key: cord-0800595-p074ffpt
authors: Mathies, D.; Rauschning, D.; Wagner, U.; Mueller, F.; Maibaum, M.; Binnemann, C.; Waldeck, S.; Thinnes, K.; Braun, M.; Schmidbauer, W.; Hagen, RM.; Bickel, C.
title: A Case of SARS‐CoV‐2‐pneumonia with successful antiviral therapy in a 77‐year‐old male with heart transplant
date: 2020-04-21
journal: Am J Transplant
DOI: 10.1111/ajt.15932
sha: dc17a192d41bbcfb91e48ac7bcbd2779f05b21f4
doc_id: 800595
cord_uid: p074ffpt

The SARS‐CoV‐2‐infection can be seen as a single disease but also affects patients with relevant comorbidities who may have an increased risk of a severe course of infection. In this report, we present a 77‐year old patient with a heart transplant under relevant immunosuppressive therapy who was tested positive for SARS‐CoV‐2 after several days of dyspnoea, dry cough and light general symptoms. The CT‐scan confirmed an interstitial pneumonia. The patient received an antiviral therapy with hydroxychloroquine showing no further deterioration of the clinical state. After 12 days of hospitalisation the patient was released SARS‐CoV‐2 negative and completely asymptomatic.

A 77-year-old male with a heart transplant was presented to our emergency department complaining about shortness of breath, pain upon inspiration and dry cough as well as body aches, fatigue and decline in body weight for three days. Fever and angina pectoris were denied. He was unaware of a contact to a SARS-CoV-2-positive patient and had not been on trip to a risk area at that time.

The patient had undergone heart transplantation surgery after ischaemic cardiomyopathy in 2003. 2019 he received a PTCA and DES of the LCX and R. marginalis due to a tandem stenosis. Further past medical history included a CMV-colitis 2005 and septicaemia following a CMV pneumonia, chronic kidney disease (G3b KDIGO-Classification), hypertension and diabetes mellitus type 2 under oral medication.

Medication included sirolimus 0,5mg 0-1-0-0, mycophenolate 500mg 1/2-0-1/2-0, acetylsalicylic acid 100mg 0-1-0-0, clopidogrel 75mg 1-0-0-0, bisoprolol 2,5mg 1-0-1, telmisartan 80mg 0-0-1-0, torasemide 5mg 0-1-0-0, atorvastatin 40mg 0-0-1-0, ezetimibe 10mg 0-0-1-0, sitagliptin 25mg 1-0-1-0, allopurinol 100mg 0-0-1-0, pantoprazole 20mg 1-0-0-0, vitamin D 20.000 IE weekly.

Clinical examination showed a cardiopulmonary stable patient with a pulse of 86/min and a blood pressure of 140/85mmHg. Body temperature was 36.7°C. Respiratory frequency was 16 per minute with an oxygen saturation of 96% without supplementary oxygen. An auscultation of the lung found dry rales in the basal compartments. Examination of the heart and abdomen was unremarkable In the initial arterial blood gas analysis pO 2 was 88mmHg with a saturation of 97.2%; pCO 2 was 20.7 with a pH of 7,535. Laboratory findings showed a PCT of 0,12ng/ml (<0,05ng/ml) and a CRP of 4,19mg/dl (<0,5mg/dl) with normal leucocytes and a BSR of 56mm/1h (<46mm/1h). The differential blood count showed monocytosis, lymphocytes were normal. There was a normocytic and normochromic anaemia.

LDH was 271 U/l (135-255 U/l), D-Dimer 2.04mg/l (<0.8mg/l), hs-Troponin T 19 pg/ml (<14pg/ml) without further increase after 3h, myoglobin 122µg/ml (28-72µg/ml). Creatinine was elevated with 2.13mg/dl (0.67-1.17mg/dl), BUN with 77.6mg/dl (16.6-48.5mg/dl), GFR calculated for Cystatin C was 22ml/min. HbA1C was 6.5%.

An initial ECG was without pathological findings. A CT-Scan of the thorax showed distinct atypical opaque infiltration of the left lower lobe consistent with a viral pneumonia as shown in figure 1. Swabs from throat and nose as well as sputum tested positive for SARS-CoV-2 in the rt-PCR on the day of admission.

This article is protected by copyright. All rights reserved Diagnosis: SARS-CoV-2-Infection with viral pneumonia in a patient with heart transplant due to coronary artery disease with ischemic cardiomyopathy

After establishing the diagnosis, we started a therapeutic trial with hydroxychloroquine with an initial dose of 400mg BID for the first day followed by 200mg BID. We refrained from a therapy with lopinavir/ritonavir in fear of possible interactions due to the shared metabolisation path via CYP3A4 with sirolimus. The Patient received piperacillin/tazobactam and cotrimoxazole pre-emptively and ganciclovir because he had a history of CMV-infections including colitis and pneumonia. In close cooperation with the transplant centre (Ludwig-Maximilians-Universität, Munich, Germany) we modified immunosuppressive medication replacing sirolimus with tacrolimus due to its potential lung toxicity [1] . Once a steady serum level was reached, we withdrew mycophenolate.

The patient was monitored in an intensive care unit for three days and received 4l Oxygen supplementation via nasal cannula. Arterial oxygen saturation dropped as low as 89% with a Horovitz index of 169mmHg and an alveolar-arterial gradient of 162mmHg (age corrected <23mmHg) indicating a potential severe case with a moderate ARDS and a consecutive VQ-mismatch. As there were no signs of further relevant deterioration the patient was transferred to our normal ward. CT was repeated four and nine days after admission, showing fluctuation of the opaque infiltrations on the first and a general decline on the second scans. The patient additionally presented with diarrhoea but stool samples showed a negative culture and multiplex PCR for pathological bacteria or viruses.

After seven days the patient started to show relevant improvement in the respiratory situation, required no further oxygen supplementation. There was no increase in procalcitonin or a left shift in granulocytes thus antibiotic treatment was discontinued. Respiratory symptoms declined after nine days so we tested sputum as well as throat and nose swabs for SARS-CoV 2 on the following two days. PCR was negative in all specimens. A multiplex PCR in another sputum as well as serological results showed no clues for a CMV-reactivation or other viral or bacterial agents. The patient received hydroxychloroquine overall 9 days. We were able to discharge the patient twelve days after admission. An overview of the course is provided in figure 2.

SARS-CoV-2, initially named 2019-nCoV, emerged in December 2019 in the People's Republic of China in Hubei region, especially in the city of Wuhan. Probably deriving from bat-borne Coronaviruses (bat-CoV), it initially caused a local outbreak of an influenza-like disease with potentially severe pulmonary complications similar to related coronaviruses like SARS and MERS [2, 3] .

The disease itself was named corona virus disease 2019 (COVID-19) and ranges from mild and unspecific upper respiratory symptoms with cough and fever to septic courses and acute respiratory distress syndrome with fatal multi-organ failure. Bacterial superinfection or other viral co-infection, for example with an influenza-virus during the current season took place simultaneously and increase the risk of a fatal outcome [4] . Especially elderly and patients with comorbidities, in particular of the lungs or the cardiovascular system, show an increased death rate [5] . Droplet infection is seen as the main way of human-to-human transmission although smear infection must be also taken into consideration. It is supposed that transmission is already possible during the asymptomatic period of incubation about 2 days after virus-inoculation [6] .

Due to our globalized society the virus easily spread around the globe in beginning of 2020 causing a pandemia with new epicentres in Southern Europe and the United States. The first confirmed patient in Germany was registered in January 27 2020 in Bavaria [7] . On April the 4 th 2020 there are more than 96,000 reported cases, 1444 of which were fatal. Worldwide more than 1,200,000 confirmed cases with already about 64,800 deaths especially in Italy and Spain are registered to this day [8] .

Only a fistful of cases of a SARS-CoV 2-Infection in patients who received a solid organ transplant has been published so far [9, 10] . The known patients have all been receiving different forms of immunosuppression. One might deduce that this would lead to more severe infections. Interestingly the clinical manifestations range from mild cases with symptoms of a mere common cold, to oxygen dependent patients up to severe respiratory failure that requires intubation and mechanical ventilation.

Here, we present a case of a patient who endured a rather mild course of SARS-CoV 2 pneumonia.

Currently antiviral therapy of COVID-19 makes up part of extended scientific efforts because an evidencebased regime has not been found yet and treatment of COVID-19 has been experimental so far. With the knowledge of the recent viral outbreaks of SARS and MERS several existing agents have been supposed to have also an effect against SARS-CoV-2 [11] . Early Chinese reports and recommendations included lopinavir/ritonavir and (Hydroxy-) chloroquine among others. As these drugs have national approvals for other indications, there is a broad experience in usage and they were available on the market for prompt delivery we decided to take them as first-line therapy for COVID-19-cases in our house guideline.

This article is protected by copyright. All rights reserved Beside the therapeutic agents also the moment of starting antiviral therapy is being discussed extensively [12] . We prefer an early start of antiviral medication in order to prevent viral shedding with the potential risk of a progress to a severe course of COVID-19. In this case the combination of radiologic signs of viral pneumonia and the supposed high-risk state of severe immunosuppression led to the decision to start an antiviral therapy immediately after receiving the positive rtPCR-results although the patient presented only mild symptoms.

Interactions between medications poses a great challenge. Cyclosporin, tacrolimus and sirolimus are hepatically metabolised via CYP 3A4 Enzymes. Lopinavir is combined with ritonavir in order to block exactly this pathway and to increase serum levels of lopinavir. In combination, this will lead to an increase of the immunosuppressive medication as well which necessitates dose adjustments and measurements of serum levels to avoid toxic levels. Hydroxychloroquine and chloroquine are metabolised via CYP 3A4 as well as CYP 2C8 thus theoretically also possessing an albeit smaller potential for interaction. Due to the medication with sirolimus and later tacrolimus we decided to treat the patient with hydroxychloroquine rather than lopinavir/ritonavir which resulted in no relevant increases in serum levels for the immunosuppressive medications. In this complicated situation internet-based databases of drug-druginteractions help to decide fast but responsibly. [13] A second question is whether patients with a solid organ transplant who receive immunosuppressive medication are at greater risk for a severe manifestation of a SARS-CoV 2-Infection or might even benefit from a reduced immunologic reaction. The answer remains uncertain due to the paucity of data considering relevant cases.

For SARS-CoV 2 we found two cases of patients with a heart transplant of which one had only mild manifestations and one required mechanical ventilation but survived [9] . The first patient was a 43-yearold male, who had undergone transplantation surgery in 2017 and had received tacrolimus and mycophenolate. Therapy included valganciclovir and arbidol as well as several antibiotics.

Immunosupressants were not cancelled. The other patient was a 51-year-old male with a transplant from 2003 also under therapy with tacrolimus and mycophenolate. Therapeutic trials included ribavirin, humane gamma globulins and methylprednisolone as well as ganciclovir, arbidol and antibiotics.

Immunosuppressive medication was paused for 13 days.

A patient with a renal transplant and medication including tacrolimus, everolimus and prednisone was on ventilation when the case was published despite omitting tacrolimus and everolimus and a therapeutic trial with lopinavir/ritonavir, hydroxychloroquin and interferon beta [10] . From a cohort of 200 paediatric Accepted Article patients with transplants, 100 patients under immunosuppression and 3 patients under chemotherapy 3 mild cases of SARS-CoV2 without pneumonia are reported but it remains unclear, whether those are patients with a solid organ transplant [14] .

For infection with SARS-CoV and MERS-CoV the data is comparable [15, 16] . There are few cases of manifestations in patients with renal or liver transplant receiving cyclosporine, azathioprine, tacrolimus, mycophenolate or prednisone. Some of the patients died although immunosuppressive medication was halted, others survived with a reduced therapy In a synopsis it is difficult to decide if immunosuppressive medication should be continued, or reduced.

The published guidelines from expert associations like ISHLT offers first guidance and recommendations.

[17] Considering withdrawal of mycophenolate or azathioprine is recommended. On the other hand, corticosteroids like methylprednisolone are a medication that has been widely used in Patients suffering from SARS-CoV-2-mediated ARDS ranging 1-2mg/kg/day for 3 to 5 days in order to mitigate the cytokine storm [18] . The effects of hydroxychloroquine in SARS-CoV 2 might also be related to its immunomodulatory effects [19] .

In summary it remains unclear whether immunosuppressive medication leads to a more serious progression or might even have a positive effect. Further investigation is required. However a certain degree of medication must be maintained to avoid transplant rejection. Considering antiviral therapy latest reports seem to confirm the in vitro efficiency of hydroxychloroquine in vivo [20] . To the best of our knowledge, this is the first case report of a successful antiviral monotherapy with hydroxychloroquine in a patient after heart transplantation while continuing a modified immunosuppressive therapy.

The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.

This article is protected by copyright. All rights reserved 

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