key: cord-0744703-5uthd99t
authors: Zimmermann, Julia; Glueck, Olaf M; Fertmann, Jan M; Sienel, Wulf G; Yavuz, Gökce; Damirov, Fuad; Kovács, Julia R; Tufman, Amanda; Irlbeck, Michael; Kneidinger, Nikolaus; Michel, Sebastian; Kauke, Teresa; Hatz, Rudolf A; Schneider, Christian P
title: COVID-19 in recent lung transplant recipients: clinical outcomes and management strategies
date: 2022-01-10
journal: Transplant Proc
DOI: 10.1016/j.transproceed.2021.12.014
sha: 8a50948fecd4bbb3b7ffe2547881e2cf6d308c02
doc_id: 744703
cord_uid: 5uthd99t

Background Covid-19 causes a wide range of symptoms, with particularly high risk of severe respiratory failure and death in patients with predisposing risk factors such as advanced age or obesity. Recipients of solid organ transplants, and in particular lung transplantation, are more susceptible to viral infection due to immune suppressive medication. As little is known about the SARS-CoV-2 infection in these patients, this study was undertaken to describe outcomes and potential management strategies in early COVID-19 infection early after lung transplantation. Methods We describe the incidence and outcome of COVID-19 in a cohort of recent lung transplant recipients in Munich. Six of 186 patients who underwent lung transplantation in the period between March 2019 until March 2021 developed COVID-19 within the first year after transplantation. We documented the clinical course and laboratory changes for all patients showing differences in the severity of the infection with COVID-19 and their outcomes. Results Three of six SARS-CoV-2 infections were hospital-acquired and the patients were still in inpatient treatment following lung transplantation. All patients suffered from symptoms. One patient did not received antiviral therapy. Remdesivir was prescribed in four patients and the remaining patient received remdesivir, bamlanivimab and convalescent plasma. Conclusion COVID-19 does not appear to cause milder disease in lung transplant recipients compared to the general population. Immunosuppression is potentially responsible for the delayed formation of antibodies and their premature loss. Several comorbidities and a general poor preoperative condition showed an extended hospital stay.

A novel pneumonia was first reported in Wuhan (China) in December 2019. In January 2020 the origin was identified as a new severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). [1] [2] [3] [4] [5] The coronavirus disease 2019 (COVID-19) pandemic followed thereafter 6 SARS-CoV-2 is transmitted via inhalation, direct contact or contaminated surfaces. The course of disease varies and ranges from asymptomatic to death within a short time. The exponential spreading, especially via asymptomatic carriers and the incubation period of 2-14 days are the biggest challenges to stop the pandemic. [8] [9] [10] [11] Several strategies and therapies were developed to combat the spreading and to treat patients affected. For quite a while no specific medicine or vaccine was available, therefore the treatment was based on different experimental approaches. 10, [12] [13] [14] [15] [16] [17] The majority of COVID-19 cases are either asymptomatic or result in a mild disease. People who were hospitalized due to a severe course of disease often had comorbidities and risk factors connected with poor prognosis. [18] [19] [20] [21] A special, smaller group suffering from a severe course are those patients having received a solid organ transplantation (SOT). It was hypothesized the first time that this group is more susceptible to the virus due to their immunosuppressive drug treatment as this impairs the immune response and therefore increases risk for an infection. Furthermore, delayed or missing formation of antibodies in these patients might have an impact on the course of the disease. A weakened immune response will impact therapy success or cause a prolonged recovery. Moreover, the dependency of high dose immunosuppression therapy promotes the occurrence of bacterial and fungal infection. [22] [23] [24] Initial observations indicated that independent of any SOT in a patient's prehistory, severe course results are significant driven by a hyper-inflammatory state. Hence, an immunosuppressive therapy is still considered to be beneficial. 25, 26 The group of immunosuppressed patients infected with SARS-CoV-2 is small. Considering just the lung transplant recipients (LTRs) the experience of manifestation, management and treatment, the group gets even smaller and there is still no evidence-based recommendation. [27] [28] [29] With almost 100 LTs per year, the Munich lung transplantation group is one of the most experienced centers in Europe. Since the beginning of the pandemic, the number of LTs has only decreased slightly. This study deals with LTRs infected with SARS-CoV-2 within the first year (early phase) after transplantation. Knowledge about such a specific patient collective is rare. 30, 31 These patients need a particularly high dose of immunosuppressive medications to reduce early organ rejection and to prevent superinfections at the same time.

The aim of this study was to identify possible risk factors of a poor outcome in early COVID-19 after LT. Furthermore, we aimed at identifying indicators influencing the clinical outcome.

This is a retrospective, monocentric study of all adult LTRs with confirmed SARS-CoV-2 infections in the early phase after LT at the Ludwig-Maximilians-University of Munich. During the period from March 2019 and March 2021 186 patients underwent LT. The first LTR with confirmed SARS-CoV-2 infection in the early phase was diagnosed on November 2 nd 2020.

Until March 2021, we diagnosed COVID-19 in six patients. Three of these SARS-CoV-2 infections were hospital-acquired and the patients were still in inpatient treatment following LT. The remaining three patients had already been discharged after transplantation and presented themselves to the emergency room with typical COVID-19 symptoms as well as worsening general condition. An admission to the hospital was necessary. In order to describe qualitative values, absolute frequencies and percentages are used. The description of qualitative variables is presented as the median and range.

A database was established with study data collected anonymously. Parameters included demographics, baseline clinical characteristics, radiological and pathological findings, immunological status, type, date and underlying diagnosis of the LT, parameter for possible organ rejection, microbiological results, comorbidities, type of current or recent immunosuppressive therapies and the treatment of COVID-19. Data used within this study cover the period August, 2019 (pre-transplantation) up to and including March 10, 2021.

The Clinical Research Ethics Committee of the Ludwig-Maximilians-University (LMU) Munich approved the study .

A total of six early LTRs diagnosed with COVID-19 were identified. An overview of demographics and clinical characteristics pre-infection is shown in Table 1 . Median age at LT was 59 (range 37-69) years, four patients were male and all of them had an interstitial lung disease (ILD) before the transplantation was performed. Half (3 of 6) of the patients had idiopathic pulmonary fibrosis (IPF).

The median lung allocation score (LAS) was 39.6. One patient had been treated with awake veno-venous extracorporeal membrane oxygenation (vv-ECMO) as bridge to transplantation. All six patients received a double lung transplantation. The operation time ranged between 4:15h to 7:36h. Mechanical ventilation could be stopped within the first 48h of four patients, two required a tracheotomy. Two patients developed a postoperative haemothorax postoperative, a re-operation was necessary. Donor specific human leukocyte antigen (HLA) antibodies could be detected in three patients after LT and were treaded by IvIg infusion. After LT a bronchoscopy and transbronchial biopsies were performed. Two patients had a mild cellular rejection (A1,B0; nomenclature in the diagnosis of lung rejection; ISHLT 32 ), intravenous pulse prednisolone was prescribed. One of these patients received this therapy right before SARS-CoV-2 infection.

Before COVID-19 onset, a triple immunosuppressive therapy with tacrolimus (trough level 12-15ng/ml), mycophenolate mofetil (MMF) and prednisolone was prescribed for all. The median forced vital capacity (FVC) in the early phase after lung transplantation was 2605ml and a 2050ml forced expiratory volume in the first second (FEV1) was achieved.

Clinical, laboratory and radiological characteristics during SARS-CoV-2 infection are summarized in Table 2 . The median interval between transplantation and COVID-19 diagnosis was 99 days (range 18-345). All patients suffered from fatigue, half of them had fever. 83% of the patients had dyspnoea and cough and four patients developed diarrhoea during the infection. Headache, expectoration, nausea and vomiting was reported in 33% each.

Five patients developed a leukopenia (median 1.5x10E3/ul; reference range 4.0-10.4x10E3/ul). Elevation of inflammatory biomarkers such as ferritin (median 733ng/ml; reference range 15-150ng/ml), d-dimer (median 0.6 µg/ml; reference range <0.5 µg/ml), interleukin 6 (median 144 pg/ml; reference range <5.9pg/ml), lactate dehydrogenase (median 673U/l; reference range <249U/l) and C-reactive protein (CRP) (median 10.8mg/dl; reference range <0.5mg/dl) was noted in all patients. Beside the inflammatory biomarkers an elevation in serum creatinine (median 2.2md/dl; reference range 0.7-1.2mg/dl) was noted.

The tacrolimus trough level was within the limits (median 12.5ng/ml). The interim presence of anti-SARS-CoV-2 antibodies could be detected in five patients, one patient was not tested. Three patients who expressed anti-SARS-CoV-2-antibodies showed an antibody loss during their inpatient stay. rRT-PCR ct-values and anti-SARS-CoV-2-antibodies are shown in Figure 1 for each patient.

The most frequently associated complication was renal failure (83%), followed by pleural effusion (n=3; 50%). 33% developed bacterial pneumonia and hepatopathy/liver failure each.

Two patients developed cytomegalovirus (CMV) reactivation during the infection, without CMV organ disease.

Besides the positive rRT-PCR the diagnosis was confirmed by HR-CT scan. The course of a mild (patient A; treated in the general ward) and a severe (patient B, admitted to the ICU) infection is pictured in Figure 2 and 3. During the infectious period ground glass opacities were described in at least in one HR-CT scan in all patients each. Four patients had additionally consolidations and interstitial abnormalities, three had pleural effusion.

In the absence of consensus guidelines, treatment was based on individual decisions and dependent on clinical, laboratory and radiological findings. The description of the antiviral and immunomodulatory therapies is shown in Table 2 .

Regarding medical treatment all patients received thromboprophylaxis. Antibiotic therapy was given in 67% (n=4). The basic immunosuppression was not stopped, apart from MMF in case of pronounced leukopenia. Prednisolone was stopped in favour of high dose dexamethasone in 4 patients (67%) for a period of time during the acute infection.

Intravenous pulse prednisolone was prescribed in two patients, as well as IvIg infusion.

Aditionally, in two cases tacrolimus was stopped and cyclosporine was given.

In terms of the specific SARS-CoV-2 treatment, one patient did not received antiviral therapy All patients required respiratory support. Two patients had to be admitted to the ICU where invasive mechanical ventilation was applied. Incidental findings showed a bacterial pneumonia in these two patients. Both patients requiring ICU care had blood type 0. Four patients were treated on the general ward. Survival was 83% (n=5) and median time to discharge was 49 days after initial diagnosis. Due to multiorgan failure and ARDS, patient B died 122 days after the first positive rRT-PCR.

In order to emphasize the variation in severity of the SARS-CoV-2 infection in initially comparable patients, patient A and B of our series were examined more closely (Figure 4 In our study each patient had at least one cardiovascular risk factor, which is associated with significantly increased risk for mortality in COVID-19. Moreover, five of them were male. 20, 21, [33] [34] [35] The woman infected by SARS-CoV-2 had a mild course, and the female patient who initially shared her room did not become infected. Patients with several comorbidities and a general poor preoperative condition showed an extended hospital stay in our study, including one death. Many of the risk factors for a severe course of COVID-19 (defined as admission to ICU) as described in literature were present in our early-phase LTRs infected with SARS-CoV-2. In addition, two LTRs admitted to ICU had clinical and radiological evidence of a bacterial superinfection. Bacterial pneumonia in LTRs with COVID-19 seemed clearly associated with admission to ICU and invasive mechanical ventilation.

Compared to other series without SOT, our patients had a similar incidence of common COVID-19 symptoms 18, 36, 37 . Fewer patients had fever (50%) and more patients developed diarrhoea (83%), which was associated with clostridium difficile in half of the cases. Within our patient collective, the frequency of symptoms correlated with the severity and duration of the course of infection. Radiological findings match those described in literature and correlate with the severity of the course as well as the additional occurrence of superinfections. 38 The duration of the course in our patients was prolonged compared to the general population. 37 Five patients were tested regularly for anti-SARS-CoV-2-antibodies and expressed them at least once during the infection. The detection of antibodies in the patient who died was also recorded after convalescent plasma was given. With three of these five patients (including the patient who died), an antibody loss was detected during the inpatient stay. Figure 1 shows the rRT-PCR ct-values and antibodies in detail for each patient.

Patients A-C were already in hospital treatment, when infection was proven. Due to the fact that the onset of symptoms of patients A-C was delayed and that their antibody formation took significantly longer, we can assume that the other three patients who presented themselves to the emergency room with typical symptoms had already been infected by the coronavirus for a longer period of time and were asymptomatic. That would also explain the faster detection of antibodies and shorter infectiousness compared to patients A-C ( Figure   1 ). It is likely that the course was not shorter, we missed the onset of the disease due to the missing of symptoms and lack of routinely performed tests, because the patients had already been discharged after LT and were already at home.

The difficulty to express anti-SARS-CoV-2-antibodies or their loss in SOT is described in a few cases. 27, 39 Due to our laboratory observations and the fact that the patient who received convalescent plasma also had a loss of antibodies within a short time, it is our opinion that immunosuppression is potentially responsible for the delayed formation of antibodies and their premature loss.

There are currently no specific treatment options for this disease, therefore various therapeutic approaches have been used based on expert opinions. In the asymptomatic period of the infection, we made no changes in medication. Our LTRs received an increased dose, bolus or switch to a more potent corticosteroid as the general condition deteriorated and the respiratory component increased. Calcineurin inhibitor therapy was continued. In patients with pronounced leukopenia, MMF was reduced or suspended. The first three cases received remdesivir at the time of medical deterioration. In the remaining patients it was added prophylactically, assuming it would shorten the time to recovery. 40 This approach seemed to show success in the acute posttransplant period. Other systemic treatments were not broadly used. One patient who developed very severe disease received monoclonal antibodies (bamlanivimab) and convalescent plasma for several times however, he did not recover. He had initial presented with very mild symptoms and his general condition and respiratory state deteriorated rapidly after a long period of mild symptoms. Convalescent plasma and monoclonal antibodies have been described to alter the course of disease.

However, they may aggravate lung injury in patients with multiple organ failure and should be infused early in the course of the disease. [41] [42] [43] However, it is unclear whether the administration of the convalescent plasma and monoclonal antibodies had a positive impact or if it even contributed to clinical deterioration in our patient.

Due to the different courses of the infection in our series, it is difficult to make a statement about the role of immunosuppressive drugs. In our experience, it is justifiable to continue calcineurin inhibitor and metabolic therapy during the infection in early phase after LT, not least to avert early rejection of the organ.

In our series, acute phase lung transplant patients showed a worse prognosis compared to the general population and were clinically similar to other SOT. 27, 29, 36, 44, 45 The following limitations of our study need to be addressed. The study design was retrospective and the size of the cohort does not allow for significant statistical analysis. In addition, we could not ensure, that we had included the entire acute posttransplant patient collective infected by SARS-CoV-2. There might be asymptomatic patients who did not present themselves to the emergency room or who were diagnosed coincidentally.

Moreover, follow-up in the post-COVID period varied between patients and did not include scheduled HR-CT scans and pulmonary function testing.

Contrary to some initial assumptions that immunosuppression might protect from severe disease, COVID-19 does not appear to cause milder disease in LTRs compared to the general population. Patients with several comorbidities and a general poor preoperative condition showed an extended hospital stay. In our series bacterial superinfection in COVID-19 patients is associated with high rates of admission to ICU and invasive mechanical ventilation. Immunosuppression is potentially responsible for the delayed formation of antibodies and their premature loss, which seems to be typical for LTR in the early phase 

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Individual course of a mild infection (Patient A) from lung transplantation to discharge. The diagram is based on a timeline including rRT-PCR ctvalues represented in black dots, which are connected by a trendline. The presence of anti-SARS-CoV-2-antibodies is shown as green Y's, no anti-SARS-CoV-2-antibodies are marked by red Y's. Medical treatment is shown above the curve and symptoms as well as other special events under the curve and on the x-axis. The green background color describes the pre-or post-infection period, red the infection.

Individual course of a severe infection (Patient B) from lung transplantation to death. The diagram is based on a timeline including rRT-PCR ctvalues represents in black dots, which are connected by a trendline. The presence of anti-SARS-CoV-2-antibodies is shown as green Y's, no anti-SARS-CoV-2-antibodies are marked by red Y's. Medical treatment is shown above the curve and symptoms as well as other special events under the curve and on the x-axis. The green background color describes the pre-infection period, red the infection.

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We would like to thank Norbert Zimmermann for his assistance.

0 (0) 1 (25) 1 (20) 0 (0) Double lung, n (%) 6 (100) 2 (100) 4 (100) 5 (100) 1 (100) Intraoperative ECMO, n (%) 4