Discussion
Severe Acute Respiratory Disease 2 (SARS-CoV-2) is a highly infectious, novel coronavirus that emerged in Wuhan, China in December of 2019 [4,5]. As of May 14, 2020, the World Health Organization has reported 4,248,386 cases of COVID-19 with 294,046 reported deaths secondary to complications related to the novel Coronavirus [1]. While this lethal disease has not spared immunocompetent patients, populations who have the highest mortality risk require special attention. At this time, there are limited case reports on solid organ transplant (SOT) patients [6]. There is insufficient data on the clinical presentation and management of immunosuppressant regimens in SOT recipients [4]. These patients may differ from the immunocompetent population in regards to presentation, diagnosis, and clinical course of Covid-19 [4]. Notably, transplant patients may present with mild or atypical symptoms and without fever. Thus, physicians must maintain broad differential diagnoses and high clinical suspicions [7]. One case series of five patients reported the most common symptoms on admission were fever, cough, myalgia/fatigue, and sputum production [5]. Other case reports have identified patients as having vague abdominal discomfort [4]. Table 2 outlines the reported cases on COVID-19 in SOT recipients. We did not find any reports of patients with double solid organ transplants reported in the literature.
Table 2 Reported cases of COVID 19 in transplant patients. MMF = Mycophenolate Mofetil. WBC = White blood cell count. CRP = C-reactive protein. LDH = lactate dehydrogenase.
Age/ Sex Solid Organ Transplant ChronicImmunomodulator Medications given during admission while receivingCOVID treatment IL-6 levels WBC(4.5–11 × 109/L) Lymphocytes (30–45 %) CRP(<0.8 mg/dL; <76.2 nmol/L) LDH(80–225 units/L) Outcome Total Days of Illness Citation
37M Liver Tacrolimus Oseltamivir, phosphate capsules, cefoperazonesulbactam sodium, methylprednisoloneTacrolimus discontinued Not Reported 2.46 48% Not reported Not Reported Acute transplant rejection, but recovered after tacrolimus was resumedFull recovery 15 days [4]
48M Kidney, 2003 Tacrolimus MMF Oseltamivir, abidol moxifloxacin, recombinant human interferon alpha, methylprednisolone, human IVIG TacrolimusMMF discontinued Not Reported 2.49 64% 31.25 Not Reported Bone marrow suppression due to MMFFull recovery 42 days [4]
38M Kidney, 2019 Glucocorticoid MMF Tacrolimus Oseltamivir, arbidol Glucocorticoids TacrolimusMMF discontinued Not Reported 4.73 63% 0.37 193 Full recovery 26 days [5]
64M Kidney, 2016 Glucocorticoid MMF rapamycin Oseltamivir or arbidol cefepime and IVIG Glucocorticoids TacrolimusMMF discontinued Not Reported 17.67 55% 1.26 180 Remained hospitalized Not Reported [5]
37F Kidney, 2019 Glucocorticoid MMF Tacrolimus Oseltamivir or arbidol cefepimeIVIG GlucocorticoidsMMF discontinuedTacrolimus discontinued, then restarted at half the dose Not Reported 5.67 31% 2.03 160 Remained hospitalized 22 days [5]
47M Kidney, 2019 Glucocorticoid MMF Tacrolimus Oseltamivir or arbidol GlucocorticoidsMMF discontinuedTacrolimus stopped and restarted Not Reported 3.99 51% 0.45 235 Remained hospitalized Not Reported [5]
38M Kidney, 2017 Glucocorticoid MMF Tacrolimus Oseltamivir or arbidol Glucocorticoids MMF Tacrolimus Not Reported 6.44 91% 0.39 248 Full recovery 23 days [5]
50 M Liver Tacrolimus Methylprednisolone. Umifenovir, Lopinavir/ritonavir,IVIG,Cefoperazone, alpha interferonTacrolimus discontinued for 4 weeks due to lymphopenia Not Reported 5.9 72% 32.1 Not Reported Full recovery 28 days [6]
49M Kidney Cyclosporine MMF Prednisone Lopinavir, ritonavir, ribavirin, interferon alpha-2b, methylprednisolone, MMF, prednisoneCyclosporine discontinued Not Reported 7.18 59% 22.73 Not Reported Full recovery 14 days [19]
50M Kidney, 1992, 2016 MMF Tacrolimus MMF, Tacrolimus,ceftriaxone 26.22 3.2 60% Not Reported Not Reported Full recovery 13 days [17]
58M Kidney, 2017 Belatacept MMF Prednisone BelataceptCyclosporinePrednisoneMMF discontinued during treatment 29 5.04 16% 14 Not Reported Full recovery 18 days [20]
36F Kidney, 1993, 1995 Tacrolimus Prednisone Hydroxychloroquine, opinavir/ritonavir, ceftriaxone, tacrolimus, methlyprednisolone Within normal limits(reported elevated IL-8) High neutrophil normal 67 Not Reported Full recovery 9 days [21]
58M Kidney MMF Prednisone MethylprednisoloneMMF discontinued during treatment Not Reported Not Reported Not Reported Not Reported Not Reported Mechanical ventilation; death due to multi-organ failure on Day 40 40 days [22]
52 M Kidney Tacrolimus MMF Prednisone Imifovir, Moxifloxacin Methylprednisolone, Biapenem, interferon alphaAll immunosuppressive agents discontinued during treatment Day 2: 19.53 Day 2: 5.54; Day 11 11.68 Day 2: 17.9 % Day 11: 12 % Day 2: 54; Day 11: 1.4 Not Reported Full recovery 18 days [23]
Recent proposals regarding the pathophysiology of COVID-19 suggest a hyper-inflammatory state resulting in COVID-19 related acute respiratory distress syndrome (ARDS) [3]. Once infected, there is loss of primary antiviral defense because of virus-induced interferon suppression with lymphopenia [8]. Subsequently, the body activates a second defense mechanism, known as the “second wave,” which results in a cytokine storm and severe tissue damage [3]. Increases in many inflammatory markers, such as erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), serum ferritin, interleukins 6, 8, and 10, procalcitonin, and interleukin-receptor have been found in COVID-19 patients [9]. Interleukin-6 (IL-6) is a marker of recent interest because of its role in the “second wave” and resulting cytokine storm. [10]
IL-6 signal transduction occurs via three main pathways: classical signal transduction, trans signal transduction, and trans presentation [11]. The classical signal transduction involves IL-6 binding to the IL-6R and forming a complex; the IL6-IL6R complex then binds to membrane gp130 and subsequently initiates intracellular transduction [11]. The trans signal transduction pathway occurs with IL-6 binding to sIL-6R and forming a complex; the IL6-sIL6R complex then binds to membrane gp130, which then initiates intracellular signal transduction [11]. The trans presentation signal involves sgp130 forming a complex with sIL-6R to prevent sIL-6R from binding to membrane-bound gp130; the JAK-STATA, RAS-RAF, and ATK-PI3K pathways are then activated [11].
Chen et al. found in a sample of 48 patients that increased levels of IL-6 significantly correlated to disease severity [12]. Another study reported a significant association between lymphopenia and increased IL-6 levels in COVID-19 non-survivors compared with survivors. [12,13] These findings suggest monitoring IL-6 levels to evaluate cytokine storm as a prognostic tool [12]. However, it is likely that physicians do not routinely follow IL-6 levels in COVID-19 patients with solid organ transplants, as it was not a commonly reported lab value in the studies we evaluated (Table 2).
Treatment with tocilizumab, a monoclonal antibody that binds to the IL-6 Receptor, has been recently published [11]. By binding to the IL-6R, tocilizumab can inhibit both the classical and trans signaling pathways leading to a reduction in the “second wave” response and preventing cytokine storm [11].
The standard treatment dosing according to the Diagnosis and Treatment Protocol for COVID-19 (7th Edition) is a first dose of 4−8 mg/kg/day, with 400 mg diluted to 100 mL with 0.9 % normal saline, infused over a 1 h period [14]. The maximal dose is 800 mg, and the maximal number of administrations is two [14]. This dosing is based on a small trial of 21 patients that received tocilizumab, in addition to the standard care recommended by the Diagnosis and Treatment Protocol for Covid-19 (6th Edition) including lopinavir, methylprednisolone, other symptom relievers, and oxygen therapy [15]. Given the small sample size, we need more research on appropriate dosing. At this time, there is a multicenter randomized controlled trial currently ongoing in China [16]. Another potential medication that decreases IL-6 levels is metronidazole [13]. In vitro and in vivo studies have shown that metronidazole decreases serum IL-6 levels [13].
Close monitoring of immunosuppressive therapy in SOT recipients infected with COVID-19 is necessary. There is a balance of allowing adequate immune response to suppress viral load and preventing transplant rejection. Previous case reports have hypothesized that immunosuppressive therapy protects SOT recipients by dampening the cytokine storm [17]. Other case reports have noted that viral RNA levels remain positive for a longer period than in immunocompetent patients [4]. This is notable because previous studies have demonstrated that ARDS occurs in SARS patients despite a decreased viral load [18]. This is important because it indicates antiviral therapy alone is inadequate treatment and supports the hypothesis that the ARDS results from the cytokine storm [18]. One case report of a liver transplant recipient that tested positive for COVID-19 suffered from acute transplant rejection despite maintaining adequate immunosuppression based on lymphocyte subtests. 4 This suggests that early IL-6 intervention to prevent the cytokine storm could improve outcomes in COVID-19 positive, SOT recipients.
One of the main concerns with IL-6 blockade in the treatment of COVID-19, however, is the appropriate timing of when to start treatment. It is possible that blocking IL-6 signal transduction can lead to a reduction in viral clearance [3]. In patients that are already immunosuppressed, this could lead to a much higher viral load as compared with immunocompetent patients. Additionally, we do not know whether IL-6 alters the levels of circulating tacrolimus. This may suggest cessation of immunosuppressive therapy until the initial cytokine storm as resolved. Temporary removal of immunosuppressive regiment is likely beneficial for transplant recipients because clinical outcomes of COVID-19 seems to mostly dependent on the virus-host interaction.
Another interesting finding in many patients with COVID-19 is the potential for a second cytokine storm. A second cytokine storm may have happened to the patient in this case report as he clinically improved and then developed a recurrence of respiratory distress that required the intubation. The IL-6 levels were also markedly elevated at this time suggesting an ongoing cytokine response. This may be the reason why several of these patients become severely hypoxic after a few days of stabilization. This may also suggest that we administer the tocilizumab in an interval fashion, approximately 4–6 days after the first administration.
In conclusion, there is limited data on the clinical presentation, management, and appropriate treatment of COVID-19 patients who are recipients of solid organ transplants. The use of IL-6 inhibitor in our patient resulted in clinical improvement initially, but it is difficult to determine if the tocilizumab played a role in the management of this patient, specifically in preventing respiratory failure. The cytokine storm appears to play a major role in these patients, and it is possible that several of them experience a second storm that results in severe respiratory distress and intubation. Thromboembolic phenomena also appear to play a role in respiratory failure. A single case does not represent the complex strategy needed when considering the treatment of COVID-19 patients with solid organ transplants. Further studies are necessary to investigate treatment modalities for COVID-19 in special populations.