key: cord-0730597-z0uvaebp
authors: Verleden, Geert M.; Godinas, Laurent; Lorent, Natalie; Van Bleyenbergh, Pascal; Dupont, Lieven; Delcroix, Marion; Yserbyt, Jonas; Dooms, Christophe; Vos, Robin
title: COVID‐19 in lung transplant patients: a case series
date: 2020-07-13
journal: Am J Transplant
DOI: 10.1111/ajt.16212
sha: 5800166a6030b4a1bccb91a7e133a60492bae51f
doc_id: 730597
cord_uid: z0uvaebp

Several case reports and small case series have been published on COVID‐19 infection after solid organ transplantation, however, thus far there are limited data on COVID‐19 infections in lung transplant patients. In the present single center case series we discuss 10 lung transplant patients with a documented SARS‐CoV‐2 infection, diagnosed with nasophanryngeal swab in 8 and broncho‐alveolar lavage in 2. Eight /10 patients needed hospital admission, of whom 1 in the intensive care unit. He died after 2 weeks from multiple organ failure. The remaining 9 patients recovered. Cell cycle inhibitors were withheld in all patients, whereas the calcineurin inhibitor and corticosteroids were continued at the same dose, with an acceptable outcome.

solid organ transplant patients with COVID-19. However, they made no separate analysis of this particular patient group (8) . In a Swiss SOT cohort, 1/21 patients was a lung transplant patient (9) and the authors concluded that overall the clinical manifestations in SOT patients are similar to the general population (9) . In the present paper, we report our experience with 10 consecutive lung transplant patients with a PCR-proven, symptomatic COVID-19 infection.

Between March, 18 th and May, 24 th , 10 symptomatic lung transplant patients (1.5 % of our total cohort of 680 lung transplant patients in follow up) were diagnosed with SARS-CoV-2. In 8/10 patients the nasopharyngeal swab was real-time Polymerase Chain Reaction (PCR) positive, whilst in the remaining two patients a bronchoalveolar lavage confirmed the diagnosis, after a negative

This article is protected by copyright. All rights reserved nasopharyngeal swab. In 6/10 patients a low dose computer tomography (CT) of the chest was performed and demonstrated typical COVID-19 alterations (bilateral ground glass opacities), in 4 patients only a chest X-ray was done which showed no abnormalities. Eight patients had to be admitted to the hospital, whilst 2 remained ambulatory. In the 2 patients with a negative nasopharyngeal swab, a bronchoscopy with BAL was performed to exclude other causes for the bilateral ground glass opacities on CT scan Characteristics of the patients, who all underwent a double lung transplantation at a median of 26 months before diagnosis (range 6-190 m) are shown in tables 1 and 2. They were all admitted for monitoring because of their symptoms and fear of progression of the disease.

All patients were at least on a double immunosuppressive regimen with a calcineurin inhibitor (CNI) and corticosteroids (CS), 6 took an additional cell cycle inhibitor (4 mycophenolate mofetil, MMF, 2 azathioprine), 1 patient was on additional everolimus. All patients received azithromycine, 250-500 mg 3 times a week as standard of care in our center.

Median C-Reactive Protein (CRP) decreased from 92.2 mg/L at initial presentation to 5.3 mg/L at discharge. D-dimers and interleukin-6 levels were not routinely measured. In 4 patients, ferritin was available (pt 6, 7, 9, 10) and it was increased in 3 (range 96-1,360 microgram/ml), with the highest value (1,360 microgram/ml) in patient 6. Three patients were treated for diabetes (2 with insulin, 1 with oral treatment), and 5 for arterial hypertension. In all patients, respiratory cultures (bacterial, fungal) and other viral PCR's at time of diagnosis were negative.

One of the patients (number 6) was immediately admitted to ICU, initially treated with high flow 100% oxygen, but needed intubation and ventilation 2 days later, because of a very low oxygen saturation. Intermittent prone ventilation was used. His CT scan showed very prominent ground glass opacities, covering 50-70% of both lungs. He received empiric meropenem, hydroxychloroquine, azithromycine (500 mg every day for 5 days), full dose anticoagulation and tocilizumab. Remdesivir was not used as it is not available in Belgium. He developed multiple organ failure and died after 13 days. The other 7 patients were all admitted to a regular COVID-19 unit and treated with supplemental oxygen, empiric IV broad spectrum antibiotics, hydroxychloroquine (400 mg every 12 hours for the first day, then 2 times 200 mg per day for 5 days) and we continued azithromycine (500 mg for 5 days), with daily QTc monitoring. They all gradually improved and were discharged home after 8.5 days (range 3-15).

One of the ambulatory patients (number 8), was admitted to hospital 6 weeks after her first positive nasopharygeal swab, because of recurrence of high fever since 48 hours, dyspnea,

This article is protected by copyright. All rights reserved tachypnea, cough and desaturation (88%). Her nasopharyngeal swab remained positive (cycle threshold initially 16.2, at admission 16.9), a CT scan demonstrated extensive bilateral ground glass opacities (>50%) and the BAL (to exclude other causes) was also positive for SARS-CoV-2 (with a cycle threshold of 20.3), without any other positive viral PCR or bacterial/fungal cultures, despite the presence of 84% neutrophils in the BAL cell differential count. She was treated as described above with hydroxychloroquine, an increased dose of azithromycine and empiric rocephine and was discharged after 18 days. At that time, her nasopharyngeal swab remained positive, with a cycle threshold of 24.1.

In all patients, CNI and CS were continued at the same dose to maintain their normal calcineurin blocker trough level, whereas cell cycle inhibitors were stopped. No steroid bolus was administered .

Although several case reports and small case series have been published of COVID-19 infection after SOT (1-6), there are only limited data on lung transplant patients (7) (8) (9) . We report on our initial experience with 10 lung transplant patients with COVID-19, amongst a total cohort of 680 patients in follow up at our center (1.5%). During the same time period, 23 lung transplant patients who had to undergo an elective bronchoscopy, either as surveillance or because of a decline in FEV1, and who were otherwise asymptomatic, underwent a nasopharyngeal swab before bronchoscopy, and tested all negative for SARS-CoV-2.

Symptomatology in our 10 SARS-CoV-2 positive patients was quite comparable to a nontransplanted population and in general was rather mild to moderate, except for one patient who had very severe disease and finally died after 2 weeks. In fact, although most patients had several risk factors for COVID-19 infection (table 2) One patient, initially ambulatory when diagnosed, had late new onset of symptoms and needed hospitalization at a low care COVID-19 unit 6 weeks later. Remarkably, her nasopharyngeal swab was still positive after 6 weeks (with a comparable cycle threshold) and also the BAL fluid at

This article is protected by copyright. All rights reserved admission was positive for SARS-CoV-2, whilst she developed ground glass opacities on CT scan.

Despite this, the course of the disease flair up was favorable and she was discharged without oxygen supplement after 18 days.

All patients were at least on dual immunosuppressive treatment with a CNI and CS, whilst 60%

were also taking a cell cycle inhibitor. Only these last drugs were stopped temporarily, whereas we did not change the CNI and CS dose. There has been a lot of debate so far, whether immunosuppressive treatment needs to be continued, lowered in dose or even temporarily stopped in case of a COVID-19 infection. This question is still not solved, although there is some evidence, specifically in a case series of liver transplant patients, that a higher trough level of CNI may result in a better outcome compared to very low levels. Indeed, in this publication, 3 patients with a very low tacrolimus trough level died, whereas 3 others, who were more recently transplanted and hence had higher trough levels, survived (6) . Also in the experience of the Columbia University kidney transplant group, the immunosuppressive medication was reduced in 15 COVID-19 kidney transplant cases, and 27% needed mechanical ventilation, but over half were discharged home by the end of follow-up (1). In another 2 kidney transplant patients, immunosuppressive treatment was left unchanged and both patients fully recovered (4). In 10 confirmed COVID-19 kidney transplant patients in Wuhan, the immunosuppressive treatment was reduced and the authors found that the severity of pneumonia was greater in the transplanted patients compared to the general population. Indeed 5 patients became severely ill and 3 critically ill, but finally 90% of their patients recovered, and only 1 died of progressive respiratory failure (11) . In their series of 90 SOT patients with COVID-19, Pereira et al. also maintained CNI and CS, but tapered/stopped cell cycle inhibitors (8) . Based on these case series and our own results, it is difficult to decide whether immunosuppressive treatment has to be reduced upfront or can be continued at the same level (at least for CNI and CS) when COVID-19 is diagnosed. From our initial experience, it seems fair to say that the outcome without reduction of CNI and CS (but with temporarily arresting MMF and azathioprine) is acceptable. This is also in line with recommendations from the COVID-19 task force from the International Society for Heart and Lung Transplantation (12) .

For the time being, it can be concluded that we do not know yet whether classical immunosuppression may alter the predisposition to acquiring infection with SARS-CoV-2. This may well be the case as 1.5% of our lung transplant cohort tested positive for SARS-CoV-2, whilst this was only 0.5% in the general Belgian population. However, it must be argued that lung Accepted Article transplant patients come to see us with minor symptoms and will thus be swabbed, whereas this does not hold true for the general population. Whether the disease may become worse or not after lung transplantation (13) , is not clear and in our small series the mortality rate was 10% (1/10), whilst this was 16.2% in the Belgian SARS-CoV-2 positive population, suggesting that COVID-19 may be somewhat more frequent after lung transplantation, but without a worse outcome, although this data should be interpreted with caution.

There is also some evidence that tacrolimus strongly inhibits the growth of human coronaviruses SARS-CoV, HcoV-NL63 and HcoV-229E at low, non-cytotoxic concentrations, at least in in-vitro cell cultures (14) , which may again support the strategy to continue the CNI at the same dose.

Furthermore, azithromycin has been suggested to be beneficial in the treatment of COVID-19 patients, at least when combined with hydroxychloroquine (15) , which has been set as standard treatment option in our center. Potential side effects when using this drug combination, especially QTc prolongation, need careful monitoring (15, 16) . Although hydroxychloroquine has been widely used in the treatment of COVID-19, it remains to be proven whether it is really beneficial in these patients. Several trials are running but convincing data are still lacking (16, 17) .

Remdesivir was recently shown to be superior to placebo in shortening the time to recovery in adults hospitalized with Covid-19 and evidence of lower respiratory tract infection and may become the treatment of choice (18) . We were not able to use this drug as it is not yet available in Belgium.

In conclusion: this is a single center report of COVID-19 infection in a series of 10 lung transplant patients. Besides a single patient with severe disease who died, disease presentation was mild/moderate in the other 9 patients. One patient had a remarkable course as she was initially ambulatory and needed hospitalization 6 weeks later for recurrent and more severe COVID-19 disease, whilst she remained/became SARS-CoV-2 positive as well in the nasopharynx as in the BAL fluid.

We adapted the policy to temporarily arrest the cell cycle inhibitors, but not to reduce the CNI and CS treatment, which, according to our initial results, seems acceptable. 

Disease in Kidney Transplant Recipients in New York

Case Report: A Kidney Transplant Patient with Mild COVID-19

COVID-19 in solid organ transplant recipients: a single-center case series from Spain

Immunosuppressive therapy maintenance in a kidney transplant recipient SARS-CoV-2 pneumonia: a case report

Clinical characteristics and immunosuppressants management of coronavirus disease 2019 in solid organ transplant recipients

COVID-19 in long-term liver transplant patients: preliminary experience from an Italian transplant centre in Lombardy

Covid-19 in a lung transplant recipient

COVID-19 in Solid Organ Transplant Recipients: Initial Report from the US Epicenter

Accepted Article This article is protected by copyright. All rights reserved

First experience of SARS-CoV-2 infections in soklid organ transplant recipients in teh swiss transplant cohort study

Risk factors of critical & mortal COVID-19 cases: A systematic literature review and meta-analysis

Coronavirus Disease 2019 Pneumonia in Immunosuppressed Renal Transplant Recipients: A Summary of 10 Confirmed Cases in Wuhan, China

Guidance from the International Society of Heart and Lung Transplantation regarding the SARS CoV-2 pandemic

COVID-19: Yet another coronavirus challenge in transplantation

Replication of human coronaviruses SARS-CoV, HcoV-NL63 and HcoV-229E is inhibited by the drug FK506

Clinical and microbiological effect of a combination of hydroxychloroquine and azithromycin in 80 COVID-19 patients with at least a six-day follow up: A pilot observational study

A rapid systematic review of clinical trials utilizing chroroquine and hydroxychloroquine as a treatment for COVID-19

Are hydroxychloroquine and Chloroquine effective in the treatment of SARS-COV-2 (CVOVID-19)?

Remdesivir for the Treatment of Covid-19 -Preliminary Report

We thank the Leuven lung transplant group for their valuable input.

This article is protected by copyright. All rights reservedThe author of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.