Sandbox: GDS

COVID-19 Infection in Transplant Patients

• Risk of COVID-19 in renal transplant patients is higher because of immunosuppression, underlying chronic kidney disease, and other co morbidities such as diabetes and hypertension, which are presently perceived as noteworthy components impacting the results in patients with COVID-19.
• It is realized that any transplant recipient presented to the infection would result in a high level of cases; however the risk of donor to recipient transmission is unknown. The chances of a donor to recipient infection might be affected by exposure of the donor, infectivity of the the donor during the incubation period and the degree of viremia as well as the viability of virus in specific organ system.In this manner, in spite of the conceivable negative outcomes, temporary interruption of kidney transplantation might be fundamental in regions where the rate of infection is high.

Epidemiology and Demographics

Epidemiological date indicates that the rate of severe complications of COVID-19 is almost 25%, and kidney is also one of the main organs affected in severe illness.

• AKI is seen in 5-15% of the SARS-CoV and MERS-CoV infection, and the mortality rate is reported to be higher than in general population at 60-90% as per the literature.
• .The risk is further increased in patients having chronic kidney disease(CKD), patients on chronic replacement therapies, and patients with kidney transplants.

Pathophysiology

• Acute Kidney Injury has been reported in patients with COVID-19 infection and presence of proteinuria, hematuria has also been reported. In a case observation, 4 out of 7 patients had AKI which may indicate that renal transplant patients are at higher risk AKI on being infected with COVID-19 whereas only 29% AKI was seen in critically ill patients of general population.
• AKI in COVID-19 infection could be from the combined effect of virus-induced cytotropic effect and cytokine induced systemic inflammatory response. The incidence of AKI is increased in patients with severe disease, acute respiratory distress syndrome (ARDS), and those admitted to ICU. Other possible causes can be from acute tubular necrosis (ATN) due to multiorgan failure and shock, volume depletion causing prerenal ATN and high fever. Drug toxicity, hemodynamic insult, and contrast exposure can also play a role.

• Uptake of SARS-Cov-2 virus into proximal tubule cells is possible explanation for the AKI seen in COVID patients. Angiotensin-converting enzyme 2 and Dipeptidyl peptidase have been implicated in the uptake of SARS-Cov and MERS-CoV. These receptors are found in the proximal tubules of kidney....ACE2: ACE ratio is higher in the kidneys compared to the respiratory system. (1:1 in the kidneys VS 1:20 in the respiratory system)).SARS-CoV2 spike(S) protein is cleaved and activated by transmembrane serine protease family (TMPRSS) after attaching to angiotensin-converting enzyme 2 (ACE2) receptors. This allows the virus to release fusion peptide that aides in membrane fusion.
• Pro-inflammatory cytokine levels are elevated in the COVID-19 infection and there is activation of T-call response. There is higher cytokine levels and there is occurrence of cytokine storm in severe cases. In cytokine storm the, the immune system damages the healthy tissue rather than virus. According to an autopsy report of six patients, the light microscopy revealed cluster of differentiation 68 (CD68)+ macrophage infiltration of the tubulointerstitium and severe ATN. The tubules showed complement 5b-9 deposition in all six cases, but deposition in glomeruli and capillaries were seldom seen. Some CD8+ T lymphocyte cells and CD56+ (natural killer) cells were seen in kidney tissue

Lab Findings

Presenting symptoms in renal transplant patients are similar to those of non-renal transplant patients.

• Respiratory symptons
  • Cough
  • Chest Pain
  • Dysnea
• Fever
• Hypoxia
• Lymphopenia
• High C-Reactive Protein

Valuable prognostic blood tests that can be done are

• Lymphocyte count
  • Renal transplant patients generally have a low lymphocyte count due to immunosuppression, hence finding a further drop in the lymphocyte count can be of prognostic value.
• D-dimer
• Ferritin
• Troponin
  • Microvascular thrombosis and disseminated intravascular coagulation( with gut ischemia) can occur later in the course of illness. They are characterized by marked increase in the levels of D-dimer particularly. D dimer, ferritin, and troponin should be measured in all patients with severe COVID-19 infection on admission and in those who fail to show any clinical improvement.

Immuno-suppression Status in Transplant patients

In renal transplant patients, the immune responses are altered, especially the T cell response, due to generalized immunosuppression. Due to recent timeframe of outbreak of COVID-19 and insufficient scientific evidence, there is limited evidence on decreasing or changing the pattern of immunosuppression in renal transplant patients who have been infected with COVID-19.

• In general, the renal transplant patients presenting with COVID 19 have clinical manifestations similar to the population not having a renal transplant. Reduction in immunosuppression can lead to rejection of graft in patients. However due to high mortality rate of COVID-19 infection in hospitalized patients, it has been suggested that case to case assessment of risks vs benefits of continuing immunosuppression should be done.

• Managing the immunosuppression in renal transplant patients is difficult and should be based on

• • Age
  • Severity of COVID-19 infection
  • Presence of Co-Morbidities
  • Time since the transplant
• In patients with mild to moderate infection, it has been a practice to continue or decrease the doses of immunosuppressive drugs, however this approach can cause high mortality in patients having COVID-19 infection.
• Antiproliferative agents such as MMF and azathioprine

• • Should be stopped at the time of admission to hospital
• Prednisolone

• • The dosage can be either increased or left unchanged. These can provide immunological protection to the renal graft.
  • Corticosteroids have beneficial effects such as
    • Immunomodulation and anti-inflammatory properties
      • Inhibition of proinflammatory cytokines
      • Reduction of white blood cell traffic
    • Vascular protective effects
      • Maintenance of integrity and permeability of endothelium.
• Tacrolimus

• • Dose should be reduced. Low doses of tacrolimus can be given but more evidence is required.
• Tocilizumab.

• • COVID-19 infection has been found to cause cytokine storm and inflammation due to antiviral immune response, hence trails of anti-interleukin 6 monoclonal antibody Tocilizumab and continuing steroids in infected patients has been considered

Treatment

Currently no vaccine has been developed against the SARS-CoV 2 virus. The mainstay of treatment currently is the supportive care.

• With regard to specific antiviral therapies, although a recent trial showed no benefit of lopinavir-ritonavir in hospitalized patients with severe COVID-19, it remains possible that treatment with these drugs as well as hydroxychloroquine will be considered in patients with COVID-19 pneumonia. Remdesiver inhibits the viral replication by pre mature termination of RNA transcription, and have shown activity in vitro against the viral agent.Food and Drug Administration (FDA) in the USA has authorized its use in patients hospitalized with COVID-19.It is not recommended in patients with lower GFR (GFR < 30 mL/min)

• The choice of calcineurin inhibitor may also be beneficial. For example, cyclosporin A has been shown to have an inhibitory effect on proliferation of corona viruses and hepatitis C virus in vitro, not seen in tacrolimus. Cyclosporin A is thought to inhibit the replication of a diverse array of coronaviruses through its impact on cyclophilin A and B.

General Considerations for Renal transplant Patients

• Maintenance of general hygiene. Washing your hands as often as possible with cleanser and water, or with a alcohol based hand sanitizer (60% alc), particularly: after utilizing the restroom, before eating, in the wake of blowing, coughing or sneezing and after direct contact with patient or their surroundings. Abstain from touching your eyes, nose and mouth before washing your hands.
• Regular cleaning of home with disinfection of objects and surfaces.
• Keep a distance of at least two metres from people with general symptoms such as fever, cough, malaise, sore throat or dyspnea). Abstain from sharing personal belongings.
• During the lockdown circumstance you should stay at home aside from the specified exemptions, as indicated by the standards built up by the political and wellbeing specialists. Telephone the kidney transplant facility at your referral community or the telephone numbers approved by the wellbeing specialists.
• Attempt to follow a right eating routine. Abstain from smoking and liquor. These substances weaken the immune system, and increase the risk of infectious diseases.
• Abstain from sharing food, utensils (cutlery, glasses, napkins, tissues etc) and different articles without cleaning them appropriately.
• The Centers for Disease Control and Prevention and (CDC): does not recommend to the general population that people who are well to wear a face mask to protect himself from respiratory diseases, including COVID-19. Today, the kidney transplant population must comply with the recommended measures of protection in the general population, especially if they are asymptomatic at home. However, the responsible physicians will recommend the use of a mask on an individual basis, mainly in cases where the patient goes to a health center or other place with agglomeration. People who show symptoms of being infected with SARS-CoV-2 should wear masks to prevent the spread of the disease to others.
• It is prudent to approve a sick leave in patients whose profession involves a high hazard for disease.
• It is recommended to screen kidney transplant patients through teleconsultation so as to decrease the time spent in healthcare centers and decrease the risk of infection

Specific recommendations for kidney transplant patients suspected of SARS-CoV-2 infection

All kidney transplant patients with suspected symptoms of COVID-19 are advised to contact their healthcare provider (ideally by phone), to discuss the full course of their treatment and other chronic conditions that they are having. Depending upon the symptoms :-

• Mild symptoms ie
  • without Dyspnea or Tachypnea
  • Temperature <38°C
  • Kidney receptor with adequate functional reserves
    • The patient can be asked to remain in contact via teleconsultation to have the diagnostic tests performed, monitor the symptoms and communicate alarming to the transplant team every 24–48h.
• Moderate/Severe symptoms
  • Temperature >38°C
  • Presence of Dyspnea
  • Presence of Tachypnea
  • Fragile Kidney receptor
    • Patient can be asked to report to Emergency Department for clinical evaluation.