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Dengue Virus Infection in Solid Organ Transplant Recipients: A Case Series and Literature Review

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  • 1 Fundación Valle del Lili, Departamento de Medicina Interna, Servicio de Enfermedades Infecciosas, Cali, Colombia;
  • 2 Fundación Valle del Lili, Centro de Investigaciones Clínicas (CIC), Cali, Colombia;
  • 3 Universidad Icesi, Facultad de Ciencias de la Salud, Cali, Colombia;
  • 4 Fundación Valle Del Lili, Unidad de Trasplantes, Cali, Colombia

Dengue fever is the most prevalent arbovirus infection among humans, and tropical regions are hyperendemic for this infection. The number of solid organ transplant recipients is continuously increasing, and there are few data regarding the clinical course and outcomes of dengue infection among this population. We report on a retrospective case series of solid organ transplant recipients with dengue virus infection from 2001 to 2018 at Fundación Valle del Lili in Cali, Colombia. A total of 20 patients were included. The median age was 50.5 years (interquartile range [IQR] = 31–63.5 years) and 65% were female. Regarding the clinical course, 75% of patients had at least one warning sign, 45% were managed in the intensive care unit, and 30% had severe dengue. The median of time from transplant and dengue infection was 27.6 months (IQR = 3.82–59.12 months), and three patients had the disease in the first month after the transplant. All patients were discharged, and none of them had graft rejection. Dengue is an endemic disease in our region and represents a threat among solid organ transplantation recipients. All patients had a full recovery after the infection, suggesting that timely and effective management of patients and the access to high-complexity services could prevent fatal cases.

INTRODUCTION

Dengue is a febrile illness caused by one of four single-stranded, positive-sense RNA viruses of the genus Flavivirus, transmitted between humans by Aedes mosquitoes.1 Although most dengue virus infections are asymptomatic, a wide variety of clinical manifestations may occur, ranging from mild febrile illness to severe and fatal disease.2

Dengue virus is one of the most relevant arboviruses and has become a public health concern worldwide.3 It is estimated that there are 390 million (95% CI: 284–528 million) dengue infections per year, of which 96 million (67–136 million) manifest apparently (any level of clinical or subclinical severity). Also, it has been estimated that the incidence of dengue has increased 143.1% between 2005 and 2015.4,5 Tropical regions have reported an increase in new cases of the disease in the general population,6 with a concomitant elevated risk of transmission in special populations such as in transplant recipients, which can acquire dengue either by an infected graft or vector transmission.7

Nowadays, solid organ transplantation (SOT) is the definitive treatment for liver, renal, and heart failure. The number of solid organ recipients is continuously increasing, and annually, more than 100,000 transplants are performed worldwide.8 In Latin America, the number of transplants has been increasing, approximately 70,000 kidney and 4,000 liver transplantations were performed in the region until 2001.9 The most commonly transplanted organs were the liver and kidney.10

The literature on dengue infection among transplant recipients is inconclusive; moreover, little is known about the natural history, clinical course, and long-term outcomes of this re-emerging tropical disease in the posttransplantation period. Furthermore, no reports are describing the course of the infection in this population in Colombia. Thus, we aim to assess the outcomes of SOT recipients with dengue fever who were attended at Fundación Valle del Lili (FVL) in Cali, Colombia, a region with a high incidence of the disease.

MATERIALS AND METHODS

We performed a retrospective case series at FVL, a nonprofit university hospital located in the southwestern region of Colombia, which serves as a referral center for highly complex patients. The hospital has an organ transplantation program since 1995, and a total of 1,814 kidney transplants (82 transplants per year, approximately) and 892 liver transplants (42 liver transplants per year, approximately) have been performed during the last 22 years.

Cases were identified retrospectively through Institutional Organ Transplantation Registry and Microbiology Registry. We selected all patients with a history of SOT and subsequent dengue virus infection attended at the FVL from 2001 to 2018; then we reviewed the clinical records. All cases were Colombian residents and they had not traveled recently (at least 3 months).

Patients who met the clinical and epidemiological criteria of dengue infection, established by the WHO,2 and had a positive NS1 antigen or positive IgM dengue antibodies were included. The SD BIOLINE Dengue® IgG/IgM test (Alere Inc., Waltham, MA) was used before 2010, and after 2011, the SD BIOLINE Dengue DUO® NS1 Ag + Ab Combo rapid test (Alere Inc.) was introduced. Detection of NS1 antigen is perhaps the most robust of all the Dengue virus (DENV) diagnostic methods with a relatively long detection window, particularly in patients with primary infection. NS1 can be viewed as a surrogate marker for viremia, with the level of NS1 shown to correlate with viral titer. However, combining NS1 detection with IgM and/or IgG detection has been shown to dramatically improve positive dengue diagnosis. Using this combination approach, detection sensitivities nearing 100% have been reported from the onset of illness through recovery.11 Chikungunya and Zika virus diagnostic tests were not performed; however, all cases were tested for cytomegalovirus, viral hepatitis, and malaria.

This study was approved by the Institutional Review Board—Comité de Ética en Investigación Biomédica at FVL (IRB/EC Protocol number 827) and was conducted following the Declaration of Helsinki.12 Patient consent was not required because this study was performed retrospectively.

Variables and outcomes.

Demographic and clinical variables were collected from medical records. Cases were classified according to WHO guidelines: dengue without alarm signs, dengue with alarm signs, and severe dengue (SD).2 Hemoconcentration was defined as an increase in hematocrit of 10% or more compared with baseline values. The outcomes of interest were death and graft rejection.

For kidney transplantation, graft rejection was defined as organ rejection confirmed by biopsy histological findings according to Banff 2013 classification.13 Regarding liver transplantation, graft rejection was defined as organ rejection confirmed by biopsy histological findings according to Banff 2016 classification.14

Data were collected retrospectively from the FVL medical charts and stored in a secure electronic database.

Statistical analysis.

Continuous variables were presented in median and interquartile ranges (IQRs). Categorical variables were presented in frequencies and percentages. Statistical analyses were performed in STATA® (StataCorp, 2019, Stata 15 Base Reference Manual, College Station, TX: StataPress).

RESULTS

A total of 20 patients with a history of SOT who had a dengue virus infection were included. The median age was 50.5 years (IQR = 31–63.5 years) and 65% (n = 13) were women. Regarding the transplanted organ, 85% (n = 17) were kidney recipients and 15% were liver recipients. The median time between transplantation and dengue infection was 27.6 months (IQR = 3.85–57 months). Three patients had dengue in the first month after transplantation. The median time from onset of symptoms to diagnosis of dengue was 4.5 days (IQR = 2–8.5 days). The most frequent immunosuppressant regimen was mycophenolate mofetil, tacrolimus, and prednisolone (35%), as shown in Table 1.

Table 1

Demographical and clinical characteristics of solid organ transplantation recipients with dengue infection (n = 20)

Characteristicsn (%)
Age (years)*50.5 (31–63.5)
Gender
 Male7 (35)
 Female13 (65)
Transplanted organ
 Liver3 (15)
 Kidney17 (85)
Donor
 Live-related4 (20)
 Deceased16 (80)
Time from transplant to dengue (months)*27.6 (3.82–59.12)
Time from onset of symptoms to dengue diagnosis*4.5 (2–8.5)
Immunosuppressive treatment
 MPM + TAC + PRED7 (35)
 MPM + CYE + PRED5 (25)
 AZA + CYE + PRED2 (10)
 MPM + TAC2 (10)
 MPM + CYE1 (5)
 MPM + EVE + PRED1 (5)
 MPM + SRL + PRED1 (5)
 SRL + PRED1(5)

AZA = azathioprine; CYE = cyclosporine; EVE = everolimus; MPM = mycophenolate mofetil; PRED = prednisolone; SRL = sirolimus; TAC = tacrolimus.

* Median (IQR).

Fever was the most frequent symptom (95%, n = 19), followed by asthenia and adynamia (60%, n = 12), see Table 2. Fifteen patients (75%) had warning signs, of which five referred persistent abdominal pain and four had hemorrhagic manifestations.

Table 2

Clinical and laboratory findings in solid organ transplantation recipients with dengue (n = 20)

Characteristicsn (%)
Clinical findings
 Fever19 (95)
 Asthenia and adynamia12 (60)
 Myalgia11 (55)
 Diarrhea11 (55)
 Headache11 (55)
 Abdominal pain9 (45)
 Arthralgia8 (40)
 Nausea and vomiting7 (35)
 Chills4 (20)
 Rash2 (10)
Warning signs15 (75)
 Thrombocytopenia6 (30)
 Abdominal pain5 (25)
 Bleeding from mucous membranes3 (15)
 Persistent vomit1 (5)
 Drowsiness/irritability1 (5)
 Decreased diuresis1 (5)
 Orthostatic hypotension1 (5)
 Hemoconcentration1 (5)
 Drop in hemoglobin1 (5)
Laboratory findings
 Leukopenia11 (55)
 Platelets < 150,000/μL14 (70)
 Platelets < 50,000/μL6 (30)
 AST > 2 times upper limit, n = 163 (19)
 AST > 3 times upper limit, n = 166 (38)
 ALT > 2 times upper limit, n = 163 (19)
 ALT > 3 times upper limit, n = 166 (38)
 Serum creatinine elevation from baseline7 (35)
WHO dengue case classification
 Dengue5 (25)
 Dengue with warning signs8 (40)
 Severe dengue7 (35)
Management
 Ambulatory1 (5)
 Emergency room1 (5)
 Inpatients wards9 (45)
 Intensive care unit9 (45)
Length of hospital stay (days)*6 (2–10)
Outcome
 Discharge20 (100)

ALT = alanine aminotransferase; AST = aspartate aminotransferase.

* Median (IQR).

A positive NS1 and/or IgM/IgG antibodies confirmed dengue infection in 19 patients; one case was diagnosed by clinical criteria and a positive IgM test. According to diagnostic tests, 11 patients had a primary dengue infection (see Table 3). Among patients with secondary infection (n = 9), five developed SD.

Table 3

Dengue diagnostic tests in solid organ transplantation recipients (n = 20)

Diagnostic testPrimary infectionSecondary infection
IgMIgGNS1
n (%)n (%)
NegativeNegativePositive4 (21)
PositiveNegativePositive3 (16)
PositivePositivePositive1 (5)
PositiveNegativeNegative2 (11)
NegativePositivePositive1 (5)
PositivePositiveNegative4 (21)
PositiveNegativeNA2 (11)
PositivePositiveNA3 (16)
Total119

NA = not available; NS1 = NS1 antigen.

Regarding laboratory findings, 14 patients (70%) had a platelet count lower than 150,000/μL and five had less than 50,000 platelets/μL. During the clinical course, 45% (n = 9) of patients had leukopenia. The median of the lowest white blood cell count was 3,940/μL (IQR = 2,150–5,760/μL). Liver tests were assessed in 80% (n = 16) of patients, of which six patients had alanine aminotransferase and aspartate aminotransferase three times greater than the upper limit value. Among kidney transplant recipients, seven patients had an elevation of creatinine from their baseline; however, none of them had graft rejection. All patients tested negative for cytomegalovirus, viral hepatitis, and malaria.

Seven patients (35%) developed SD (six kidney and one liver recipients), their median age was 54 years (IQR = 24–42.5 years), six of them were female, and the median time between transplantation and dengue infection was 113.5 months (IQR = 97–180 months), see Table 4. Among these patients, one kidney recipient developed symptoms 10 days after transplantation and presented major hemorrhage in the surgical site, shock, and signs compatible with organ failure (hepatitis).

Table 4

Clinical and laboratory findings in solid organ transplantation recipients with severe dengue (n = 7)

Patients
VariablesP1P2P3P4P5P6P7
Age (years)24316716546869
GenderMaleFemaleFemaleFemaleFemaleFemaleFemale
OrganKidneyKidneyKidneyKidneyKidneyKidneyLiver
DonorLivingDeceasedDeceasedLivingDeceasedDeceasedDeceased
Transplant age (months)2580.310582102154122
ImmunosuppressionMPM, TACMPM, CYE, PREDMPM, TAC PREDCYE, AZA, PREDMPM, TAC, PREDMPM, TAC, PREDMPM, EVE, PRED
Warning signsHCTPMucosal bleedingTP and Mucosal bleedingOliguriaMucosal bleedingHypotension
Graft function alterationYesNoNoNoYesNoNo
Severity criteriaOrgan impairment (AKI)*Severe bleeding and hepatitisSevere bleedingSevere bleedingOrgan impairment (AKI)*Organ impairmentOrgan impairment (AKI)*
Positive DENV diagnostic testsIgM, IgGIgM, IgG, NS1NS1IgM, IgGIgM, IgGIgG, NS1IgM

AZA = azathioprine; CYE = cyclosporine; EVE = everolimus; HC = hemoconcentration; MPM = mycophenolate mofetil; PRED = prednisolone; TAC = tacrolimus; TP = Thrombocytopenia.

* AKI = acute kidney injury.

Eighteen patients (90%) required inhospital management, of which nine were managed in the intensive care unit (ICU). The ICU admission criteria were sepsis, hemodynamic instability, comorbidities (acute kidney injury, severe thrombocytopenia, acid–base disorder, and hepatitis), and SD.

Five patients required modifications in the immunosuppressive treatment and the clinical management was individualized. Mycophenolate mofetil was suspended in four patients, azathioprine in one case, and the dose of tacrolimus was adjusted for one patient. Regarding the outcomes, there were no fatal cases and no cases of graft rejection at 1 month of follow-up (see Table 2).

DISCUSSION AND LITERATURE REVIEW

Dengue is an endemic disease in our region and represents a threat among SOT recipients. A total of 20 cases were documented in 15 years in our institution, and all patients had a full recovery after the infection, suggesting that timely and effective management of patients and the access to a hospital with experience in the management of dengue fever may aid in the prevention of fatal cases.

To date, there are approximately 180 reported cases of dengue virus infection in SOT recipients (see Table 5). The first two cases described were published more than a decade ago and, unlike the patients described in this series, were fatal.15,16 A late diagnosis could have contributed to these findings.

Table 5

Reports of solid organ transplantation recipients with dengue virus infection

StudyCountryNumber of casesAge*GenderOrganTime from transplant to infection (months)*ThrombocytopeniaSevere dengueGraft function alterationGraft rejectionDeceases
Tan et al.15Singapore123MKidney0.1611000
García et al.16Brazil166MLiver0.7111N/A1
Renaud et al.17Singapore656.1M: 4Kidney53.3N/A0000
F: 2
Azevedo et al.18Brazil2737 ± 14†M: 18KidneyN/AN/A1N/A01
F: 9
Park et al.34South Korea129FKidney15610000
Prasad et al.19India836.5 (26.3–46,6)M: 4Kidney22 (2.75–61)83433
F: 4
Tangnararatchakit K et al.35Thailand116FKidney0.211100
Nasim et al.23Pakistan10228M: 75Kidney1.27 (2 days–14.5 years)97126897
Weerakkody et al.7Sri Lanka146MLiver2611100
Maia et al.31Brazil218†M: 2Kidney0.12221
Costa et al.36Brazil1037 (22.8–A43.8)M: 5Kidney44.5 (8.3–A55.7)74800
F: 5
Subbiah et al.37India2031.9 ± 8.8†M: 20Kidney12,6 (0.03–108.3)182811
Kenwar et al.38India3237.2 (19–64)M: 27Kidney36.2 (0–168)26122
F: 5
Rosso et al.Colombia2050.5 (31–63.5)F:133 livers27.6 (3.82–A59.2)67700
17 kidneys

F = female; M = male; N/A = not available.

* Years median (IQR).

† Years mean ± SD.

Subsequent reports describe that the clinical course of dengue infection in SOT recipients is similar to dengue in nontransplanted population.17,18 Nevertheless, some studies suggest a higher risk of SD and impaired graft function in SOT recipients with dengue,19 and a recent systematic review of the literature reports an increased risk of SD and dengue mortality in this population.7 Contrary to these results, we had no fatal cases in our series, which could be explained by early diagnosis and access to ICU with continuous monitoring and integrated approach based on resuscitation goals.

The treatment of dengue patients in SOT was based on the resuscitation objectives considered in the International Campaign Surviving Sepsis,20 although these definitions were not developed using cohorts of dengue patients. Clinical management included early admission to the ICU, early diagnosis of etiology, and monitoring of hematocrit, platelets, and liver and kidney function. None of the cases required transfusion of blood components.

Patient management also included administration of isotonic fluids (mainly 0.9% saline and Ringer’s lactate) with a follow-up of fluid balance. Studies in this matter have shown that fluid therapy in dengue patients is essential in clinical outcomes. There is no clear advantage between different types of fluids, but a difference in recovery time has been identified between colloid therapy and Ringer’s lactate,21,22 which should be considered in the cases with transplant conditions.

Some cases required adjustments in the immunosuppressive treatment, but this was not related to dengue severity or mortality in our case series, which is different from reported in the literature. Nasim et al.23 showed that patients who are on tacrolimus treatment had higher mortality (n = 102, P = 0.031), but in the final analysis showed no association (n = 131, P = 0.28).

Secondary dengue infection implies the presence of preexisting antibodies specific for dengue virus, which generate a robust activation of the immune response mediated by cytokines and T cells and, therefore, increase the risk of SD.24,25 Although differentiating primary from secondary dengue could be difficult in SOT because of immunosuppressive therapy and subsequent alterations in immunologic response,23 in this series, seven patients had SD and five of them had a secondary infection characterized by a positive IgG.

The median time from the onset of symptoms to diagnosis was 4.5 days, which coincides with the critical phase of the disease. It is presumed that dengue diagnosis among SOT recipients could be difficult because of the immunosuppressive regimen that may mask dengue symptoms.17,26 In addition, the symptoms can be attributed to comorbidities, opportunistic infections, or the adverse effects of some immunosuppressive drugs,27,28 all of which can delay dengue diagnosis with the subsequent deterioration of patient outcomes. Thus, in regions where the virus is endemic, dengue should be suspected early in SOT recipients and opportunely evaluated by infectious diseases specialist and a timely critical care unit access should be assured.

In the first month after transplant, three patients had dengue and NS1 antigen was also positive in their donors, suggesting a donor-derived transmission of dengue infection. Recently, a scoping review found a knowledge gap regarding screening for dengue virus in solid organ transplant donors and recipients in dengue-endemic areas.29 Although donor screening is not standardized in current guidelines,30 we suggest testing donors for dengue antigen and antibodies during outbreaks in endemic countries.

One patient got the infection 10 days after transplantation and developed SD with major bleeding. Maia et al.31 reported two cases of patients with kidney transplant and dengue with severe hemorrhagic manifestations in the first posttransplant week, suggesting that in the first posttransplant month, dengue may constitute a severe condition. Regarding the symptoms, one of our patients did not report fever, and there was a low percentage of arthralgia (40%). These findings could be associated with the immunosuppressive therapy used after transplantation and are similar to previous studies which report less frequently fever in patients on high-dose steroids compared with low-dose steroids.23

Regarding graft function, among kidney recipients, seven patients presented elevated serum creatinine, with progression to acute renal failure in three cases. Prasad et al.19 postulated that kidney transplant recipients might have an increased risk of SD and mortality; however, none of our patients died (see Table 5).

Although some patients had modifications in the immunosuppressant regimen (30%), it is not clear whether this indication influenced the course of the disease. Previous reports indicate that immunosuppression does not change the outcome of the patient26,32 and that the use of steroids in the management of SD has not shown a decrease in mortality.33 The patients in this series who received immunosuppression with azathioprine, cyclosporine and steroids (n = 2) had severe and prolonged thrombocytopenia; Nasim et al. reported this finding in 44.4% of their patients with this immunosuppressive regimen.

Limitations.

Our results should be interpreted in the context of a case series. The information in this study was collected from medical records. There is a probable subregistration of dengue infection among SOT recipients because of alterations in antibody response in SOT recipients or mild/self-limited presentation of dengue infection.

Because of the rapid growth of the population of SOT recipients and donors in hyperendemic countries, with active transmission of dengue, it is necessary to establish evidence-based clinical practice guidelines for the diagnosis and management of SOT recipients with dengue virus infection. Likewise, in these specific regions, routine diagnostic tests for the disease should be considered to deliver appropriate management to this particular population and, thereby, reduce the possible complications and associated fatal outcomes.

Acknowledgments:

We thank the Centro de Investigaciones Clínicas – Fundación Valle del Lili for their constant support.

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Author Notes

Address correspondence to Fernando Rosso, Fundación Valle del Lili, Cra. 98 Nro. 18-49, Cali 760032, Colombia. E-mails: fernando.rosso@fvl.org.co or frosso07@gmail.com

Authors’ addresses: Fernando Rosso, Pablo Andrés Moncada, Juan Diego Vélez, and Luis Armando Caicedo, Fundación Valle del Lili, Universidad Icesi, Cali, Colombia, E-mails: fernando.rosso@fvl.org.co, drpmoncada@gmail.com, jdvelez1@gmail.com, and caicedo.luis7@gmail.com. Ana María Sanz and Luis Gabriel Parra-Lara, Fundación Valle del Lili, Cali, Colombia, E-mails: asanzm92@gmail.com and luisgabrielparralara@hotmail.com.

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