Case Report: Transmission of Dengue Virus from a Deceased Donor to a Kidney Transplant Recipient Previously Infected by Dengue Virus

Abstract.

Since 2018, a dengue epidemic has been ongoing in the French overseas department of Reunion Island, in the Indian Ocean, with more than 25,000 serologically confirmed cases. Currently, three dengue serotypes have been identified in Réunion Island (DENV-1, DENV-2, and DENV-3) progressing in the form of epidemic outbreaks. This arbovirus is mainly transmitted by mosquitoes of the genus Aedes and may be responsible for serious clinical forms. To date, very few cases of kidney transplant–related dengue virus infection have been described. Here we report the first case of severe dengue virus infection related to kidney transplantation from a patient previously infected with dengue. Testing for dengue fever with PCR search in donor’s urine may help complete the pretransplant assessment in areas where this disease occurs.

INTRODUCTION

Dengue fever, an arboviral disease caused by one of four serotypes of dengue virus (DENV 1–4), is very common in tropical areas. In 2018, a dengue epidemic broke out in the French overseas department of Reunion Island, in the Indian Ocean.¹ Initially, the main circulating serotype of dengue virus on the island was DENV-2. Since 2019, DENV-1 and DENV-3 serotypes have been increasingly common, and in 2020 the most frequently isolated serotype was DENV-1.² The most common vector of dengue virus is a mosquito of the genus Aedes, with Aedes albopictus being the main cause of infection in Reunion Island. Cases of dengue transmitted via solid organ transplantation are rare because organ transplant centers in dengue-endemic areas are trained to screen for dengue virus in potential organ donors and recipients.

Case summary.

This is the case of a 58-year-old man with a history of treated hypertension who had presented with end-stage renal disease due to nephrolithiasis requiring hemodialysis for 3 years before kidney transplantation.

Pretransplant serology (Dengue Virus IgM/IgG Capture DxSelect ELISA) indicated a past dengue infection (IgM index 0.2 and IgG index 2.1), and the patient was asymptomatic at the time of transplantation. The donor was a 62-year-old man with no medical history who was in a state of brain death due to severe head trauma. The donor was tested for dengue prior to organ removal: blood polymerase chain reaction (PCR) (Nucli Sens easyMAG, Biomerieux, NJ) was negative, and serology indicated a recent infection (IgM index 5.9 and IgG index 2.7). Urine PCR was not performed. The donor was also screened for chikungunya: blood PCR was negative, and serology indicated an old infection (IgM index 0.1 and IgG index 3.9). Both his kidneys were harvested and transplanted, the right kidney in our patient (in the right iliac fossa) without surgical complications and the left kidney in another patient on the same day (also in the right iliac fossa). On the day of transplantation (day 1), the first recipient presented with preoperative hemoglobin of 12.8 g/dL, a platelet count of 153 G/L, a white blood cell count of 5.64 G/L, normal liver function (AST 22 IU/L and ALT 24 IU/L), and creatinine level at 1,317 µmol/L. The postoperative course was marked by oligo-anuria, and on day 2 he presented with creatinine of 1,287 µmol/L and urea of 27.4 mmol/L, which prompted the resumption of intermittent hemodialysis sessions. The patient was treated with mycophenolate mofetil, methylprednisolone, thymoglobulin, and tacrolimus to prevent kidney transplant rejection. A Doppler ultrasound of the graft performed on day 3 was normal. On day 11, the patient’s hemodynamic status deteriorated (blood pressure 76/43 mm Hg, heart rate 119 beats/min, temperature 36°C, and plasma lactate 1.2 mmol/L) with abdominal pain (but no fever), prompting transfer to the intensive care unit. Biological analysis showed thrombocytopenia (50 G/L), anemia (8.0 g/dL with no sudden drop in hemoglobin), a normal coagulation profile (prothrombin level at 95%, fibrinogen level at 3.8 g/L, activated thromboplastin time ratio at 0.83), and hepatic cytolysis (AST 116 IU/L and ALT 36 IU/L). A noninjected abdomino-pelvic computed tomography scan revealed a right-lateralized hydroaeric collection in the abdominal wall, suggesting an infectious complication. The patient was urgently reoperated to evacuate the collection, but the operation was complicated by hemorrhagic shock. Four additional operations were required over the next 36 hours because effective hemostasis could not be achieved despite four platelet transfusions and three injections of activated Factor VII (NovoSeven^®).

His clinical condition required 10 days of vasopressor support without the need of inotropic support consistent with the development of a distributive shock, which was monitored with laboratory parameters (lactates level, ScVo2...) and echocardiography (Sepsis-related Organ Failure Assessment score was 15). The intraoperative sampling of the collection came back positive for Staphylococcus epidermidis, and antibiotic therapy with vancomycin was begun for a total duration of 7 days.

On day 11, blood PCR was positive for DENV-1. On day 14, the patient presented with thrombocytopenia (34 G/L) despite several platelet transfusions, anemia (7.7 g/dL), hepatic cytolysis (AST 3,725 IU/L and ALT 1,116 IU/L), and leukopenia (2.04 G/L) with immunosuppressive therapy. Due to a ventilator-associated pneumonia caused by an extended spectrum beta-lactamase Klebsiella pneumoniae, antibiotic therapy with meropenem was introduced for 7 days. The outcome was secondarily favorable under antibiotic treatment, allowing discontinuation of mechanical ventilation after 14 days, and was followed with 7 days of nasal oxygen. On day 30, seroconversion was demonstrated (IgM index 1.1 and IgG index 2.7). Thrombocytopenia (46 G/L) persisted, and liver function was normalized. On Day 32, both blood and urine PCR were negative for dengue. The secondary course was favorable, and dialysis was stopped. He received a total transfusion of eight packed red blood cells, six fresh-frozen plasma concentrates, and six platelets concentrates during his intensive care unit stay. The patient was discharged from the intensive care unit on day 39 and sent home on day 55 without the need for dialysis to be resumed (creatinine 288 µmol/L at hospital discharge).

The recipient of the left kidney was a 61-year-old man. The early postoperative course was simple, with satisfactory graft function from the outset. The patient was treated with mycophenolate mofetil, methylprednisolone, thymoglobulin, and tacrolimus to prevent kidney transplant rejection. On day 12, he presented with thrombocytopenia (64 G/L) associated with hepatic cytolysis (AST 220 IU/L and ALT 181 IU/L) and a normal clinical examination. Both blood and urine PCR were positive for DENV-1, and dengue serology was negative (IgM index 0.5 and IgG index 0.1).

On day 28, thrombocytopenia has improved (100 G/L), and liver function was normalized. On day 30, blood PCR was negative for dengue, but urine PCR was positive. Dengue serology indicated a recent infection (IgM index 1.5 and IgG index 1.9). On day 38, the patient was sent home with persistent renal failure (creatinine 271 µmol/L) with no need for repeat dialysis.

DISCUSSION

The incidence of dengue fever has increased significantly over the last 30 years. The dengue virus is present in more than 100 countries, and its four serotypes are responsible for more than 30 million cases of dengue fever each year.³ In the French overseas department of Reunion Island, where a dengue epidemic has been ongoing since 2018, three serotypes of the virus (DENV-1, DENV-2, and DENV-3) have been identified.¹ In 2018, the majority of cases were linked to DENV-2, whereas the majority of the nearly 16,000 confirmed cases since January 2020 have been linked to DENV-1.⁴ Although dengue virus is mainly transmitted via mosquitoes of the genus Aedes, several cases of percutaneous, nosocomial, and vertical transmission have also been described.⁵ Cases of transmission via solid organ transplantation, however, remain anecdotal.^6,7 The few available studies suggest that the initial symptoms of dengue-infected transplant recipients is identical across cases.^8,9

A systematic review from 2017 found a higher incidence of severe dengue fever and a higher mortality rate (of up to 8.9%) in patients who contracted the virus through transplantation.¹⁰ The review also found that more than 60% of transplanted patients had transient renal dysfunction, and 6.5% had graft loss. However, no association was detected between selected immunosuppressive strategy and disease severity.¹⁰ Although primary infection with dengue virus results in the production of serotype-specific antibodies and confers long-term immunity against that serotype, antibodies produced during secondary infection with a different serotype are unable to neutralize the virus, which may contribute to the formation of immune complexes that favor the entry and multiplication of the virus in cells. Secondary infection is therefore associated with more severe forms of the disease, regardless of the implicated serotype.¹¹ This could explain why our patient, who was likely infected with DENV-2 (the predominant serotype in Reunion Island until 2019)⁴ before contracting the DENV-1 serotype during kidney transplantation, developed a severe form of dengue fever.

Studies have found that dengue RNA can be detected in urine for a longer period of time than in blood.^12,13 Moreover, case studies of dengue after kidney transplantation have shown that infectious virus, and not only genetic material, persists in recipients’ urine.¹⁰ It remains to be established, however, whether the persistence of dengue virus in urine is due to viral replication in the renal parenchyma or to viruria.

This clinical case illustrates the need to screen the urine of donors during the pretransplant assessment due to the risk of dengue transmission through transplantation where dengue occurs both as an endemic disease and as epidemic outbreaks.