COVID-19 Infection in Transplant Patients

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For COVID-19 frequently asked inpatient questions, click here
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Gurmandeep Singh Sandhu,M.B.B.S.[2]

Overview

Renal transplant patients are under immunosuppression to modulate the immune response to graft. Moreover these patients have various underlying chronic kidney diseases and other co-morbidities such as diabetes and hypertension, which can impact the results in COVID-19 infection. Hence these patients are at a higher risk of developing COVID-19 associated complications. The clinical manifestations, treatment, and prognosis of COVID-19 infection may be different from the general population. It is believed that any transplant recipient presented to the infection would result in a high level of cases; however, the risk of the donor to recipient transmission is unknown.

Historical Perspectives

Classification

COVID-19 infection may be classified according to WHO into four subtypes based on severity. Classification of COVID-19 infection in renal transplant patients depends on the severity of COVID-19 manifestations is following:[6]

Mild Disease Symptomatic patients meeting the case definition for COVID-19

No pneumonia

No hypoxia

Moderate Disease Adolescent or adult

Pneumonia with fever, dyspnea, cough, and fast breathing

SpO2 > or = 90%

Child

Signs of non-severe pneumonia

(cough, difficulty breathing, fast breathing or chest indrawing)

Fast breathing(breaths/min)

<2 months: > or = 60

2-11 months: > or = 50

1-5 years: > or = 40

Diagnosis can be made clinically, Chest Imaging (radiograph, CT scan, Ultrasound) may assist in diagnosis.

Severe Disease Severe Pneumonia Adolescent or adult

Signs of Pneumonia plus one of following:

Respiratory rate > 30 breaths/min

Severe Respiratory Distress

SpO2 < 90%

Child

Pneumonia plus at least one of following

Central cyanosis or SpO2 < 90%

Severe respiratory distress (fast breathing, grunting, severe chest indrawing)

General danger signs such as inability to breastfeed or drink, lethargy, or unconsciousness or convulsions

Fast breathing(breaths/min)

<2 months: > or = 60

2-11 months: > or = 50

1-5 years: > or = 40

Diagnosis can be made clinically, Chest Imaging (radiograph, CT scan, Ultrasound) may assist in diagnosis.

Critical Disease Acute Respiratory Distress Syndrome (ARDS) Onset: within 1 week of pneumonia or new worsening respiratory symptoms.

Chest imaging:

(radiograph, CT scan, or lung ultrasound): bilateral opacities,

not related to volume overload, lobar or lung collapse, or nodules

Origin of pulmonary infiltrates:

Respiratory failure not explained by

cardiac failure or fluid overload.

Oxygenation impairment in adults:

-Mild ARDS: 200 mmHg < PaO2/FiO2a ≤ 300 mmHg (with PEEP or CPAP ≥ 5 cmH2O)

-Moderate ARDS: 100 mmHg < PaO2/FiO2 ≤ 200 mmHg (with PEEP ≥ 5 cmH2O)

-Severe ARDS: PaO2/FiO2 ≤ 100 mmHg (with PEEP ≥ 5 cmH2O)

Oxygenation impairment in children: note OI and OSI.

Use OI when available. If PaO2 not available, wean FiO2 to maintain SpO2 ≤ 97% to calculate OSI or SpO2/FiO2 ratio:

• Bilevel (NIV or CPAP) ≥ 5 cmH2O via full face mask: PaO2/FiO2

≤ 300 mmHg or SpO2/FiO2 ≤ 264.

• Mild ARDS (invasively ventilated): 4 ≤ OI < 8 or 5 ≤ OSI < 7.5.

• Moderate ARDS (invasively ventilated): 8 ≤ OI < 16 or 7.5 ≤ OSI < 12.3.

• Severe ARDS (invasively ventilated): OI ≥ 16 or OSI ≥ 12.3.

Sepsis Adults:

Acute life-threatening organ dysfunction caused by a dysregulated host response to suspected or proven infection. Signs of organ dysfunction: altered mental status, difficult or fast breathing, low oxygen saturation, reduced urine output, fast heart rate, weak pulse, cold extremities or low blood pressure, skin mottling, laboratory evidence of coagulopathy, thrombocytopenia, acidosis, high lactate, or hyperbilirubinemia.

Children

Suspected or proven infection and ≥ 2 age-based systemic inflammatory response syndrome (SIRS) criteria, of which one must be abnormal temperature or white blood cell count.

Septic shock Adults:

Persistent hypotension despite volume resuscitation, requiring vasopressors to maintain MAP ≥ 65 mmHg and serum lactate level > 2 mmol/L

Children:

Any hypotension (SBP < 5th centile or > 2 SD below normal for age) or two or three of the following: altered mental status; bradycardia or tachycardia (HR < 90 bpm or > 160 bpm in infants and heart rate < 70 bpm or > 150 bpm in children); prolonged capillary refill (> 2 sec) or weak pulse; fast breathing; mottled or cool skin or petechial or purpuric rash; high lactate; reduced urine output; hyperthermia or hypothermia

Pathophysiology

The normal physiology of in renal transplant patients can be understood as follows to that in general population[7]. However, the renal transplant recipients are at remain at higher risk to catch COVID-19[8]and develop severe complications due to chronic immunosuppressed state which is implicated in various viral infections such as cytomegalovirus, herpes zoster, norovirus infections.[8][9][10]

Genetics

Associated Conditions

  • Acute Kidney Injury has been reported in patients with COVID-19 infection along with presence of proteinuria, hematuria. 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.[21]
  • Acute Kidney Injury seen in COVID-19 infection can be from the cytotropic effect (Uptake of SARS-Cov-2 virus into proximal tubule cells is possible explanation for the AKI seen in COVID patients[11][12]) of the viral particles as well as systemic inflammatory response induced by the cytokines. Patients admitted with severe disease, acute respiratory distress syndrome (ARDS) or in patients admitted to ICU have a higher incidence of AKI . [8]. Other possible reasons that can play a role in AKI development, are multi-organ failure resulting in acute tubular necrosis (ATN), volume reduction causing prerenal ATN, high fever, drug toxicity, hypotension, and contrast exposure. [22] [23]
  • Pro-inflammatory cytokine levels are elevated in the COVID-19 infection and there is activation of T-cell response. [24]
  • 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.[25] According to an autopsy report of six patients, the light microscopy indicated 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[26]

Causes

Life Threatening Causes

  • Even though the CT findings in COVID-19 pneumonia were similar in renal transplant recipients and general population, due to chronic immunosuppression, the clinical features of COVID-19 in renal transplant patients may be atypical.[27][28]
  • In one of the study, nine of the 10 patients had fever, cough, shortness of breath, and fatigue; three had diarrhea; eight had lymphopenia; six had renal injury; and six had liver function damage.[29][30][7]
  • It needs to be verified whether the severity of COVID-19 pneumonia differs in immunocompromised transplant patients than non-immunocompromised population. According to a report from China’s Infectious Disease Information system, out of 72,314 COVID-19 cases in general population, 81% were reported as mild, whereas 19% were either severe or critical. And, in report from study in renal transplant patients, the number of severe cases were 80% compared to only 10% in their infected family members and 19% in general population. Moreover, average duration of illness was nearly twice i.e. 35 days compared to 18 days in control group and 17-20 days reported in general population.[31][7]


Differentiating from other Diseases

  • As the general presentation of COVID-19 is similar in general population and renal transplant patients, it should be differentiated from other diseases presenting with cough, fever, shortness of breath, and tachypnea.
    • To review the differential diagnosis, click here

Epidemiology and Demographics

Incidence

  • Due to the lack of broad screening that includes the general population (including asymptomatic patients) and the lack of PCR and antibody tests with acceptable sensitivity and specificity, an accurate estimate of the incidence rate of coronavirus disease 2019 (COVID-19) cannot be accurately estimated.
  • Data 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.[32]. The risk is further increased in patients having chronic kidney disease(CKD), patients on chronic replacement therapies, and patients with kidney transplants.[33]
  • AKI is seen in 5-15% of the SARS-CoV and MERS-CoV infection[33]

Prevalence

[38] [39] [40] [41][42],

    • Median interval of transplantation - 4 years. (range .25-30.1)

Case-fatality rate

  • Due to limited testing of asymptomatic individuals, the potential inaccuracies of early PCR tests and antibody tests, the inconsistent reporting and lack of organized data, an accurate case-fatality rate of COVID-19 has yet to be established.
  • According to analysis of recent studies[34][35][36][37]

[38] [39] [40] [41][42], a fatality rate of 17.4% (4/23) in renal transplant patients was reported

Age

  • Renal transplant patients of all ages are at a higher risk of COVID-19 due to immunosuppression.
  • The youngest renal transplant patient who died of COVID-19 according to recent studies was 71 years old.[34][35][36]

[37] [38][40] [41][42]

  • In general population, COVID-19 associated AKI has higher incidence in elderly.

Gender

  • Male are more commonly affected by COVID-19 than female.[43]
  • Female dying from COVID-19 are generally elder than men(median age: 82 vs. 79 years for women vs. men, respectively).[43]

Race

  • According to study done in New York, 14 recipients affected by COVID-19, (39%) were black, and 15 recipients (42%) were Hispanic.[44]

Risk Factors

Common risk factors in the development of transplant patients to COVID-19 are:

Screening

According to one of the COVID-19 Rapid Guidelines for renal transplant patients:[47]

 
 
 
 
 
 
 
 
 
Patient presents with Sore throat,Dry cough or Fever
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dypsnea, RR>30/min, SpO2<93%
 
If Present Then refer for admission
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Creatinine is raised but no Lymphopenia or No Abnormality on CT chest
 
 
 
If not, check Creatinine, C-RP, CXR & CT chest
 
 
 
Lymphopenia but Creatinine normal and Ct chest normal
 
Admit in usual ward and evaluate Lymphopenia
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Evaluate the Causes of rise in creatinine
 
 
 
Is Xray positive for COVID-19?
 
 
If No, then Do CT Chest
 
If CT Chest is negative then refer a patient for Home Care, Medical Treatment, Diagnostic Test, and Daily Follow-ups
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
If Chest Xray or CT chest is indicative of COVID-19 infection: Admit the patient
 
 
 
 
 
 
 
 
 

Screening for AKI

Serial monitoring of kidney function tests should be considered in renal transplant patients[48]

Gut Ischemia, coagulopathies, and disseminated intravascular coagulopation have been seen later in the course of illness[45]

Natural History, Complications and Prognosis

The majority of renal transplant recipients with COVID-19 present with same course of infection as in general population[49]. The clinical features in renal transplant recipients may be atypical due to chronic state of suppressed immune system and other chronic co-morbidities in transplant patients[8][50][5]. Early clinical features include cough, fever, fatigue, diarrhea, sore throat, and shortness of breath. If left untreated, COVID-19 in transplant recipients may progress to develop dypsnea, hypoxemia, oliguria, confusion, fluid retention and pro coagulative state[49]. Common complications of COVID-19 in renal patients may include Pneumonia, Acute Respiratory Distress Syndrome, Acute Kidney Injury and Disseminated Intravascular Coagulation[31][49][45]. Prognosis is generally worse than the prognosis in general population due to underlying immunosuppression and chronic co morbidities (eg. Hypertension, Diabetes, Chronic renal Failure etc, and the mortality rate in renal transplant patients with COVID-19 has been reported to be higher than the general population[5][50][8].

Diagnosis

Diagnosis of Choice

  • Renal transplant patients present with similar CT an Chest X-Ray finding which are seen in the general population, although the features of COVID-19 infection may be atypical in such patients.
  • Renal Transplant patients who develop AKI can be diagnosed using KDIGO criteria:
    • Increase in S. Creatinine: ≥0.3 mg/dl (≥26.5 μmol/l) within 48 hours
    • Increase in S. Creatinine: ≥1.5 times baseline within the previous 7 days
    • Urine volume < 0.5 ml/kg/h for >6 hours

Symptoms

Presenting symptoms in renal transplant patients are similar to those of non-renal transplant patients. Further symptomology depends on the clinical complications that develop due to COVID-19.

Further classification of patients into the severity index can be done using the WHO guidelines.[6]

Physical Examinationin

Physical examination of COVID-19 in renal transplant patients are similar to ones seen in general population.: COVID Physical Exam


If the patient develops Acute Kidney physical examination is remarkable for[51]:


Past Medical History

Laboratory Findings


If the renal transplant patients reports AKI then following laboratory findings can be done[53]:

Electrocardiogram

X Ray

  • X-ray findings in the renal transplant patients were similar to the findings seen in the general population.
  • To view the x-ray finidings on COVID-19, click here.

Echocardiography or Ultrasound

CT

  • CT scan finding in renal transplant patients infected with COVID-19 were similar to those in the general population.
  • To view the CT scan findings on COVID-19, click here.

MRI

Other Imaging Findings

  • To view other imaging findings on COVID-19, click here.

Other Diagnostic Studies

  • To view other diagnostic studies for COVID-19, click here.

Treatment

Medical Therapy

Acute Pharmacotherapy

Currently, there are a variable number of protocols that have been described for the management of COVID-19 in renal transplant patients:-

According to the British Transplantation Society Guideline[41]:-


 
 
 
 
 
 
 
Follow local guidelines for use of PPE
• Do the general assessment of the patient and swab for SARS-Cov-2
• Exclude other causes like CMV, pneumocystis, community or hospital acquired pneumonia, influenza, urinary sepsis, lymphoma and fluid overload)
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
If the patient doesn't require hospitalization

• Stop antiproliferative agents (MMF/azathioprine)
• Review total burden of immunosuppression and consider reduction of CNI
• High or increased dose steroid is NOT recommended at this stage
• Patients should self isolate in line with national guidance
• Closely monitor patients remotely for change in symptoms
• Consider restarting immunosuppression 14 days after onset of symptoms if symptom free in absence of anti-pyretics for minimum of 3 days

• Consider early monitoring of graft function when safe to do so and risk of transmissionto others is low
 
 
 
 
 
 
 
 
If the patient is deteriorates or requires ventilatory support

• Stop antiproliferative agents (MMF/azathioprine)
• Dramatically reduce or stop CNI
• Consider high dose steroids in discussion with ITU team
• Ventilatory support in line with local or national guidance

• Adjunctive support or antivirals in line with local practice or clinical trials
 
 
 
 
 
 
 
 
 
If the patient is unwell and requires admission

• Stop antiproliferative agents (MMF/azathioprine)
• Consider reducing or stopping CNI
• Consider increasing steroids if currently taking them.
• There is no evidence for benefit of high dose steroids at this stage
• Oxygen therapy to achieve saturations over 94% (unless COPD)
• Regular observations, especially saturations, to monitor for rapid deterioration
• Conservative fluid administration
• Consider adjunctive antibiotics if superadded bacterial infection is suspected

• Early discussion of ceilings of care
 
 
 
 
 
 

According to a protocol described in Iranian Medical Journal[47]

 
 
 
Admitted Patients
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
O2 Saturation <93%
 
 
 
O2 saturation >93%
 
 
S. Creatinine is raised,Then Consider Kidney Biospy
 
 
If there are signs of kidney rejection
• Stop Anti Metabolite Drug
Prednisolone: 20 mg/d
Cyclosporine Trough Level: 75-150ng/ml
Tacrolimus Trough Level: 4 to 6 ng/mL
IVIG: 1-2 g/kg Divided Doses in 5 Days
Anti Viral Therapy According to Protocol
Azithromycin: 500 mg Stat and 250 mg
• Daily for 4 Days
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• Stop Anti Metabolite Drug
• Stop CNI
• IV Methyl Prednisolone: 40mg/d
IVIG: 1-2 g/kg Divided Doses in 5 Days
Anti Viral Therapy According to Protocol
Azithromycin: 500 mg Stat and 250 mg
• Daily for 4 Days
 
 
 
• If S.Creatinine is Normal
• Stop Anti Metabolite Drug
Prednisolone: 20 mg/d
Cyclosporine Trough Level: 75-150ng/ml
Tacrolimus Trough Level: 4 to 6 ng/mL
Anti Viral Therapy According to Protocol
Azithromycin: 500 mg Stat and 250 mg
• Daily for 4 Days
 
 
If No Sign of rejection then same protocol as for Normal Serum Creatinine and O2 sat. >93%
 
 

For general COVID-19 Medical Therapy click here

Chronic Pharmacotherapy

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. [57]

  • Clinical presentation of COVID-19 infection in renal transplant patients are like the clinical presentations of infection in general population. [57].Moreover, renal transplant patients are generally immunocompromised, and this predisposes them to severe infection with COVID-19. Rejection of the graft can occur if immunosuppression is reduced in these patients. Hence given the high rate of mortality in COVID-19 infections, it is suggested that a careful risk vs benefits assessment of whether to continue immunosuppression should be done.[58]
  • Managing the immunosuppression in renal transplant patients is difficult and should be based on[58]
    • 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.[58]

Commonly followed protocols for the used immuno-suppressant drugs is as follows:-

  • Antiproliferative agents such as MMF and azathioprine [59]
    • Should be stopped at the time of admission to hospital
  • Prednisolone[59]
    • The dosage can be either increased or left unchanged. These can provide immunological protection to the renal graft.
    • Corticosteroids have beneficial effects such as
  • Tacrolimus[59]
    • Low doses of tacrolimus can be given but more evidence is required.[59]

Surgery and Device Based Therapy

Currently there are no suurgical intervention required for COVID-19 infection in renal transplant patients.

Transplantation

  • The risk of the donor to recipient transmission is unknown.
  • The chances of a donor to recipient infection might be affected by exposure of the donor, the infectivity of the donor during the incubation period, and the degree of viremia as well as the viability of virus in the specific organ system. An avid knowledge of local epidemiology is required to identify donors and recipients who may recently be exposed. One method is to have both donor and recipient practice strict social distancing i.e. 2-week home segregation prior to transplant and PCR testing for both individuals, before transplant[64]. The reason for swabbing at the end of the segregation period is to screen asymptomatic shedders.[65]


  • In spite of the conceivable negative outcomes, temporary interruption of kidney transplantation might be needed in regions where the rate of infection is high.. [28]
  • If a life-saving procedure needs to be performed, then appropriate assessment of infection in donor and recipient must be done along with appropriate informed consent.[66]
  • If a transplant candidate is found to be infected with COVID-19, the transplant should be delayed until the patient shows clinical improvement as well as no viral detection. Viral shedding for an increased duration of time has been reported[8][67].
    • Patients should be tested 10-14 days after symptom onset and only once all the symptoms have resolved.
    • Patients should have 2 negative PCRs at least 24hrs apart[68]

Primary Prevention

  • The kidney transplant population must comply with the recommended measures of protection in the general population. Physicians can recommend the use of a mask on an individual basis, especially when the patient goes to 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..[69]
  • It is prudent to approve a sick leave in patients whose profession involves a high hazard for disease.[69]
  • 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 [69]
  • 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.[69]
  • Regular cleaning of home with disinfection of objects and surfaces.[69]
  • 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.[69]
  • 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.[69]
  • 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.[69]

Secondary Prevention

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..[69]

Cost Effectiveness of Therapy

Currently various investigational and experimental pharmacological therapies are being tested for COVID-19 treatment. The cost of treatment generally depends on the multitude of COVID-19 complications that an individual develops.

Future or Investigational Therapies

Various pharmacological therapies are currently under investigation as potentials to treat COVID-19

For detailed information click here

References

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  4. Chiu, Man-Chun (2003). "Suggested management of immunocompromized kidney patients suffering from SARS". Pediatric Nephrology. 18 (12): 1204–1205. doi:10.1007/s00467-003-1325-8. ISSN 0931-041X.
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  6. 6.0 6.1 "Clinical management of COVID-19".
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