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Id Subject Object Predicate Lexical cue
T1 0-136 Sentence denotes Early use of tocilizumab in respiratory failure associated with acute COVID -19 pneumonia in recipients with solid organ transplantation
T2 138-146 Sentence denotes Abstract
T3 147-334 Sentence denotes As of May 14, 2020, the World Health Organization has reported approximately 4.3 million cases of the novel Coronavirus Disease (COVID-19) with approximately 294,046 deaths worldwide [1].
T4 335-532 Sentence denotes Solid organ transplant recipients who are on chronic immunosuppressants fall within a special population of COVID-19 patients since they are more susceptible to complications secondary to COVID-19.
T5 533-675 Sentence denotes Currently, we do not have data on treating COVID-19 patients with solid organ transplants with tocilizumab, an interleukin-6 (IL-6) inhibitor.
T6 676-922 Sentence denotes We report a case of COVID-19 in a patient with a kidney and liver transplant and discuss the early use of tocilizumab to prevent the cytokine storm and attempt to reduce the likelihood of progression to Acute Respiratory Distress Syndrome (ARDS).
T7 923-1067 Sentence denotes In addition, we present other COVID-19 related transplant cases reported in the literature outlining the presenting clinical signs and outcomes.
T8 1069-1081 Sentence denotes Introduction
T9 1082-1266 Sentence denotes 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].
T10 1267-1396 Sentence denotes In the United States, the Center for Disease Control (CDC) reported 1,364,061 total cases and 82,246 COVID-19 related deaths [2].
T11 1397-1556 Sentence denotes A common complication reported secondary to COVID-19 is Acute Respiratory Distress Syndrome (ARDS) requiring endotracheal intubation and ventilator management.
T12 1557-1699 Sentence denotes Experts currently believe that ARDS possibly results from a state of hyper-inflammation mediated by a cytokine storm in COVID-19 patients [3].
T13 1700-1896 Sentence denotes Recipients of solid organ transplants are included in a special population of patients who may face increased risks of COVID-19 related complications given their use of chronic immunosuppressants.
T14 1897-2067 Sentence denotes Immunosuppression in this population can further reduce cell-mediated immunity, which may prolong viral shedding and increase the risk of COVID related complications [3].
T15 2068-2258 Sentence denotes As reported by McGonagle et al., interleukin-6 (IL-6) plays an important role in lung repair following viral insults and the administration of IL-6 inhibitor drugs may be time-sensitive [3].
T16 2259-2416 Sentence denotes We report a case of COVID-19 in a patient with kidney and liver transplant and discuss the use of IL-6 inhibitor to prevent a cytokine storm in this setting.
T17 2418-2429 Sentence denotes Case report
T18 2430-2621 Sentence denotes The patient is a 63-year-old male kidney and liver transplant recipient who presented to the Emergency Department (ED) after developing symptoms of mild fever, shortness of breath, and cough.
T19 2622-2753 Sentence denotes His vitals and physical exam in the Emergency Department were within normal limits, except for a temperature of 38 degrees Celsius.
T20 2754-2827 Sentence denotes His initial chest x-ray on the day of admission (Day 1) was unremarkable.
T21 2828-2943 Sentence denotes He tested negative for influenza and COVID-19 via polymerase chain reaction (PCR) and was admitted to the hospital.
T22 2944-3106 Sentence denotes At the time of admission, he had a normal white blood cell count (6.94 × 109/liter), decreased absolute lymphocyte count (2.9 %), and normal liver function tests.
T23 3107-3170 Sentence denotes Cytomegalovirus and Bordetella PCR serology were also negative.
T24 3171-3326 Sentence denotes His home immunosuppressant regimen consisted of mycophenolic acid 500 milligrams daily, prednisone 5 milligrams daily, tacrolimus 2 milligrams twice a day.
T25 3327-3481 Sentence denotes On day 2 of the admission, the patient was switched from oral prednisone to methylprednisolone 40 milligrams administered every eight hours intravenously.
T26 3482-3532 Sentence denotes On day 3, he received cefepime 1 g over six hours.
T27 3533-3610 Sentence denotes He also received five doses of hydroxychloroquine 400 milligrams on days 3–7.
T28 3611-3681 Sentence denotes On day 4, the fever subsided and vitals remained within normal limits.
T29 3682-3788 Sentence denotes However, he developed increasing shortness of breath with new diffuse expiratory wheezes on physical exam.
T30 3789-3995 Sentence denotes Repeat chest x-ray showed right lower lobe infiltrates and CT Thorax without contrast showed right upper, middle, and lower lobe infiltrates with ground glass appearance consistent with a viral pneumonitis.
T31 3996-4148 Sentence denotes This later progressed to bilateral ground glass opacities as pictured in Fig. 1, Fig. 2, Fig. 3 and warranted transfer to the Intensive Care Unit (ICU).
T32 4149-4248 Sentence denotes Test for COVID-19 serum antibodies performed at this time was positive for COVID-19 IgG antibodies.
T33 4249-4309 Sentence denotes On Day 4, he received one dose of tocilizumab 4 mL/kilogram.
T34 4310-4395 Sentence denotes Within 24 h of receiving this medication, his shortness of breath started to improve.
T35 4396-4546 Sentence denotes His oxygen requirement dropped to 2–3 liters via nasal cannula with exercise while maintaining an oxygen saturation of 86–94 % over the next two days.
T36 4547-4608 Sentence denotes His chest x-ray also showed improvement, as shown in Fig. 4 .
T37 4609-4665 Sentence denotes Overall, he began to show clinical signs of improvement.
T38 4666-4726 Sentence denotes Mycophenolic acid and tacrolimus were discontinued on day 5.
T39 4727-4823 Sentence denotes Table 1 shows the lab results for the patient through the first seven days of his hospital stay.
T40 4824-4892 Sentence denotes Fig. 1 CT Thorax without contrast: bilateral ground glass opacities.
T41 4893-4961 Sentence denotes Fig. 2 CT Thorax without contrast: bilateral ground glass opacities.
T42 4962-5030 Sentence denotes Fig. 3 CT Thorax without contrast: bilateral ground glass opacities.
T43 5031-5087 Sentence denotes Fig. 4 Chest x-ray improved after six days of treatment.
T44 5088-5123 Sentence denotes Table 1 Patient labs from Day 1–10.
T45 5124-5251 Sentence denotes Labratory Test Results 4/11/20Day 1 4/13/20day 3 4/14/20day 4 4/15/20day 5 4/16/20day 6 4/17/20day 7 4/18/20day 8 4/20/20day 10
T46 5252-5302 Sentence denotes WBC(4.5–11 × 109/L) 6.94 6.73 12.13 8.27 8.03 8.89
T47 5303-5351 Sentence denotes Lymphocytes(30–45 %) 2.90 % 3.70 % 3.30 % 6.50 %
T48 5352-5368 Sentence denotes Creatinine(Male:
T49 5369-5420 Sentence denotes 0.70−1.30 mg/dL) 1.20 1.30 1.50 1.10 1.00 0.90 0.90
T50 5421-5460 Sentence denotes AST(10−40 units/L) 21 25 29 34 37 25 22
T51 5461-5500 Sentence denotes ALT(10−40 units/L) 29 26 28 45 64 53 51
T52 5501-5558 Sentence denotes Alkaline phosphatase(30−120 units/L) 81 75 72 68 63 63 72
T53 5559-5592 Sentence denotes LDH(80–225 units/L) 226.00 344.00
T54 5593-5639 Sentence denotes C-reactive protein (<0.8 mg/dL) 3.70 1.20 0.60
T55 5640-5679 Sentence denotes IL-6(5−15 pg/mL) 18.2 670.8 392.8 280.7
T56 5680-5739 Sentence denotes Prograf/ Tacrolimus levels(5.0−15.0 ng/mL) 17.30 14.80 7.90
T57 5740-5754 Sentence denotes Ferritin(male:
T58 5755-5783 Sentence denotes 54–755 pmol/L) 336.50 225.90
T59 5784-5818 Sentence denotes VBG pH 7.47pO2 81pCO2 32HCO3 23.20
T60 5819-5852 Sentence denotes ABG pH 7.42pO2 72pCO2 33HCO3 21.4
T61 5853-5861 Sentence denotes Serology
T62 5862-5880 Sentence denotes Influenza Negative
T63 5881-5910 Sentence denotes Coronavirus Negative Positive
T64 5911-5995 Sentence denotes However, on Day 7, he decompensated requiring intubation and mechanical ventilation.
T65 5996-6052 Sentence denotes The critical care team also placed him on a rotator bed.
T66 6053-6150 Sentence denotes On day 8, his oxygen requirements substantially increased requiring an increase of oxygen to 1 L.
T67 6151-6206 Sentence denotes At this time, he received a second dose of tocilizumab.
T68 6207-6264 Sentence denotes The patient remained critically ill following intubation.
T69 6265-6359 Sentence denotes Seven days after intubation he developed a right sided pneumothorax and required a chest tube.
T70 6360-6444 Sentence denotes The liver function tests, blood urea nitrogen (BUN), and creatinine remained stable.
T71 6445-6515 Sentence denotes During his ICU stay, he was fully therapeutically heparinized as well.
T72 6516-6574 Sentence denotes He developed no evidence of secondary bacterial infection.
T73 6575-6642 Sentence denotes We obtained consent and administered 200 mL of convalescent plasma.
T74 6643-6733 Sentence denotes He remained stable without significant change in his condition over the next several days.
T75 6734-6811 Sentence denotes On Day 14, the pneumothorax resolved and he began weaning off the ventilator.
T76 6813-6823 Sentence denotes Discussion
T77 6824-6969 Sentence denotes 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].
T78 6970-7154 Sentence denotes 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].
T79 7155-7296 Sentence denotes While this lethal disease has not spared immunocompetent patients, populations who have the highest mortality risk require special attention.
T80 7297-7387 Sentence denotes At this time, there are limited case reports on solid organ transplant (SOT) patients [6].
T81 7388-7511 Sentence denotes There is insufficient data on the clinical presentation and management of immunosuppressant regimens in SOT recipients [4].
T82 7512-7649 Sentence denotes These patients may differ from the immunocompetent population in regards to presentation, diagnosis, and clinical course of Covid-19 [4].
T83 7650-7740 Sentence denotes Notably, transplant patients may present with mild or atypical symptoms and without fever.
T84 7741-7834 Sentence denotes Thus, physicians must maintain broad differential diagnoses and high clinical suspicions [7].
T85 7835-7977 Sentence denotes One case series of five patients reported the most common symptoms on admission were fever, cough, myalgia/fatigue, and sputum production [5].
T86 7978-8063 Sentence denotes Other case reports have identified patients as having vague abdominal discomfort [4].
T87 8064-8130 Sentence denotes Table 2 outlines the reported cases on COVID-19 in SOT recipients.
T88 8131-8234 Sentence denotes We did not find any reports of patients with double solid organ transplants reported in the literature.
T89 8235-8293 Sentence denotes Table 2 Reported cases of COVID 19 in transplant patients.
T90 8294-8322 Sentence denotes MMF = Mycophenolate Mofetil.
T91 8323-8352 Sentence denotes WBC = White blood cell count.
T92 8353-8378 Sentence denotes CRP = C-reactive protein.
T93 8379-8407 Sentence denotes LDH = lactate dehydrogenase.
T94 8408-8671 Sentence denotes 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
T95 8672-8941 Sentence denotes 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]
T96 8942-9202 Sentence denotes 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]
T97 9203-9370 Sentence denotes 38M Kidney, 2019 Glucocorticoid MMF Tacrolimus Oseltamivir, arbidol Glucocorticoids TacrolimusMMF discontinued Not Reported 4.73 63% 0.37 193 Full recovery 26 days [5]
T98 9371-9571 Sentence denotes 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]
T99 9572-9807 Sentence denotes 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]
T100 9808-10011 Sentence denotes 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]
T101 10012-10169 Sentence denotes 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]
T102 10170-10211 Sentence denotes 50 M Liver Tacrolimus Methylprednisolone.
T103 10212-10398 Sentence denotes 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]
T104 10399-10620 Sentence denotes 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]
T105 10621-10753 Sentence denotes 50M Kidney, 1992, 2016 MMF Tacrolimus MMF, Tacrolimus,ceftriaxone 26.22 3.2 60% Not Reported Not Reported Full recovery 13 days [17]
T106 10754-10917 Sentence denotes 58M Kidney, 2017 Belatacept MMF Prednisone BelataceptCyclosporinePrednisoneMMF discontinued during treatment 29 5.04 16% 14 Not Reported Full recovery 18 days [20]
T107 10918-11156 Sentence denotes 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]
T108 11157-11379 Sentence denotes 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]
T109 11380-11552 Sentence denotes 52 M Kidney Tacrolimus MMF Prednisone Imifovir, Moxifloxacin Methylprednisolone, Biapenem, interferon alphaAll immunosuppressive agents discontinued during treatment Day 2:
T110 11553-11565 Sentence denotes 19.53 Day 2:
T111 11566-11591 Sentence denotes 5.54; Day 11 11.68 Day 2:
T112 11592-11606 Sentence denotes 17.9 % Day 11:
T113 11607-11618 Sentence denotes 12 % Day 2:
T114 11619-11630 Sentence denotes 54; Day 11:
T115 11631-11674 Sentence denotes 1.4 Not Reported Full recovery 18 days [23]
T116 11675-11846 Sentence denotes Recent proposals regarding the pathophysiology of COVID-19 suggest a hyper-inflammatory state resulting in COVID-19 related acute respiratory distress syndrome (ARDS) [3].
T117 11847-11974 Sentence denotes Once infected, there is loss of primary antiviral defense because of virus-induced interferon suppression with lymphopenia [8].
T118 11975-12127 Sentence denotes Subsequently, the body activates a second defense mechanism, known as the “second wave,” which results in a cytokine storm and severe tissue damage [3].
T119 12128-12364 Sentence denotes 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].
T120 12365-12492 Sentence denotes Interleukin-6 (IL-6) is a marker of recent interest because of its role in the “second wave” and resulting cytokine storm. [10]
T121 12493-12636 Sentence denotes IL-6 signal transduction occurs via three main pathways: classical signal transduction, trans signal transduction, and trans presentation [11].
T122 12637-12838 Sentence denotes 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].
T123 12839-13047 Sentence denotes 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].
T124 13048-13250 Sentence denotes 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].
T125 13251-13376 Sentence denotes Chen et al. found in a sample of 48 patients that increased levels of IL-6 significantly correlated to disease severity [12].
T126 13377-13630 Sentence denotes 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].
T127 13631-13838 Sentence denotes 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).
T128 13839-13955 Sentence denotes Treatment with tocilizumab, a monoclonal antibody that binds to the IL-6 Receptor, has been recently published [11].
T129 13956-14141 Sentence denotes 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].
T130 14142-14370 Sentence denotes 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].
T131 14371-14453 Sentence denotes The maximal dose is 800 mg, and the maximal number of administrations is two [14].
T132 14454-14736 Sentence denotes 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].
T133 14737-14810 Sentence denotes Given the small sample size, we need more research on appropriate dosing.
T134 14811-14908 Sentence denotes At this time, there is a multicenter randomized controlled trial currently ongoing in China [16].
T135 14909-14987 Sentence denotes Another potential medication that decreases IL-6 levels is metronidazole [13].
T136 14988-15080 Sentence denotes In vitro and in vivo studies have shown that metronidazole decreases serum IL-6 levels [13].
T137 15081-15181 Sentence denotes Close monitoring of immunosuppressive therapy in SOT recipients infected with COVID-19 is necessary.
T138 15182-15297 Sentence denotes There is a balance of allowing adequate immune response to suppress viral load and preventing transplant rejection.
T139 15298-15430 Sentence denotes Previous case reports have hypothesized that immunosuppressive therapy protects SOT recipients by dampening the cytokine storm [17].
T140 15431-15556 Sentence denotes Other case reports have noted that viral RNA levels remain positive for a longer period than in immunocompetent patients [4].
T141 15557-15686 Sentence denotes This is notable because previous studies have demonstrated that ARDS occurs in SARS patients despite a decreased viral load [18].
T142 15687-15853 Sentence denotes 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].
T143 15854-16053 Sentence denotes 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.
T144 16054-16189 Sentence denotes 4 This suggests that early IL-6 intervention to prevent the cytokine storm could improve outcomes in COVID-19 positive, SOT recipients.
T145 16190-16326 Sentence denotes 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.
T146 16327-16428 Sentence denotes It is possible that blocking IL-6 signal transduction can lead to a reduction in viral clearance [3].
T147 16429-16562 Sentence denotes In patients that are already immunosuppressed, this could lead to a much higher viral load as compared with immunocompetent patients.
T148 16563-16649 Sentence denotes Additionally, we do not know whether IL-6 alters the levels of circulating tacrolimus.
T149 16650-16751 Sentence denotes This may suggest cessation of immunosuppressive therapy until the initial cytokine storm as resolved.
T150 16752-16941 Sentence denotes 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.
T151 16942-17046 Sentence denotes Another interesting finding in many patients with COVID-19 is the potential for a second cytokine storm.
T152 17047-17235 Sentence denotes 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.
T153 17236-17333 Sentence denotes The IL-6 levels were also markedly elevated at this time suggesting an ongoing cytokine response.
T154 17334-17445 Sentence denotes This may be the reason why several of these patients become severely hypoxic after a few days of stabilization.
T155 17446-17581 Sentence denotes This may also suggest that we administer the tocilizumab in an interval fashion, approximately 4–6 days after the first administration.
T156 17582-17754 Sentence denotes 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.
T157 17755-17988 Sentence denotes 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.
T158 17989-18181 Sentence denotes 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.
T159 18182-18257 Sentence denotes Thromboembolic phenomena also appear to play a role in respiratory failure.
T160 18258-18400 Sentence denotes A single case does not represent the complex strategy needed when considering the treatment of COVID-19 patients with solid organ transplants.
T161 18401-18503 Sentence denotes Further studies are necessary to investigate treatment modalities for COVID-19 in special populations.