Transplant patients face many health challenges and require careful monitoring for drug side effects and possible infections due to the immunosuppressive drugs they need to prevent organ rejection17. Our systematic review and meta-analysis provided evidence for the clinical outcomes, laboratory values, diagnostic imaging, and various treatment modalities used amongst transplant patients diagnosed with COVID-19.
Regarding the clinical outcomes, our findings revealed that fever (74.4%) and cough (61.1%) are the most frequently encountered symptoms. A meta-analysis done by Li et al. focused on the general populace in 1995 COVID-19 cases. The most common symptoms encountered in this meta-analysis were fever (88.5%) and cough (68.6%), which matches the same clinical profile of our meta-analysis69. The values may have slight variation due to the number of studies included in each meta-analysis; however, both studies can attest to fever and cough being the most encountered symptoms. Additionally, we found that diarrhea and dyspnea occur frequently with an event rate of 31.2% and 46.6%, respectively. The meta-analysis done by Li et. al. showed diarrhea to be a minor symptoms with an event rate of 4.8% and dyspnea to be considered a main clinical symptom with an event rate of 21.9%69. Although diarrhea could be a side effect of COVID-19, the high event rate of diarrhea from our meta-analysis could be due to the side effects of medications and polypharmacy instead of COVID-19, since post-transplant patients, compared to the general populace, commonly experience diarrhea as a symptom70. Expectoration (sputum production) occurs rarely with an event rate of 2.3% in our meta-analysis. Compared to the general population with an expectoration event rate of 28.2%, our findings were reduced69. We did not expect expectoration to be an infrequent symptom, as it seems to be common in the general populace71.
The connection between the kidney and the lung is well established. Since most of our study involves kidney transplant patients with a single working kidney, dysfunction in that single kidney may cause these patients to be more susceptible to acidosis during an infection, leading to hyperventilation and dyspnoea as respiratory compensation 71,72. In our meta-analysis, intubation event rate was found to be 33.7%. A systematic review and meta-analysis showed the crude prevalence of invasive mechanical ventilation in the COVID-19 general populace to be 6.79%. When compared to our population, intubation rate is significantly higher at a 26.9% difference, which supports our findings of greater respiratory distress in transplant patients73. Another consideration should be the similarity of symptoms between COVID-19 and influenza within vulnerable populations. Both viruses have been shown to present with similar symptoms like fever, diarrhoea, myalgia, malaise, and dyspnoea. The initial outbreak of COVID-19 occurred during a period where there were high rates of respiratory viruses such as respiratory syncytial virus, influenza, and many others. Vaccines such as the influenza vaccine are useful in reducing the confusion between symptoms caused by COVID-19 and other similar respiratory viruses74. Obtaining knowledge of the vaccination history as well as prior infection history of our patients in our study may help better explain some of our findings25. Obtaining prior knowledge is particularly important since the aforementioned respiratory viruses, in addition to the respiratory syncytial virus, parainfluenza virus, and rhinovirus, are becoming more recognized as major causes of respiratory illnesses in patients after receiving a single organ transplant26.
Additionally, comorbid conditions like diabetes and heart failure in transplant patients are common and may further complicate the COVID-19 infection. For instance, in a study that assessed comorbid conditions in kidney transplant patients, diabetes was found in 30.3% of patients and heart failure was found in 11.9% 74. Another study that explored comorbid conditions in lung transplant patients showed that, out of 223 people, 19.7% had diabetes and 9% had heart failure. These conditions seem to be common in transplant patients, compared to the 9.7% who had diabetes and 8.4% who had cardiovascular disease as seen in a systematic review and meta-analysis reviewing commodities in the general COVID-19 infected population; therefore, increased prevalence of certain comorbidities could also affect the clinical outcome of transplant patients25,29.
Regarding the laboratory values found within our meta-analysis, abnormalities were typical for all patients hospitalized with COVID-19 and not just transplant patients. Liver injury secondary to COVID-19, like prolonged prothrombin time, elevated aminotransferases, and hypoproteinemia, have been reported by numerous studies and are thought to be due to direct liver damage from the virus itself, drug hepatotoxicity, and immune-mediated inflammation26. COVID-19 is associated with immunosuppression, causing a depression in CD4+ and CD8+ lymphocytes and leading to lymphopenia. Elevated ESR, CRP, and D-Dimer reflect an inflammatory state typical of a COVID-19 infection, with an increase of LDH reflecting systematic damage in the body 23. There is a parallel response in the inflammatory mediators in COVID-19 and the disease severity. The laboratory findings in our meta-analysis show that 59.3% of our patients had elevated IL-6 markers. IL-6 is an interleukin that stimulates acute phase responses, immune reactions, and haematopoiesis as a response to tissue injury and infections. An increasing rise in this marker may be an indication of the severity of COVID-1923. According to the case report done by Hammami et al., the timing of the administration of particular immunosuppressive therapy may help reverse the progression from mild to severe inflammatory response associated with COVID-1923.
In reference to the diagnostic imaging reported by our meta-analysis, our study showed that consolidation had an event rate of 58.4% and was the 2nd most frequent characteristic. When compared to a systematic review of different imaging features in 919 COVID-19 patients, only 10 studies reported consolidation; thus, demonstrating the lease percentage of cases at 31.8 75. Other than this discrepancy, our findings generally agree that COVID-19 images for transplant patients are often bilateral with consolidation and ground glass opacity, with pleural effusion being the least prevalent feature 24. The severity of COVID-19 is believed to primarily be influenced by the inflammatory response that was discussed previously. Patients who present with COVID-19 pneumonia with progression to acute respiratory distress syndrome therefore have a higher inflammation-related index. The consolidation and characteristic pleural effusion represent the pulmonary inflammatory response caused by the elevated IL-6 in the blood23.
We found that 11% of the total patients in our study experienced transplant rejection. Rejection varied from minimal cellular rejection to acute organ rejection and deterioration in donor organ function. According to the data available, there is no exact relationship between change in the regimen of treatment and rejection, although it was reported that respiratory viral infection may lead to rejection 28. Acute organ rejection was witnessed in four patients; however, the rejections occurred before COVID-19 infection, which suggests that acute rejection secondary to COVID-19 is likely a minimal feature26.
We found the death rate of COVID-19 transplant patients to be 18.2%. In a meta-analysis and systematic review done by Jutzeler et. al which measured COVID-19 in the general population, the death rate was 7.97%73. The death rate found in the transplant patients within our meta-analysis is almost double this value. This does not come as a surprise when analysing potential causes of death in solid organ transplant patients infected with COVID-19 within similar studies. Our findings agree with the 2007 study done by Fishman et.al. which found that transplant patients using immunosuppressants are susceptible to serious infection and other complications3. However, our meta-analysis shows that most patients were not put on anti-coagulation, which had an event ratio of 44.9%. Our analysis did not include causes of death; however, we can surmise from the anti-coagulation event rate that lack of anticoagulation could have elevated the fatality rate due to complications arising from venous thromboembolism for all types of COVID-19 infected transplant patients. According to Ahmed et al., targeting COVID-19 without reducing the risk for thrombosis is rudimentary, since the formation of microthrombi is common in these patients. These microthrombi have been shown to form in the lung vasculature and alter lung perfusion, thus leading to hypoxemia that can ultimately lead to death76,77.
Finally, in reference to various treatment methods presented in our meta-analysis, the most common treatment found in organ transplant patients diagnosed with COVID-19 are immunosuppressants23,24,27. Jutzeler et al. corticosteroids are commonly administered to hospitalized patients with severe disease despite the controversy of their benefit 73. From the studies included, hydroxychloroquine was the second most frequently administered drug, followed by antibiotics and antivirals 78. According to In our meta-analysis, we observed high percentages of withdrawal or decrease in dosage of such immunosuppressant drugs, with kidney transplant patients having the highest event rates of withdrawal at 63% and liver transplant patients with the highest event rates of dosage decrease at 75.0%. It is possible that patients began experiencing side-effects of immunosuppressive therapy or acquired comorbidities such as hypertension, kidney failure, chronic myelosuppression, or others, which may explain the high event rates 27. Another possible explanation is that patients began to improve to a point that did not warrant the dosages of immunosuppressant drugs that were initially prescribed.
Our meta-analysis did not analyse the clinical complications in each study, such as myocarditis, arrhythmias, heart attacks, strokes, or bacterial co-infection. The number of lung transplant, heart transplant, and liver transplant patients infected by COVID-19 is limited in this study, as most patients in this study are kidney transplant patients. Therefore, the results from the meta-analysis must be taken carefully for non-kidney transplant patients. This study did not meta-analyse the difference between transplant and non-transplant patients. Most of the included studies are case reports/series with short follow up. This increases the need for a randomized control trial comparing the outcomes between the two populations.