE Epidemiology and Outcomes of Early-Onset and Late-Onset Adenovirus Infections in Kidney Transplant Recipients 1,2 2,3 4 4 2,5 1 Jackrapong Bruminhent, Suchin Worawichawong, Chutatip Tongsook, Ekawat Pasomsub, Sarinya Boongird, and Siriorn P. Watcharananan 1 2 Division of Infectious Diseases, Department of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand, Excellence Center of Organ Transplantation, Faculty 3 4 of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand, Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand, Division of Virology, Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand, and Division of Nephrology, Department of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand Objective. Adenovirus (ADV) infection aer k ft idney transplantation (KT) causes significant morbidity. Patient characteristics and outcomes of ADV infection in KT recipients were investigated. Method. All adult KT recipients with ADV infection between January 2015 and June 2019 were included. ADV infection/dis- ease was defined as detection of ADV DNA in clinical specimens/plus symptoms. Clinical and laboratory findings, treatments, and outcomes were assessed. Results. Adenovirus infection was diagnosed in 24 of 751 (3.2%) KT recipients. Twenty (83%) were male with a median age of 47 years (interquartile range [IQR], 36–58). Fifteen (63%) underwent deceased donor KT, and 13 (54%) received induction therapy. Twenty-one (88%) and 4 (17%) patients developed hemorrhagic cystitis and disseminated disease, respectively. There were equal distributions of early-onset (EOI) (≤3  months) and late-onset (LOI) (>3  months) infections. Patients who were diagnosed with 3 3 EOI had lower median absolute lymphocyte counts compared with those with LOI (735/mm [IQR, 543–1123] vs 1122/mm [IQR, 784–1344], P = .04). All achieved resolution aer r ft eduction of their immunosuppression regimen and 13 (54%) received cidofovir therapy. Eighteen (75%) developed allograft dysfunction, of which 67% were transient. One (4%) underwent nephrectomy for al- lograft failure and 1 (4%) died (non-ADV–related). Patients with EOI were more likely to receive cidofovir therapy (75% vs 33%, P = .04) and develop other opportunistic infections (75% vs 8%, P < .001). Conclusions. Adenovirus infection aer KT t ft ypically involves a genitourinary system and transiently impairs an allograft func- tion. Those who developed early infection tend to have more lymphopenia, coinfection, and receive antiviral therapy. Keywords: absolute lymphocyte count; cidofovir; cytomegalovirus; hemorrhagic cystitis; human adenovirus; lymphopenia. INTRODUCTION pneumonitis, hepatitis, and gastroenteritis, which occasionally result in severe disseminated infection affecting multiple organs Adenovirus (ADV) is a nonenveloped double-stranded DNA [2]. Only a few published reports mention the epidemiology of virus that can cause a wide variety of clinical symptoms in hu- ADV infection in adult KT recipients. Our team retrospectively mans. Adenovirus infection usually is asymptomatic or mild reviewed the incidence of ADV infection in adult KT recipients, in immunocompetent individuals, but it can cause substantial and it was approximately 4.9% [3, 4]. As well as clinical and morbidity in immunocompromised individuals [1]. In kidney histopathological findings, nucleic acid amplification testing transplant (KT) patients, ADV can cause localized and invasive (NAAT) has been utilized for the diagnosis and monitoring of end-organ diseases, including hemorrhagic cystitis, nephritis, ADV infection after KT [2]. Virus-specific immune monitoring has recently been explored in the management of solid organ transplant (SOT) recipients [5, 6]. A  low absolute lymphocyte Received 13 August 2019; editorial decision 6 November 2019; accepted 11 November 2019. count (ALC) is associated with early ADV infection resulting in Correspondence: Jackrapong Bruminhent, MD, Division of Infectious Diseases, Department of Medicine and the Excellence Center of Organ Transplantation, Faculty of significant morbidity after KT [3]. In a recent study, the restora- Medicine Ramathibodi Hospital, Mahidol University, 270 Rama VI Rd., Ratchathewi, Bangkok, tion of ALC and ADV-specific T-cell immunity was correlated 10400, Thailand. Email: jbruminhent@gmail.com with viral clearance in KT recipients [7]. The management of Open Forum Infectious Diseases © The Author(s) 2019. Published by Oxford University Press on behalf of Infectious Diseases ADV infection in SOT recipients mainly involves the reduction Society of America. This is an Open Access article distributed under the terms of the Creative of their immunosuppression regimen combined with cidofovir Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/ by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any therapy. For the last few years, NAAT and cidofovir have been medium, provided the original work is not altered or transformed in any way, and that the accessible more at our transplant center. In the present study, we work is properly cited. For commercial re-use, please contact journals.permissions@oup.com DOI: 10.1093/ofid/ofz489 investigated the incidence of ADV infection after KT, aspects of Adenovirus Infection in Kidney Transplant • ofid • 1 Downloaded from https://academic.oup.com/ofid/article-abstract/6/12/ofz489/5625281 by DeepDyve user on 06 December 2019 its epidemiology, diagnosis, and management, and patient out- recorded, as were treatment details. Intravenous (IV) cidofovir comes during the study period. Severe or disseminated ADV at a dose of 5  mg/kg, 1  mg/kg 3 times weekly, or 0.5  mg/kg 3 infection can require cidofovir therapy, but clinicians may hes- times weekly (those with creatinine clearance <50  mL/min) itate to administer it to KT recipients in view of potential drug- and IV immunoglobulin (IVIG) therapy at doses ranging from related nephrotoxicity. Herein, we report our experiences in the 0.5–2.0  g/kg was prescribed based on current guidelines [8]. management of ADV infection in KT recipients using cidofovir, Outcomes were recorded, including clinical and virological res- in terms of clinical and virological resolutions, adverse reac- olution, patient survival, allograft function, and opportunistic tions, allograft outcomes, and rates of rejection after therapy. infection other than ADV. Allograft function was calculated as the estimated glomerular filtration rate as determined via ei- METHODS ther the Cockcroft‐Gault Formula, the Modification of Diet in Renal Disease Study Equation, or the Chronic Kidney Disease All adult KT recipients diagnosed with ADV infection between Epidemiology Collaboration equation. Transient allograft dys- January 2015 and June 2019 at a single transplant center in function was defined as any estimated glomerular filtration rate Bangkok, Thailand, were included in the present study. At our (eGFR) reduction compared to baseline that subsequently re- center, trimethoprim/sulfamethoxazole for pneumocystis pro- turned to baseline after the resolution of infection. Allograft phylaxis, acyclovir for herpes simplex virus prophylaxis, and failure and loss was defined as an irreversible estimated glo- isoniazid for latent tuberculous infection therapy (regardless of merular filtration rate reduction requiring chronic hemodial- status) were prescribed in all patients. Surveillance testing for ysis and/or retransplantation. The Institutional Review Board cytomegalovirus (CMV) infection was performed due to a high of the Faculty of Medicine of Ramathibodi Hospital, Mahidol prevalence of CMV-seropositive recipients, except for those re- University, Bangkok, Thailand, approved the study protocol quiring antithymocyte globulin induction therapy when (val) and waived the requirement to obtain any informed consent. ganciclovir prophylaxis was implemented. Instead, surveillance for ADV infection was not performed routinely. Only patients Statistical Analyses clinically suspected of ADV infection or exhibiting a consistent Patient demographic data and clinical characteristics were as- etiology underwent investigation, and other pathogens that sessed via descriptive analysis. Categorical data were described were potentially responsible for their symptoms were excluded as absolute and relative frequencies, and continuous data were in the patients included in the study. Adenovirus infection was described as medians with interquartile ranges (IQRs). Clinical defined as detection of ADV by NAAT in plasma or organ- and laboratory findings, treatments, and outcomes in those specific specimens. Adenovirus disease was defined as ADV with EOI and LOI were compared via the Mann-Whitney test infection combined with at least 1 specific organ symptom. and χ test for continuous and categorical data, respectively. P Disseminated ADV disease was defined as ADV disease with values <.05 determined via a 2-tailed test were considered sta- the involvement of at least 2 specific organs. Early (EOI) and tistically significant. Statistical analyses were performed with late (LOI) onset ADV infection was defined as the occurrence Stata statistical software (version 15, StataCorp, LLC, College within and after 3 months, respectively. Adenovirus DNA loads Station, TX). in plasma and urine specimens were measured via quantitative real-time polymerase chain reaction (PCR) assays (Adenovirus RESULTS R-Gene US Real-Time PCR kit, bioMérieux, Marcy l’Etoile, France, from January 2015 until August 2018, and Adenovirus Epidemiology and Demographic Data ELITe MGB Kit, ELITech Group SpA, Turin, Italy, thereafter). During the study period, 751 KTs were performed at our trans- Adenovirus DNA load was reported as log10 copies/mL with plant center, and of these, 24 (3.2%) patients subsequently were limits of quantification of 2.0–6.0 log10 copies/mL for the diagnosed with ADV infection. Each and overall patient char- R-Gene kit and 2.4–6.0 log10 copies/mL for the ELITe MGB kit. acteristics are shown in Table 1 and 2, respectively. Twenty Adenovirus DNA in respiratory specimens was measured via (83%) patients were male and the median age was 47 years (IQR qualitative PCR assays (xTAG Respiratory Viral Panel, Luminex 36–58  years). Twenty-three (96%) patients received their first Corporation, Austin, TX). Imaging and histopathologic ana- KT, and 15 patients (63%) received an allograft from a deceased lyses were performed as appropriate based on clinical indica- donor. The most common etiology of end-stage renal disease tions. Plasma ADV DNA loads were determined at the time of was unknown (67%). Thirteen patients (54%) received induc- diagnosis and twice weekly after treatment until no ADV DNA tion therapy, including 12 (50%) who received antithymocyte load was detected in 2 consecutive tests. Clinical resolution globulin (ATG) and 1 (4%) who received interleukin-2 receptor was defined as resolution of all symptoms. Virological reso- antagonist. The majority was followed by maintenance therapy, lution was defined as undetectable ADV DNA load in plasma including tacrolimus (75%), mycophenolate mofetil (83%), or urine on 2 consecutive occasions. Demographic, clinical, and prednisolone (100%). All donors and recipients were se- laboratory, and virological data pertaining to all patients were ropositive for CMV; hence, preemptive CMV monitoring was 2 • ofid • Bruminhent et al Downloaded from https://academic.oup.com/ofid/article-abstract/6/12/ofz489/5625281 by DeepDyve user on 06 December 2019 Table 1. Baseline Characteristics of 24 Kidney Transplant Recipients shortness of breath (8%), reduced allograft function (8%), and testicular pain (8%). Urinalysis results included pyuria (n = 7), Characteristics, n (%) N = 24 microscopic hematuria (n  =  8), and proteinuria (n  =  10). Age (median, IQR; years) 47 (36–58) Twenty-two (92%) patients had a detectable plasma ADV DNA Male sex 20 (83) load. Among those, the median initial plasma ADV load was 5.3 Etiologies of end-stage renal disease log copies/mL (IQR, 3.5–6.0 log copies/mL), then it increased - Diabetic nephropathy 2 (8) to a median peak plasma ADV load of 5.5 log copies/mL (IQR, - IgA nephritis 3 (13) - Lupus nephritis 2 (8) 5.3–6.0 log copies/mL). Twenty (83%) patients had detectable - Chronic glomerulonephritis 1 (4) ADV DNA in urine and the majority (85%) had a urine ADV - Unknown etiology 16 (67) load of 6.0 log copies/mL or more. Two (17%) had detectable Deceased-donor kidney transplantation 15 (63) ADV DNA in respiratory specimens. At diagnosis, the median Immunosuppressive regimens total white blood cell count was 6255/mm (IQR, 4208–10498/ Induction therapy 3 3 mm ) and the median ALC was 883/mm (IQR, 704–1398/ - None 11 (46) - Antithymocyte globulin 1 (4) mm ). Probable ADV pneumonitis was diagnosed via the de- - Interleukin-2 receptor antagonist 12 (50) tection of ADV DNA from bronchoalveolar lavage fluid via Maintenance therapy PCR, histopathology revealed no viral cytopathic change, and - Tacrolimus 18 (75) ADV in situ hybridization was not detected. Adenovirus inter- - Cyclosporine 6 (25) stitial nephritis was defined as the detection of viral cytopathic - Mycophenolate mofetil 20 (83) - Mycophenolate sodium 3 (13) changes in tubular cells; ADV in situ hybridization was detected - Everolimus 1 (4) in 1 patient (proven) and it was inconclusive in another. In 2 - Prednisolone 24 (100) patients, a diagnosis of probable epididymo-orchitis was sup- Abbreviations: ADV, adenovirus; Ig, immunoglobulin; IQR, interquartile range. ported by compatible symptoms, Doppler ultrasonography, and detectable ADV DNA in urine without histopathological confirmation that was deemed to be invasive. Clinical, radio- undertaken after KT in the majority of cases. One patient un- logical, and histopathological findings of representative patients derwent a second KT requiring ATG induction therapy and who were diagnosed with hemorrhagic cystitis, pneumonitis, received IV ganciclovir prophylaxis during admission and sub- epididymo-orchitis, and interstitial nephritis are shown in sequently was switched to preemptive approaches for 3 months Figure 1. after KT. Trimethoprim/sulfamethoxazole for pneumocystis Patients who were diagnosed with LOI were slightly more prophylaxis, acyclovir for herpes simplex virus prophylaxis, frequent to present with hemorrhagic cystitis compared to EOI and isoniazid for latent tuberculous infection therapy were pre- (100% vs 75%, P = .06) Table 3. Patients who were diagnosed scribed in all patients. with EOI were more likely to be febrile compared with those with LOI, but this was not statistically significant (83% vs 58%, Diagnosis of Adenovirus Infection P  =  .18). Patients with EOI had lower median absolute lym- The distribution of ADV infection onset after KT included 7 (29%) phocyte counts (ALCs) than those with LOI (735/mm [IQR, patients who developed infection within 1 month after KT, 5 (21%) 543–1123] vs 1122/mm [IQR, 784–1344], P = .04). There was between 1 and 3  months, and 12 (50%) after 1  year. There were no different in median peak plasma and urine ADV DNA load equal distributions of patients diagnosed with EOI and LOI. Seven between 2 groups. (29%) and 17 (71%) patients developed infection during a wet season (June to October) and a dry season (November to May), Management respectively. Among 7 patients (no respiratory symptoms) who underwent an investigation for possible route of acquisition, naso- After diagnosis the immunosuppression regimen was reduced pharyngeal (NP) swab for ADV PCR was detectable in 2 (29%) pa- in all patients. Mycophenolic acid was discontinued. The me- tients. Among the LOI group, there was no patients who developed dian dose reduction of mycophenolate mofetil was 1.5 g (IQR, rejection within 3 months prior to ADV infection. 1.25–1.50 g). Calcineurin inhibitors were reduced to maintained e Th infections were classified as asymptomatic ADV trough levels of 3–5 ng/mL in patients who were on tacrolimus (4%), ADV disease (4%), hemorrhagic cystitis (88%), upper and 50–100  ng/mL in patients who were on cyclosporine. respiratory tract infection (4%), lower respiratory tract Prednisolone was maintained as tolerated, to a median dose of infection (8%), gastroenteritis (4%), hepatitis (8%), interstitial 7.5  mg/day (IQR, 5–15  mg/day). Thirteen (54%) patients re- nephritis (8%), epididymo-orchitis (8%), and disseminated dis- ceived IV cidofovir with prehydration and posthydration with ease (17%). Initial presentations included dysuria (83%), gross 1  L of 0.9% normal saline solution, and, of those patients, 10 hematuria (83%), fever (46%), sore throat/runny nose (4%), (77%) received oral probenecid with dosing of a total of 4 g oral Adenovirus Infection in Kidney Transplant • ofid • 3 Downloaded from https://academic.oup.com/ofid/article-abstract/6/12/ofz489/5625281 by DeepDyve user on 06 December 2019 4 • ofid • Bruminhent et al Table 2. Patient Characteristics, Management, and Outcomes in 24 Kidney Transplant Recipients Diagnosed With Adenovirus Infection Mainte- Plasma/urine Age Type Induction nance Onset After Peak ADV DNA Load Clinical Outcome/Other Allograft Patient (Years) Sex of KT Regimen Regimens KT (Months) Diagnosis (Log Copies/mL) Cidofovir IVIG Infections Outcome Survived 1 37 M LRKT IL2RA TAC 0.50 ADV-associated 5.4/ > 6.0 Yes, 3 mg/kg/wk (divided Yes, 0.5 g/kg Resolved Transient allograft Yes Everolimus hemorrhagic cystitis as 3 times a wk) at wk 0 at week 1 dysfunction Pred without oral probenecid 2 45 M DDKT IL2RA TAC 0.50 Disseminated ADV > 6.0/> 6.0 Yes, 1.5–3.0 mg/kg/wk (di- Yes, 2 g/kg (in Resolved/ Transient allograft Yes MMF disease (hemor- vided as 3 times a 5 divided asymptomatic CMV dysfunction Pred rhagic cystitis, right wk) at wk 0,1 with oral doses daily) infection epididymo-orchitis) probenecid 3 38 F DDKT IL2RA TAC 0.50 ADV-associated 4.2/> 6.0 Yes, 1.5–3.0 mg/kg/wk (di- No Resolved Transient allograft Yes MMF hemorrhagic cystitis vided as 3 times a dysfunction Pred wk) at wk 0,1 with oral probenecid 4 58 M LRKT IL2RA CsA 0.75 ADV-associated > 6.0/> 6.0 Yes, 5 mg/kg/wk at wk 0,1 No Resolved/ Allograft dysfunc- Yes MMF hemorrhagic cystitis with oral probenecid asymptomatic CMV tion Pred infection 5 42 M LRKT IL2RA TAC 1 Asymptomatic ADV 3.6/4.6 No No Resolved/asymptomatic No allograft Yes MMF infection CMV infection dysfunction Pred 6 34 F Re-DDKT ATG TAC 1 ADV-associated > 6.0/> 6.0 Yes, 1.5 mg/kg/wk (divided as Yes, 2.8 g/ Resolved, human Allograft failure, Yes MMF hemorrhagic cystitis, 3 times a wk) at wk 0,1,2 kg (in 7 parainfluenza URI, acute antibody- Pred ADV interstitial with oral probenecid divided E. coli UTI mediated and nephritis doses daily) T-cell–mediated rejection/graft loss 7 60 M LRKT None CsA 1 ADV pneumonitis < LLOQ/not detected No No Organizing pneumonia, Transient allograft No (non- MMF resolved/asympto- dysfunction ADV – Pred matic CMV infection related) 8 56 M LRKT None CsA 1.50 ADV-associated 5.1/> 6.0 No No Resolved Transient allograft Yes MMF hemorrhagic cystitis dysfunction Pred 9 42 M LRKT IL2RA CsA 1.50 ADV-associated > 6.0/> 6.0 Yes, 5 mg/kg/wk at wk 0,1 No Resolved/ESBL- Allograft dysfunc- Yes MMF hemorrhagic cystitis without oral probenecid producing E. coli UTI tion, acute Pred T-cell–mediated rejection 10 36 M DDKT IL2RA TAC 2 Disseminated ADV > 6.0/> 6.0 Yes, 3 mg/kg/wk (divided as 3 Yes, 2 g/kg (in Resolved/asymptomatic Transient allograft Yes MMF disease (hemor- times a wk) at wk 0,1 with 5 divided CMV infection dysfunction Pred rhagic cystitis, left oral probenecid doses daily) epididymo-orchitis, pneumonitis, hepatitis) 11 59 F DDKT IL2RA TAC 2 ADV-associated 5.7/> 6.0 Yes, 5 mg/kg/wk at wk 0,1 No Resolved/Enterococcus No allograft Yes MMF hemorrhagic cystitis with oral probenecid spp. UTI, BKVAN dysfunction Pred 12 30 M LRKT None CsA 3 ADV syndrome 5.5/N/A Yes, 5 mg/kg/wk at wk 0, 1, 3, No Resolved/asymptomatic No allograft Yes MMF (fever with leukopenia) 5 with oral probenecid CMV infection dysfunction Pred Downloaded from https://academic.oup.com/ofid/article-abstract/6/12/ofz489/5625281 by DeepDyve user on 06 December 2019 Adenovirus Infection in Kidney Transplant • ofid • 5 Table 2. Continued Mainte- Plasma/urine Age Type Induction nance Onset After Peak ADV DNA Load Clinical Outcome/Other Allograft Patient (Years) Sex of KT Regimen Regimens KT (Months) Diagnosis (Log Copies/mL) Cidofovir IVIG Infections Outcome Survived 13 53 M DDKT IL2RA TAC 12 ADV-associated 5.4/> 6.0 Yes, 3 mg/kg/wk (divided as Yes, 2 g/kg (in Resolved Allograft Yes MMF hemorrhagic cystitis, 3 times a wk) at wk 0,1 5 divided dysfunction Pred ADV interstitial without oral probenecid doses daily) nephritis 14 55 F DDKT None TAC 16 ADV-associated > 6.0/5.0 Yes, 3 mg/kg/wk (divided as 3 No Resolved No allograft Yes MMF hemorrhagic cystitis times a wk) at wk 0, then dysfunction Pred 5 mg/kg/wk at wk 1, 3, 5 without oral probenecid 15 29 M LRKT None TAC 15 Disseminated ADV > 6.0/> 6.0 Yes, 5 mg/kg/wk at wk 0,1 No Resolved Transient allograft Yes MMF disease (hemor- with oral probenecid dysfunction Pred rhagic cystitis, hep- atitis) 16 43 M DDKT None CsA 22 Disseminated disease 5.7/> 6.0 No Yes, 1 g/kg (in Resolved/CMV Transient allograft Yes MMF (hemorrhagic 3 divided syndrome, BKVAN dysfunction Pred cystitis, doses daily) gastroenteritis, upper respiratory tract infection) 17 49 M DDKT IL2RA TAC 22 ADV-associated < LLOQ/5.6 No No Resolved Transient allograft Yes MMF hemorrhagic cystitis dysfunction Pred 18 62 M DDKT None TAC 27 ADV-associated 5.3/> 6.0 Yes, 3 mg/kg/wk (divided as No Resolved No allograft Yes MPS hemorrhagic cystitis 3 times a wk) at wk 0 with dysfunction Pred oral probenecid 19 59 M DDKT None TAC 36 ADV-associated > 6.0/> 6.0 No No Resolved Transient allograft Yes MMF hemorrhagic cystitis dysfunction Pred 20 54 M DDKT IL2RA TAC 39 ADV-associated 5.0/> 6.0 No No Resolved Allograft Yes MPS hemorrhagic cystitis dysfunction Pred 21 57 M DDKT None TAC 40 ADV-associated > 6.0/> 6.0 No No Resolved No allograft Yes MMF hemorrhagic cystitis dysfunction Pred 22 67 M DDKT None TAC 47 ADV-associated 3.9/> 6.0 No No Resolved Transient allograft Yes MPS hemorrhagic cystitis dysfunction Pred 23 24 M LRKT None TAC 59 ADV-associated 5.1/> 6.0 No No Resolved Transient allograft Yes MMF hemorrhagic cystitis dysfunction Pred 24 34 M DDKT IL2RA TAC 63 ADV-associated 5.3/> 6.0 No No Resolved Allograft Yes MMF hemorrhagic cystitis dysfunction, Pred acute T-cell–medi- ated rejection Abbreviations: ADV, adenovirus; ALC, absolute lymphocyte count; ATG, antithymocyte globulin; BKVAN, BK polyomavirus-associated nephropathy; CMV, cytomegalovirus; CsA, cyclosporine; DDKT, deceased-donor kidney transplantation; DNA, deoxyribo- nucleic acid; ESBL, extended-spectrum beta-lactamase; F, female; IL2RA, interleukin-2 receptor antagonist; IVIG, intravenous immunoglobulin; LLOQ, lower limit of quantification; M, male; MMF, mycophenolate mofetil; MPS, mycophenolate sodium; LRKT, living-related kidney transplantation; N/A, not applicable; Pred, prednisolone; TAC, tacrolimus; UTI, urinary tract infection; wk, week. Downloaded from https://academic.oup.com/ofid/article-abstract/6/12/ofz489/5625281 by DeepDyve user on 06 December 2019 Outcome probenecid,with 2 g 3 hours prior to infusion, 1 g 2 hours after infusion, and 1 g 8 hours after infusion. The details of cidofovir In all patients, the median time from diagnosis to clinical reso- dosing are shown in Table 2. Five patients received weekly IV lution of 9 days (IQR, 5–13 days) was significantly shorter than cidofovir at a dose of 5  mg/kg, 5 patients received 1  mg/kg 3 virological resolution of 46 days (IQR, 30–60 days) (P < .001). times per week, and 3 patients received 0.5 mg/kg 3 times per Infection completely resolved without complications in 23 pa- week (those with creatinine clearance <50 mL/min) for 2 con- tients (96%). One patient was diagnosed with probable ADV secutive weeks followed by every other week until clinical and pneumonitis that was subsequently complicated by organizing viral clearance in most cases. Different doses of cidofovir was pneumonia requiring a tapered course of prednisolone therapy. selected on clinician preference based on the doses that were re- Recurrence with low-level ADV DNAemia that was not clini- commended by an international guideline. Patients diagnosed cally significant occurred in 1 patient (4%) after the resumption with EOI were more likely to receive IV cidofovir therapy (75% of immunosuppressant. Ten patients (42%) developed oppor- vs 33%, P = .04) compared with those who diagnosed with LOI. tunistic infections other than ADV, including CMV (including Among 13 patients who received IV cidofovir, the creatinine in- asymptomatic CMV infection; n=6), CMV syndrome (n=1), creased in 9 (69%) patients after therapy and 5 (38%) returned BK polyomavirus-associated nephropathy (n=2), human para- to baseline. Allograft dysfunction occurred more frequently influenza virus upper respiratory tract infection (n=1), uri- in patients who received IV cidofovir therapy compared with nary tract infection with Enterococcus spp. (n=1), Escherichia those withheld from therapy (38% vs 18%, P  =  .66) as well as coli (n=1), and extended-spectrum beta-lactamase-producing those received once weekly (40%) compared with thrice-weekly E.  coli (n=1). Patients diagnosed with EOI were more likely to regimen (40% vs 25%, P = .57), though the trends were not sta- develop opportunistic infection other than ADV (75% vs 8%, tistically significant. No patients developed uveitis, significant P  <  .001), including CMV coinfection (50% vs 8%, P  =  .03), neutropenia, anemia, or proteinuria, or adverse reactions to compared with those diagnosed with LOI. probenecid, including fever, rash, headache, or nausea. Eighteen (75%) patients developed allograft dysfunction, and Six (25%) patients received IVIG at doses ranging from 0.5– 67% of these were transient. Three (13%) patients developed 2.0 g/kg as adjunctive therapy. Aer r ft esolution, all patients were acute T-cell–mediated allograft rejection aer ft therapy, and 1 restarted gradually on mycophenolic acid closed to baseline (4%) of them developed concurrent antibody-mediated rejec- dosing. Calcineurin inhibitors were kept at appropriate trough tion. One patient (4%) underwent nephrectomy for allogra ft levels and low dose prednisolone was maintained. failure and 1 (4%) died from a non-ADV–related cause. A B CD Figure 1. Clinical, Radiographic, and Histopathology Findings in Kidney Transplant Recipients Diagnosed With Adenovirus Infection A, Gross hematuria. B, computed to- mography of the chest showed newly developed patchy ground glass opacities with overlying consolidation opacity as well as several scattering solid nodules in both lungs. C, Doppler ultrasonography of the testes showed relatively enlarged size and increased vascularity of the right testis without mass or abnormal echogenicity. D, histopa- thology findings of the renal allograft biopsy showed lymphoplasmacytic infiltration in the interstitium with tubular injury and focal tubulitis. (P AS X 400). 6 • ofid • Bruminhent et al Downloaded from https://academic.oup.com/ofid/article-abstract/6/12/ofz489/5625281 by DeepDyve user on 06 December 2019 Table 3. Clinical, Laboratory, Management, and Outcome Data Derived From 24 Kidney Transplant Recipients Who Were Diagnosed with Early and Late Onset ADV Infection Early onset Late onset (n = 12) (n = 12) P value ADV infection, n (%) - Asymptomatic infection 1 (8) 0 .30 - Hemorrhagic cystitis 9 (75) 12 (100) .06 - Interstitial nephritis 1 (8) 1 (8) >.999 - Hepatitis 1 (8) 1 (8) >.999 - Upper respiratory tract infection 0 1 (8) .30 - Pneumonitis 2 (17) 0 .14 - Gastroenteritis 0 1 (8) .30 - Epididymo-orchitis 2 (17) 0 .14 - ADV syndrome 1 (8) 0 .30 - Disseminated infection 2 (17) 2 (17) >.999 Clinical presentations, n (%) - Fever 10 (83) 7 (58) .18 - Dysuria 9 (75) 11 (92) .27 - Gross hematuria 9 (75) 11 (92) .27 - Testicular pain 2 (17) 0 .14 - Shortness of breath 2 (17) 0 .14 Laboratory findings at diagnosis, median (IQR) - Total white blood cell count (cells/mm ) 7670 6050 .37 (4013–10658) (4208–7423) - Absolute lymphocyte count (cells/mm ) 735 1122 .04 (543–1122) (784–1344) - Peak urine ADV DNA load (log10 copies/mL) 6.0 (6.0–6.0) 6 (6.0–6.0) >.999 - Peak plasma ADV DNA load (log10 copies/mL) 5.7 (5.1–6.0) 5.4 (5.1–6.0) .70 Treatment, n (%) - Cidofovir 9 (75) 4 (33) .04 - Intravenous immunoglobulin 4 (25) 2 (17) .35 Outcome, n (%) - Time to virological resolution (median, IQR; days) 56 (35–60) 43 (28–52) .24 - Time to clinical resolution (median, IQR; days) 10 (5–17) 6 (5–11) .30 - Opportunistic infection other than ADV 9 (75) 1 (8) <.001 - Cytomegalovirus coinfection 6 (50) 1 (8) .03 - Normal allograft function 3 (25) 3 (25) 1.00 - Transient allograft dysfunction 6 (50) 6 (50) 1.00 - Allograft dysfunction 2 (17) 3 (25) .62 - Allograft failure 1 (8) 0 .30 - Acute T-cell–mediated rejection 2 (17) 1 (8) .54 - Antibody-mediated rejection 1 (8) 0 .30 - Hemodialysis required after transplantation 1 (8) 0 .30 - Mortality (non-ADV–related) 1 (8) 0 .30 Abbreviations: ADV, adenovirus; DNA, deoxyribonucleic acid; IQR, interquartile range; RBC, red blood cell. DISCUSSION at diagnosis, opportunistic infection (other than ADV), and receive cidofovir therapy. Although reduction of the immuno- Herein, we have reported the most recent and comprehensive suppression regimen combined with IV cidofovir evidently can data on the epidemiology, clinical characteristics, manage- achieve a favorable clinical and virological outcome, transient ment, and outcomes of ADV infection in KT recipients from allograft dysfunction remains a substantial consideration. a retrospectively analyzed cohort at a single transplant center. Kidney transplant recipients have been considered to be at The genitourinary tract was the most commonly involved low to moderate risk of ADV infection compared with those system, followed by some unusual presentations rarely seen who undergo liver or thoracic organ transplantation, likely due in clinical practice. Nucleic acid amplification testing with or to less intense immunosuppression [9]. A  large cohort study without histopathological testing is the main diagnostic tool of KT performed previously at our center provided an oppor- used to achieve a diagnosis. Patients who developed ADV in- tunity to investigate this uncommon infection aer KT ft . The fection early posttransplant seem to have more lymphopenia Adenovirus Infection in Kidney Transplant • ofid • 7 Downloaded from https://academic.oup.com/ofid/article-abstract/6/12/ofz489/5625281 by DeepDyve user on 06 December 2019 prevalence of ADV infection in KT recipients were decreased study [13]) due to the recent increased availability of the slightly during 2 periods of time approximately a decade apart, medication at our institution. Cidofovir was considered to 4.9% from 2007 to 2010 [3], and 3.2% during the current study be cost-prohibitive in our resource-limited setting. Some period of 2015 to 2019. Time to diagnosis varied similarly in the patients were able to complete the induction phase but not 2 studies, ranging widely from a few months to years aer KT ft the maintenance phase as recommended in the aforemen- [3]. Although ADV infection can occur all year round without tioned guideline [8]. However, both early clinical and viro- seasonal variability [10], the majority of ADV infection in our logical improvement in those patients would be less likely cohort occurred during the wet season. Kidney transplant re- to require further treatment. The combination of an anti- cipients with ADV infection can present with symptoms ran- ADV agent and optimized immunosuppression has been ging from absent or mild to severe disseminated disease [8]. shown to improve clinical and virological outcomes, and the e p Th resent cohort was concordant with previous studies with strategy reportedly facilitates more rapid clinical resolution regard to similar initial presentations and organ involvement of although it takes approximately 2  months to achieve viro- ADV infection with hemorrhagic cystitis in the majority of pa- logical clearance. The present patients tolerated IV cidofovir tients. Nanmoku et al [11] recently reported a high incidence well, without hematological or ocular toxicities. We found of ADV genitourinary tract infection (4.5%) in their cohort. In those who received IV cidofovir were more likely to develop contrast, we also detected uncommon presentations of ADV in- allograft dysfunction. However, the majority of the patients fection that are somewhat unique and specific to immunocom- developed transient increases in serum creatinine, which is promised patients, such as pneumonitis, epididymo-orchitis, known to be derived from multifactorial etiologies, including and interstitial nephritis, due to the availability of NAAT and cidofovir exposure, but the incidence of permanent damage immunohistochemical testing at our institution, in which clin- in this context is reportedly low [14]. Patients diagnosed icians who are managing these patients should be aware of. In with EOI were more likely to receive IV cidofovir therapy; the present study, median initial and peak ADV loads were both this could be explained by the complexity of the infection >5 log copies/mL, which is greater than they were in a previous during a period with more intense immunosuppression. We study [3]. found less allograft dysfunction had occurred in those who Observations in the present study were concordant with our received a once-weekly regimen compared with the thrice- previous study in which patients with early infection (onset weekly regimen (40% vs 25%) and a true explanation for this within 3 months aer KT) t ft hat was more severe tended to have different outcome has been elucidating. However, we did not lower ALCs at weeks 1 and 3 than patients with late infections observe other significant complications apart from nephro- [3]. In the present cohort, half of the patients developed ADV toxicity in our cohort. infection within 3 months post-KT, and these patients exhibited Although a few patients did not receive oral probenecid (be- variable ALCs. Nierenberg et al [12] reported that lymphopenia cause a high urine drug concentration was achieved in order to (<500 cells/mm ) measured prior to transplantation is a poten- treat ADV genitourinary tract infection), the allograft outcome tial tool for predicting opportunistic infection aer li ft ver trans- was acceptable. This may have been due to aggressive IV saline plantation. Absolute lymphocyte count indirectly represents hydration concomitantly with cidofovir therapy. However, it is impairment of nonspecific cell-mediated immunity (CMI) important to monitor renal function closely (including protein- in these patients. Our team recently reported low nonspecific uria) both before and during treatment. CMI as indicated by the total lymphocyte count and lympho- Anti-ADV agents were implemented in the majority of + + cyte subset proportions (CD4 and CD8 T-cells), as well as the current patients who were diagnosed with ADV dis- ADV-specific CMI in patients diagnosed with ADV infection, ease, facilitating evaluation of the efficacy of these agents. wherein this immunity was later restored aer r ft esolution [7]. Cidofovir with and without IVIG has been reported to be ef- Because there is no commercial assay available for measuring fective in some SOT, including KT recipients diagnosed with ADV-specific immunity in clinical practice, we encourage the disseminated disease [15, 16]. The true efficacy of cidofovir use of a practical and simple tool to at least stratify and predict and/or IVIG is difficult to assess based on outcome, because those who may develop severe infection. all patients underwent reduction of their immunosuppres- Although no ideal management strategy for ADV infec- sion regimen. Because there has been no randomized con- tion has been established, all patients underwent reduc- trol trial of cidofovir and IVIG to support efficacy, a current tion of their immunosuppression regimen as recommended guideline suggested considering those agents for severe or in a current guideline [8], including discontinuation of disseminated ADV disease and hypogammaglobulinemia, re- mycophenolate, maintenance of low calcineurin inhibitor spectively [8]. trough level, and the lowest dose of prednisolone tolerated Apart from antiviral agents and adjunctive therapies, it has [2] in the present study. More than half of the patients re- been reported that ADV-specific immunity is related to ADV ceived IV cidofovir (compared with a quarter in a previous clearance in KT recipients [5, 7]. Allograft rejection may occur 8 • ofid • Bruminhent et al Downloaded from https://academic.oup.com/ofid/article-abstract/6/12/ofz489/5625281 by DeepDyve user on 06 December 2019 Sinee Disthabanchong, Atiporn Ingsathit, Arkom Nongnuch, Montira as a consequence of reduction of an immunosuppressive reg- Assanatham, and Punlop Wiwattanathum. imen. Therefore, 1 goal is to balance immunosuppression Author contributions. J.B. and S.P.W. conceptualizatized this work. J.B., during infection and maintain the allograft by resuming im- S.W., and C.T. performed data collection. J.B. analyzed the data and com- posed the original draft of the manuscript. This manuscript was revised and munosuppression as soon as the infection is controlled. A  fu- edited by J.B., S.W., C.T., E.P., S.B., and S.P.W. ture study measuring specific ADV-specific immunity in order Financial support. None reported. to facilitate optimal management in this setting is encouraged. Potential conifl cts of interest. All authors: No reported conflicts of in- Although KT recipients with disseminated disease are at a high terest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to risk of mortality, there were no cases of disseminated disease- the content of the manuscript have been disclosed. associated mortality in the present study. That was likely due to early diagnosis, prompt reduction of an immunosuppressive regimen, and vigilant management [6]. References 1. Bruminhent  J, Watcharananan  SP. Adenovirus beyond “pink eye”. J Infect Dis e Th current study had some limitations. er Th e is an inherent Antimicrob Agents 2018; 35:191–4. possibility of bias due to the retrospective nature of the study. 2. Florescu DF, Stohs EJ. Approach to infection and disease due to adenoviruses in e t Th rue incidence of ADV infection likely was underestimated solid organ transplantation. Curr Opin Infect Dis 2019; 32:300–6. 3. Watcharananan  SP, Avery  R, Ingsathit  A, et  al. Adenovirus disease after kidney due to a lack of preemptive ADV load monitoring, which would transplantation: course of infection and outcome in relation to blood viral load have facilitated the diagnosis of asymptomatic ADV infection. and immune recovery. Am J Transplant 2011; 11:1308–14. 4. Watcharananan  SP, Junchotikul  P, Srichanrusmi  C, et  al. Adenovirus infection Such preemptive ADV load monitoring currently is not advo- after kidney transplantation in Thailand: seasonal distribution and potential cated, and, in Humar et al [17], half of the patients developed route of acquisition. Transplant Proc 2010; 42:4091–3. 5. Sester M, Leboeuf C, Schmidt T, Hirsch HH. The “ABC” of virus-specific T cell transient and self-limiting reactivation without clinical sig- immunity in solid organ transplantation. Am J Transplant 2016; 16:1697–706. nificance. Accordingly, preemptive monitoring is not recom- 6. Florescu  MC, Miles  CD, Florescu  DF. What do we know about adenovirus in renal transplantation? Nephrol Dial Transplant 2013; 28:2003–10. mended in the aforementioned guidelines [8]. Additionally, 7. Bruminhent  J, Apiwattanakul  N, Hongeng  S, Kantachuvesiri S, Watcharananan approximately one-third of patients had CMV coinfection, a SP. Absolute lymphocyte count and human adenovirus-specific T-cell immune restoration of human adenovirus infection after kidney transplantation. J Med sole effect of each pathogen that contributes to the idea that the Virol 2019; 91:1432–9. symptoms could be limited. An immunomodulatory effect of 8. Florescu  DF, Schaenman  JM; AST Infectious Diseases Community of Practice. CMV infection is known to place patients at risk of infection Adenovirus in solid organ transplant recipients: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin from another opportunistic pathogen [18]. Last, because the Transplant 2019; e13527. rarity of the disease could limit a sample size, independent risk 9. Florescu DF, Kwon JY, Dumitru I. Adenovirus infections in heart transplantation. Cardiol Rev 2013; 21:203–6. factors analyzed from multivariate analysis to investigate from 10. Ison  MG. Adenovirus infections in transplant recipients. Clin Infect Dis 2006; this small cohort would not be allowed. 43:331–9. 11. Nanmoku K, Ishikawa N, Kurosawa A, et al. Clinical characteristics and outcomes During recent years, ADV has remained a relatively uncommon of adenovirus infection of the urinary tract after renal transplantation. Transpl pathogen that can cause genitourinary tract infection in adult Infect Dis 2016; 18:234–9. 12. Nierenberg  NE, Poutsiaka  DD, Chow  JK, et  al. Pretransplant lymphopenia is a KT recipients. Low ALC at the time of diagnosis may predict novel prognostic factor in cytomegalovirus and noncytomegalovirus invasive in- an increased risk of ADV infection in KT recipients early post fections after liver transplantation. Liver Transpl 2014; 20:1497–507. 13. Bruminhent  J, Rotjanapan  P, Watcharananan  SP. Epidemiology and outcome of KT. Effective management is facilitated by early diagnosis and is ganciclovir-resistant cytomegalovirus infection after solid organ transplantation: a assisted by readily available NAAT, supportive care, and reduc- single transplant center experience in Thailand. Transplant Proc 2017; 49:1048–52. tion of immunosuppression. This combination evidently can 14. Neofytos D, Ojha A, Mookerjee B, et al. Treatment of adenovirus disease in stem cell transplant recipients with cidofovir. Biol Blood Marrow Transplant 2007; 13:74–81. achieve favorable clinical and virological outcomes. Although 15. Saquib R, Melton LB, Chandrakantan A, et al. Disseminated adenovirus infection transient worsening of allograft function may occur, it is not in renal transplant recipients: the role of cidofovir and intravenous immunoglob- ulin. Transpl Infect Dis 2010; 12:77–83. associated with high mortality. 16. Bruminhent J, Athas DM, Hess BD, Flomenberg P. Disseminated adenovirus dis- ease in heart transplant recipient presenting with conjunctivitis. Transpl Infect Dis 2015; 17:125–8. Acknowledgments 17. Humar A, Kumar D, Mazzulli T, et al; PV16000 Study Group. A surveillance study We thank Darunee Chotiprasitsakul, Nantanee Rungpethwong, of adenovirus infection in adult solid organ transplant recipients. Am J Transplant Subencha Pinsai, and Charat Thongprayoon for their helpful participa- 2005; 5:2555–9. tion in discussions. We also thank the Ramathibodi Kidney Transplant 18. Razonable RR, Humar A. Cytomegalovirus in solid organ transplant recipients- Cohort Study team: Vasant Sumethkul, Somnuek Domrongkitchaiporn, Guidelines of the American Society of Transplantation Infectious Diseases Surasak Kantachuvesiri, Bunyong Phakdeekitcharoen, Chagriya Kitiyakara, Community of Practice. Clin Transplant 2019; 33:e13512. Adenovirus Infection in Kidney Transplant • ofid • 9

Journal

Open Forum Infectious Diseases – Oxford University Press

Published: Dec 1, 2019

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