Case Report: Delayed Lung Transplantation With Intraoperative ECMO Support for Herbicide Intoxication-Related Irreversible Pulmonary Fibrosis: Strategy and Outcome

Background: Lung transplantation is recognized as the only therapeutic option for patients who develop irreversible pulmonary fibrosis after herbicide intoxication. Methods: We have collected and presented clinical course and outcome of four patients who received lung transplantation due to paraquat and diquat intoxication from 2018 to 2021. Another patient who received initial lung transplantation due to paraquat intoxication and re-transplantation due to chronic lung allograft dysfunction in 2019, was further reported. Patients were admitted in lung transplantation centers, including the 1st affiliated hospital of Zhengzhou University and Wuxi Lung transplantation center. Previous reported cases from Europe, Canada and China were also summarized as benchmark. Results: During the period from the year of 2018 to 2021, there have been four patients in China, who received lung transplantation due to herbicide intoxication. Median age of the four patients was 37 (IQR 34.5, 39.75) years old. Median time from intoxication to lung transplantation was 27.5 (IQR 27, 30.5) days. Bilateral lung transplantation was performed in three patients, while one single lung transplantation was performed in an urgent listed patient. Extracorporeal Membrane Oxygenation (ECMO) and hemopurification support were used in all patients (100%). Details of the cases with follow-ups were further presented and analyzed. Conclusions: Late timing of bilateral lung transplantation can be performed successfully for pulmonary fibrosis after paraquat or diquat intoxication. The survival of patients with complex perioperative conditions can be achieved with a multidisciplinary team to manage the irreversible effects of intoxication.


INTRODUCTION
The compound 1,1 ′ -dimethyl-4,4 ′ -bipyridinium dichloride, known as paraquat, is a widely used, highly toxic contact herbicide that has been banned in many countries. As no antidotes exist, paraquat causes severe and potentially fatal intoxication (1). Other analogs, such as diquat, demonstrates similar pathological changes to the lungs (2). Paraquat can be taken up by the tissues and cleared by the kidney. High levels of paraquat could still be detected as late as 9 weeks after ingestion (3). The lungs have been recognized as the main target organs that are injured by the active accumulation of paraquat, which results in irreversible pulmonary fibrosis. Respiratory failure has been recognized as the main cause of death in the late phase of paraquat intoxication. The current treatments for patients with paraquat poisoning are mostly empirical and supportive, such as early gastric lavage to prevent absorption, emesis induction to promote excretion, laxative administration, and hemoperfusion for detoxification, together with the administration of antioxidants, immunosuppressive agents and even mesenchymal stem cells (4)(5)(6)(7)(8).
Since the lung transplantation technique was established, reports have shown that patients suffering from paraquat intoxication could receive lung transplantation as a salvage therapy after exhausting all existing therapeutic regimens (1,9). Progressive lung damage has been demonstrated without any doubt. Time for considering lung transplantation referral and evaluation, as well as the perioperative support strategy, were discussed in published cases. Here, we summarized the cases performed in China, as well as in the European and North American centers (1968-2017), serving as a useful reference for clinicians in the future.

Study Design and Data Collection
We retrospectively analyzed the medical records of patients from the 1 st affiliated hospital of Zhengzhou University (Case 1-4), Wuxi Lung transplantation center and Beijing Chaoyang Hospital (Case 5), submitted to lung transplantation due to herbicide-induced-lung fibrosis or re-transplantation, between 2018 and 2021. Information collected from all patients included demographic data, surgical details, and follow-up data. Another case was admitted and treated in the 1 st hospital of Guangzhou Medical University, while detailed data has been reported by Jiang et al. (10). Early cases reported with detailed data from Edinburgh, Toronto and Geneva were also summarized and benchmarked to demonstrate the transition of therapeutic strategy on transplantation timing and perioperative support. Summary of cases are shown in Table 1. Continuous data with normal distributions are presented as median with interquartile ranges.

Ethics
The Institutional Ethics Committees of all centers involved in this study approved the procedures, including verbal consent procedures and data collection. Written informed consent was obtained from the patients and next of kin. The transplanted organs were obtained from volunteer donations, and the next of kin voluntarily provided written informed consent. No lungs were obtained from executed prisoners.

Perioperative Assessment and Perioperative Management
Preoperative investigations included lab tests, lung function evaluation, functional assessment of other vital organs, and anesthetic evaluation. Preoperative chest X-ray or computed tomography (CT) examinations did not reveal any pulmonary infections or other pulmonary diseases among the donors with PaO 2 /FiO 2 (P/F) >300 mmHg.
Patients received gastric lavage, antioxidants, immunosuppressive agents, hemopurification as conservative therapy. However, bilateral lung fibrosis still progressed as shown in chest imaging (Figures 1.1-4A). Patients had progressively worsening dyspnea and low P/F ratio. Continuous renal replacement therapy, hemoperfusion or hemodialysis was performed due to acute kidney injury in most cases per admitted centers' protocols. Although patients could be stabilized on liver and renal function, while paraquat was not detected in urine, patients could not be weaned from intubation and pulmonary fibrosis progressed. Lung transplantation was thus performed for these patients.
Postoperatively, all patients were admitted in ICU. The immunosuppressive drugs administered included mycophenolate mofetil, tacrolimus, and prednisone. All patients received prophylactic antimicrobial and antiviral medications to prevent bacterial, fungal, and viral infections. Postoperative blood examinations, chest radiography, and bronchoscopy were performed per routine institutional protocol.    presented in Supplementary Table 1. In addition, we presented the long-term follow-up of another case (Case 5) who received initial lung transplantation due to paraquat intoxication and re-transplantation due to chronic lung allograft dysfunction. Multiple perioperative complications occurred in these patients. Case 1 developed deep vein thrombosis on postoperative day 2 (POD2) and an inferior vena cava filter was implanted. Acute pancreatitis was diagnosed on POD14 after initiating oral feeding. After receiving conservative therapy as per institutional protocol, patient's status was stabilized and recovered on POD39 and discharged. During the routine follow-up, on POD61, bilateral bronchial stenosis in the proximal termino-terminal bronchial anastomosis was observed. Cryosurgery under bronchoscopy was performed on POD 64, POD67 and POD101 under general anesthesia. Case 4 also experienced bronchial stenosis and was treated by cryosurgery under bronchoscopy. These patients survived to date with improved respiratory symptoms and no obvious lung abnormalities on CT images (Figures 1.1B, 4B). In Case 2, episodes of infection occurred and fully resolved 1 month after lung transplantation. Hemodialysis was continued up to 4 months after surgery. Upon follow-up, patient has fully recovered renal function and pulmonary imaging was normal (Figure 1.2B). All these three cases have been regularly followed up in lung transplantation clinics. They survived and returned to work.

RESULTS AND CASE PRESENTATION
Emergent V-A ECMO support for acute respiratory distress syndrome as bridging to lung transplantation was performed in Case 3. Urgent single lung transplantation was performed under V-AV ECMO to improve oxygenation. Mode of ECMO support was transited to V-V ECMO support post-lung transplantation. Cardiac arrhythmia and grade 3 primary graft dysfunction occurred sequentially and could not be wean-off ECMO (Figure 1.3B). Patient died on POD12 due to sepsis caused by multi-drug resistant organisms' infection.
From the perspective of long-term outcome, Case 5 had bilateral lung transplantation in the year of 2014 and survived up to 5 years post-lung transplantation. The clinical course of her 1 st lung transplantation has been reported previously in detail (11). Patient had progressively worsening dyspnea and headache from the 4 th year after surgery. Significant elevation of pulmonary artery pressure (40 mmHg) was detected. Pseudomonas aeruginosa was cultured from sputum. Lung function showed FEV1 0.48 L and FVC 1.19L with deteriorating chest imaging of chronic lung allograft dysfunction (Figure 1.5A). Bilateral lung transplantation was performed and postoperative recovery period was uneventful (Figure 1.5B). Follow-up lung function showed FEV1 1.9 L, FVC 2.29 L.

DISCUSSION
Paraquat was introduced to the market as an herbicide in 1962 (12). Diquat is recognized as the second widely used herbicide in the world (13). Over the last few decades, numerous paraquat intoxication cases have been reported, mainly caused by accidental or voluntary ingestion or extensive skin contamination. Much fewer cases of diquat intoxication have been reported in the literature than those of paraquat poisoning, thus, clinicians are still warranted to give attention to its high mortality rate. Due to the abundant polyamine transport systems of type I and II alveolar cells and Clara cells, the lungs are believed to be the main target organ of paraquat poisoning. Paraquat that has accumulated in the lungs and muscle remains even after it is no longer present in blood or urine (14). Mechanism of diquat toxicity is also related to oxidative stress and cell death, aggravating the damage of lungs and kidneys (15).
Respiratory symptoms after intoxication vary from no manifestations to severe shortness of breath, leading to death within as short as 24 h but typically within 2-4 weeks. Treatment strategy for herbicide intoxication, includes gastric lavage, antioxidant therapy, hemoperfusion and hemodialysis as well as immunosuppressive agents. All our patients received the treatments listed above, bilateral pulmonary fibrosis still progressed to the irreversible stage and acute respiratory distress syndrome manifested. All the cases performed in China after 2017 had access to more life support strategies, such as hemopurification and ECMO, which could be used to support organ function and bridge to transplant.
Early cases reported in Europe and Toronto had high mortality rate before 1997 (3,9,16,17). Apart from lack of lifesupport modalities, single lung transplantation was performed in most cases. All those patients received transplantation within 1 month after intoxication, paraquat could be detected in the blood and death was unavoidable in short term. Toronto team tried secondary contralateral lung transplantation after the initial graft failed. Having been the pioneer of lung transplantation in the world, Toronto team has performed prolonged ECMO support and trachea-innominate artery fistula was well-detected and managed. Death still occurred due to massive cerebral infarction, which is also recognized as the most fatal complication of ECMO.
The case reported by Geneva team after 1997 achieved long-term survival success (3,17). Single lung transplantation was performed, however, the time for transplantation was delayed to 44 th day, beyond 1 month after intoxication. Toxic neuromyopathy still existed while hemodialysis continued post-lung transplantation. The patient recovered and survived for over 1 year as reported. This case was the first to demonstrate that late timing of lung transplantation could benefit patients on long-term survival. In our report, patients received lung transplantation after 1 month from intoxication. Further, bilateral lung transplantation was performed in most cases. Only Case 3 received single lung transplantation in an urgent manner and did not survive. Thus, late timing of bilateral lung transplantation might be critical for saving these patients' lives.
Like in other end-stage pulmonary fibrosis patients, ECMO is crucial for intraoperative lung transplantation support and bridging to urgent lung transplantation. While combining with the treatment of hemopurification, more herbicide could be cleared, thus ensuring the long-term benefit for postlung transplantation survival. In addition, immunosuppressive drugs are also effective for transplantation as well as the intoxication. Poison was not detected in the explanted lungs of our cases. Pathology examination showed extensive effusions, inflammation and congestion in all the intoxicated lungs (Figure 3).
Long-term follow-up for these patients is mandated to ensure life quality as they received transplantation in their middle ages. Some of the patients may have unstable emotion before intoxication or even experienced suicidal tendencies. After we evaluated their psychological status thoroughly, we determined to list them as lung transplantation candidates. Close cooperation between doctors and patients is of key importance for maintenance of long-term graft function. The Case 5 patient is a famous singer in China. After re-transplantation, doctors encouraged the patient to continue vocal training and the patient went back to performing on stage. All the patients who were transplanted and survived cherished their lives, continued treatment and followed up regularly in outpatient clinics.
Our experience of successfully treating these patients highlights the efficacy of multi-disciplinary approaches in such complicated scenarios, which could guide clinical practice and inspire the management of these patients who wish to live. Patients after herbicide intoxication showed rapid progression of irreversible pulmonary fibrosis and even acute respiratory distress syndrome. When considering lung transplantation referral timing and strategy, bilateral lung transplantation after 1 month of intoxication with hemopurification and ECMO support will be crucial for long-term survival. These patients warrant physical and psychological rehabilitation during followup. Potential intrinsic correlations between poisonous effects and post-operative complications must be explored to further improve quality of life.

DATA AVAILABILITY STATEMENT
The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author/s.