According to the clinical characteristics, coronavirus disease 2019 (COVID-19) can be divided into mild type, common type, severe type, and critical type.[1] Elderly men were demographic most severely affected by COVID-19.[2] Moreover, 173 in 1099 patients with COVID-19 had severe disease, median age was 52 years, 57.8% were male.[3] Pulmonary fibrosis is recognized sequelae of ARDS.[4] Especially, elderly population is more easily to develop viral-induced pulmonary fibrosis due to immunosenescence and with viral infections acting as cofactors.[5] Considering the scale of pandemic, the burden of pulmonary fibrosis secondary SARS-CoV-2 infection is likely to be high.[2] Patients with severe pulmonary fibrosis have lung function inexorably declines, leading to respiratory failure or eventually death and lung transplantation being the only treatment that improves outcomes.[6] We report a critical type COVID-19 patient with extensive pulmonary fibrosis. After 73 days of extracorporeal membrane oxygenation (ECMO) assistance, he finally received double-lung transplantation. He developed Candida parapsilosis infection after operation, but was successfully cured.

A 54-year-old male presented to hospital with muscle soreness and fatigue on January 24, 2020. After 2 days, he showed fever of 39°C and was diagnosed as COVID-19. Although antiviral, antibacterial, and immunomodulatory agents were given for symptomatic and supportive treatment, the disease gradually worsened and dyspnea occurred. Non-invasive ventilation was given on February 5, and tracheal intubation and invasive ventilation were started on February 11, assisted by venovenous ECMO. Although various therapeutic measures have been tried, such as anti-virus, anti-infection, improving immunity, prone position ventilation, and airway cleaning by fiber-optic bronchoscope, the respiratory mechanics of patient suggest that lung compliance cannot be effectively recovered. On March 19, after using 300 ml plasma from convalescent COVID-19 patients, the patient’s SARS-COV-2 nucleic acid test finally turned negative. After passing through several hospitals, the patient came to our hospital on April 11. The physical examination showed body temperature of 36.6°C, heart rate 59 beats per minute, respiratory rate 20 breaths per minute, and blood pressure 141/75 mmHg. After admitted, he was under nasotracheal intubation, ventilator-assisted ventilation, and ECMO-assisted therapy. His left pupil was about 3.0 mm in diameter and the right pupil was about 2.5 m in diameter with obtuse light reflex. Coarse breath sounds can hear in both lungs, with scattered moist rales. His heart rate was normal without pathological murmur. Liver and spleen were not touched. There was a 4 × 5 cm pressure sore in the sacrococcygeal skin with dark purple ulcerated epidermis, and its surface was exudation. The lower limbs were slightly edema, the right side was more obvious.

On laboratory examination, white blood cell count was 10.70 × 109/L, red blood cell count was 2.79 × 1012/L, hemoglobin was 82.00g/L, platelet count was 86.00 × 109/L, lymphocyte count was 1.24 × 109/L, neutrophil count was 8.25 × 109/L, neutrocyte percentage was 77.10%, and lymphocyte percentage was 11.60%. Activated partial thromboplastin time 55.70 S, prothrombin time 16.90 S, and D-dimer 10.85 mg/L, all were increased. Fibrinogen 1.2 g/L was decreased. Blood urea nitrogen 20.61 mmol/L, glucose 8.04 mmol/L, n-terminal pro-brain natriuretic peptide 1719.00 pg/ml, procalcitonin 0.83 ng/ml, and C-reactive protein 283.30 mg/L were increased. Blood culture revealed Candida albicans. Sputum culture showed Acinetobacter baumannii. Common cultures were positive for Burkholderia cepacia.

As a severe COVID-19 patient in rehabilitation period, his manifestations were severe pneumonia (bacterial and fungal mixed infection), acute respiratory distress syndrome (ARDS), pulmonary hypertension, right ventricular dysfunction, right atrial thrombus, pressure sore, liver dysfunction, anemia, and thrombocytopenia. After given anti-infection treatment and symptomatic support treatment, his nucleic acid testing turned negative, but still developed irreversible extensive pulmonary fibrosis. Experts in our hospital have carefully studied the indications of lung transplantation for this patient with COVID-19 and the safe implementation of operation during epidemic. After fully prepared, 73 days after, the patient was assisted by ventilator and ECMO, experts from our hospital successfully performed double-lung transplantation for the patient on April 24. On the 2nd day after operation (April 25), cytomorphological examination of alveolar lavage fluid was carried out from the transplanted lung of the patient. Various types of alveolar macrophages were found and a few cells contained more vacuoles present foam-like. Individual cells contain phagocytic particles (dust cells). Non-specific esterase and periodic acid–Schiff staining showed weakly positive to strongly positive, chloroacetic acid AS-D naphthol esterase staining was weakly positive, and myeloperoxidase staining was negative. The morphology of all kinds of cells was normal [Figure 1].

Figure 1:: Bronchial lavage fluid on the 2nd day after lung transplantation. Different shapes of alveolar macrophages with blood cells (including erythrocytes, lymphocytes, neutrophils, and eosinophils). (a) The size of alveolar macrophages was varied, cytoplasm was moderate to rich, stained light blue to gray-blue, purple-red granules can be seen in some cytoplasm, nuclear chromatin varies in thickness, and nucleolus can be seen in some cells (Wright-Giemsa stain, ×400). (b) Binuclear alveolar macrophages with vacuoles in some cells (Wright-Giemsa stain, ×1000).

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On May 14, 20th day after transplantation, chest radiograph showed a large slice of dense shadow in the middle of the right lung, and ultrasound revealed a little pleural effusion in the right thoracic cavity. On May 15, the patient underwent fiber-optic bronchoscopy, the secretion of the right bronchus was collected for pathogen culture, and the right bronchus anastomosis was brushed for cytological examination [Figure 2]. Besides some ciliated columnar epithelial cells and neutrophils with a few macrophages, a small amount of yeast-like fungal spores were also found, which were confirmed as C. parapsilosis infection by fungal culture. We used ceftazidime, polymyxin B, aztreonam, and voriconazole to resist infection, ganciclovir to prevent cytomegalovirus infection, strengthen oral care, and add amphotericin B and polymyxin E by atomization. Pulmonary physiotherapy and limb rehabilitation were used for the patient and cleaned up respiratory secretions in time. At the same time, it strengthens the symptomatic support treatment, such as protecting gastric mucosa, promoting gastrointestinal motility, regulating intestinal flora, and using enteral nutrition. By May 21, after under double-lung transplantation for 27 days, the patient was able to move and stand independently. Until July 29, 96 days after transplantation, the patient was recovery and discharged from hospital.

Figure 2:: Cytological examination of bronchial brush, 21 days after lung transplantation. There were a few columnar epithelial cells, some neutrophils, a few macrophages and erythrocytes, and a few yeast-like fungal spores. (a) A few columnar cells, some neutrophils, and necrotic components (Wright-Giemsa stain, ×400). (b) Neutrophils, alveolar macrophages and fungal spores, and budding reproduction phenomenon can be seen (Wright-Giemsa stain, ×1000).

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Besides asymptomatic infected persons, COVID-19 patients experienced diverse symptoms, varying from mild upper respiratory tract symptoms to severe ARDS. A study of 50,466 patients with SARS-CoV-2 infection shows that 14.8% of patients developed ARDS.[7] In general, patients with end-stage ARDS post-COVID-19 have extensive hemorrhage and fibrosis.[8] In fatal cases of COVID-19, pulmonary fibrosis is generally present at autopsy.[2] Fibrous stripes were found in 17.5% of COVID-19 patients.[9] The median age of COVID-19 patients present pulmonary fibrosis is 54.0 years, and the median levels of C-reactive protein and interleukin-6 were also higher.[10] Patients with multiple lesions or severe conditions are more prone to fibrosis.[11] Some author used clinical and thin-section computed tomographic (CT) data from patients with COVID-19 to predict the development of pulmonary fibrosis after hospital discharge, and 39% of follow-up patients showed residual fibrosis.[11] Pulmonary fibrosis may become the most serious complication after this epidemic.[12,13]

At present, there is no complete treatment for post-inflammatory pulmonary fibrosis after coronavirus infection. However, some therapies may be considered, as pirfenidone, nintedanib, steroids, spironolactone, fibrinolytic agents, antiviral agents, tocilizumab, etc.[1,2,12,13] Traditional Chinese medicine also has a good therapeutic effect for pulmonary fibrosis.[14] Lung transplantation is the only treatment to improve the prognosis of patients with severe pulmonary fibrosis.[12,15] In our case, the patient suffered severe complication, especially ARDS and extensive pulmonary fibrosis. Although mechanical ventilation and later ECMO were used, the patient’s lung function was irreversibly deteriorated. After full evaluation of the pathological condition of the patient, lung transplantation was regarded as an urgently needed salvage therapy. Therefore, he underwent lung transplantation.

The major complications after lung transplantation are allograft rejection and infection. To improve allograft survival, immunosuppressive drugs are often used for lung transplant recipients to prevent rejection and maintain allograft function. However, it may also increase the risk of opportunistic infections, including invasive fungal disease. The most common pathogens that cause invasive fungal infections after lung transplantation were Aspergillus sp. (44%) and Candida sp. (23%).[16] From a research of 639 cases of invasive candidiasis infected solid organ transplant recipients, the most common species was C. albicans (46.3%) followed by Candida glabrata (24.4%) and C. parapsilosis (8.1%). All-cause mortality at 90 days was 26.5% for all species while Candida tropicalis (44%) and C. parapsilosis (35.2%) were among the highest.[17] Therefore, it is particularly important to prevent fungal infection after lung transplantation. Bronchial brushing is often used to obtain supplementary samples for diagnosing lung cancer,[18,19] but the existence of fungi was often ignored. In our case, the fungi observed in bronchial brushing provide a direct and rapid diagnosis basis for clinic. The COVID-19 patient in our essay was critical type. On the 21st days after double-lung transplantation, yeast-like fungal spores were found from cytomorphological examination of brush specimens by fiber-optic bronchoscope, which was confirmed as C. parapsilosis by fungal culture. He recovered well due to the careful treatment and nursing in our hospital. Until July 29, 96 days after transplantation, the patient was recovery and discharged from hospital.

Pulmonary fibrosis can occur in the advanced stage, rehabilitation stage, and after discharge of COVID-19, and some patients are at risk of developing progressive pulmonary fibrosis. How to prevent and reduce pulmonary fibrosis in COVID-19 patients is an urgent problem to be solved. CT is essential for monitoring to find early fibrosis. Lung transplantation is the only treatment to improve the prognosis of patients with severe pulmonary fibrosis, but it also has a high invasive fungal infection rate which deserves prevention and treatment. Cytomorphological examination and fungal culture of fiber-optic bronchoscope brush specimens are conducive to diagnosing fungal infection. In our case, the patient had C. parapsilosis infection after double-lung transplantation and was successfully cured.