COVID-19 and cytomegalovirus coinfection in kidney transplant recipients: about two cases

¹Department of Nephrology, Dialysis and Kidney Transplantation, Fattouma Bourguiba University Hospital of Monastir, Avenue Farhat Hached, 5000 Monastir, Tunisia, ²Department of Radiology, Fattouma Bourguiba University Hospital of Monastir, Monastir, Tunisia

^&Corresponding author
Meriem Ben Salem, Department of Nephrology, Dialysis and Kidney Transplantation, Fattouma Bourguiba University Hospital of Monastir, Avenue Farhat Hached, 5000 Monastir, Tunisia

Introduction    

The COVID-19 management in kidney transplant recipients is very challenging because of their immunosuppression, comorbidity, and susceptibility to a diversity of viral pathogens [1]. Cytomegalovirus (CMV) is one of the most common persistent viral infections and the most prevalent germ-generating renal transplantation complication [2,3]. Herein, we describe two cases of COVID-19 and CMV co-infection in kidney transplant recipients and discuss the challenge in the diagnosis as well as the management of this co-infection.

Patient and observation     

Patient 1

Patient information: a 50-year-old man with a deceased donor kidney transplant in October 2019. Thereafter, he developed post-transplant diabetes mellitus, hypertension, and recurrent urinary tract infections due to vesicoureteral reflux. His immunosuppressant regime included tacrolimus with levels between 5 and 8 ng/ml, mycophenolate mofetil (MMF) 1g twice a day, and prednisone 10mg daily. His other medications included amlodipine, repaglinide, and fosfomycin. He presented with a dry cough and headache evolving for 2 days.

Clinical findings: physical examination revealed pallor, dyspnea, and bilateral mild base crackles on lung auscultation, blood pressure was 130/75 mmHg, pulse rate was 75 beats per minute, respiratory rate was 20 breaths per minute, Sat O₂ was 98% on room air, and a temperature of 38°C.

Timeline of the current episode: COVID-19 was suspected based on a clinical score and Reverse transcription-polymerase chain reaction (RT-PCR) COVID-19 in nasopharyngeal swab was positive. The patient was put on cefotaxime 1g every 12 hours, enoxaparin 4000 UI daily, paracetamol according to fever, vitamin C 1000mg daily, and zinc 30 mg daily. He showed partial improvement in symptoms. On day 10 of hospitalization, he developed diarrhea with a high fever thus we replaced cefotaxime with imipenem and metronidazole.

Diagnostic assessment: whole-body CT scan showed peripheral bilateral ground-glass opacities occupying 25% of lung parenchyma volume in addition to colonic wall thickening and pericolic fat infiltration suggestive of acute colitis. The blood test showed leukopenia with high lactate dehydrogenase (LDH) levels (Table 1). Serum polymerase chain reaction (PCR) for CMV reached 148,000 copies/ml.

Diagnosis: COVID-19 and CMV co-infection in a kidney transplant recipient.

Therapeutic interventions: mycophenolate mofetil was discontinued and ganciclovir was started, 72 hours later fever and diarrhea resolved (Table 1). He received ganciclovir for 21 days.

Follow-up and outcomes: he completely recovered.

Patient perspective: “I trust science”

Informed consent: he has given informed consent.

Patient 2

Patient information: a 36-year-old woman with a history of lupus nephritis developed the end-stage renal disease in 2014 and received a deceased donor kidney transplant in October 2019. Her immunosuppressant regime included tacrolimus 0.15mg/kg/day, sirolimus 1mg daily, and prednisone 5mg daily. Of note, the hydroxychloroquine was interrupted six years ago due to toxic maculopathy. As complications, she developed thrombophlebitis, adrenal insufficiency, and recurrent cytomegalovirus (CMV) infection. She was hospitalized in our department with decreased visual acuity of her left eye and abdominal pain related to CMV disease (CMV retinitis and colitis) and treated by intravenous ganciclovir 10mg/kg/day.

Timeline of the current episode: on day 35 of hospitalization, she developed an isolated cough.

Clinical findings: a lung exam reveals normal breath sounds and her oxygen saturation was 98% on room air.

Diagnostic assessment: a routine blood test showed worsening lymphopenia, initially improved with the ganciclovir therapy, and elevated CRP and LDH. The liver enzymes were slightly increased, and her serum creatinine was still in the normal range (Table 1). On chest X-ray, we reported bilateral increased broncho vascular markings with hilar congestion. COVID-19 disease was suspected and confirmed by a positive RT-PCR COVID-19.

Diagnosis: COVID-19 and CMV co-infection in a kidney transplant recipient.

Therapeutic interventions: the patient was kept under ganciclovir and immunosuppressive therapy was unchanged (Table 1).

Follow-up and outcomes: 72 hours later cough disappeared, and biological abnormalities subsided one week later.

Patient perspective: she said: “I have the hope to be cured”.

Informed consent: she has given informed consent.

Discussion     

The COVID-19 management in kidney transplant patients is very challenging due to their chronic immunosuppression and the possibility of concurrent CMV infections. We discuss the challenges we faced managing our cases below.

Challenge 1: could the diarrhea be attributed to COVID-19?

The first patient was initially presented with a dry cough and headache with laboratory evidence of SARS-CoV-2 infection. Initially, he showed clinical improvement but on day 10 of hospitalization, he developed diarrhea with high fever and colitis signs on CT scan study. These findings could be attributed to COVID-19 but should be confirmed by SARS-CoV-2 stool analysis. Virus RNA can be detected in stool of COVID-19 patients, but unfortunately, this test was not available in Tunisia and thus not performed. The meta-analysis of Cheung et al. [4], including 4243 patients found that the prevalence of gastrointestinal manifestations was 17.6% and the most common was diarrhea. Aguila et al. [5] reported that intestinal symptoms preceded the respiratory manifestations and were more frequent in critical COVID-19 cases than in mild COVID-19. The late onset of diarrhea, the reappearance of fever after clinical improvement and the onset of leucopenia, all suggest CMV reactivation rather than COVID-19.

Challenge 2: could cough and biological abnormalities be attributed to CMV infection?

The second patient hospitalized for CMV disease treated by ganciclovir. On day 35 of hospitalization, she presented an isolated cough, worsened her lymphopenia after being initially improved with the ganciclovir therapy and showed elevated CRP, LDH and liver enzymes. Cytomegalovirus infection could induce cough and biological abnormalities but with our patient the viral load decreased under ganciclovir therapy and then she developed cough and worsened her lymphopenia which are more due to COVID-19 as it was concomitant with these clinical and laboratory abnormalities. On the other hand, ganciclovir therapy could induce these abnormalities, however they resolved rapidly without reducing or interrupting the ganciclovir dose.

Challenge 3: an association between COVID-19 and CMV co-infection has not been too much described

Little of studies described the association between SARS-CoV-2 and CMV co-infection. D'Ardes et al. [6] reported the first case of this co-infection: she was a 92-year-old woman treated with hydroxychloroquine and ritonavir/lopinavir and died 6 days after admission due to severe respiratory failure. Our first patient was initially tested positive for SARS-CoV-2, and CMV reactivation was diagnosed 10 days after admission. Recently, in this regard, Moss [3] suggested that any such association might be considered by the influence exerted by the acute inflammation due to COVID-19 and leading to enhanced CMV reactivation. Of knowledge, CMV-specific antibody titers are increased in events of inflammation, stress or intercurrent disease [7]. Relating to the second patient, CMV reactivation preceded the SARS-CoV-2 infection. She presented a relatively mild infection, made of an isolated cough which resolved rapidly. The known immunomodulatory effects of CMV would suggest that this virus, may act as an important influence on the clinical presentation of SARS-CoV-2 infection [3].

Challenge 4: could us considered ganciclovir as a potential drug for SARS-CoV-2?

Despite their immunosuppression and their comorbidities, our patients developed a mild COVID-19. Ganciclovir therapy was given for CMV infection in our two patients with subsequent clinical recovery. Despite the concomitant COVID-19 and CMV infection we should not exclude the possibility that ganciclovir could be a potential drug for SARS-CoV-2. Little of studies showed the efficacy of ganciclovir in treatment of COVID-19. Hang et al. [8] described complete recuperation in patient treated with ganciclovir. In recent times, Haiping et al. [9] by the utilization of a deep learning drug screening, had identified ganciclovir as a potential drug for SARS-CoV-2. But the efficacy of this drugs for 2019-nCoV infection need to be appraised by clinical trials.

Conclusion     

We reported successful management of CMV and COVID-19 co-infection in tow kidney transplant recipients. Further scientific research is necessary to find this relationship and its clinical significance. Specific medications to treat SARS-CoV-2 infection have not yet been revealed. Ganciclovir can be considered as a potential drug for SARS-CoV-2 infection, but its efficacy need to be appraised by clinical trials.

Competing interests     

The authors declare no competing interests.

Authors' contributions     

Meriem Ben Salem, Insaf Handous, Khwla Ajimi and Jamel Saad participated in the data collection and the study design and wrote the manuscript. Nouha Ben Mahmoud, Manel Ben Saleh, and Ahmed Letaief provided intellectual content and participated in the conception and interpretation. Mouna Hamouda, Sabra Aloui and Habib Skhiri provided intellectual content of critical importance to the work and reviewed the article. All authors read and approved the final manuscript.

Table     

Table 1: patient characteristics

References