EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Key words : Acute rejection, Coronavirus disease 2019, Severe acute respiratory syndrome coronavirus 2, Solid-organ transplantation

COVID-19 caused by SARS-CoV-2 was declared a pandemic by the World Health Organization on March 11, 2020.¹ By the end of 2020, there were 72.8 million confirmed coronavirus cases globally, of which 1.6 million resulted in death.² The pandemic has affected the entire world for more than a year. SARS-CoV-2 is highly contagious through droplets and aerosols. The course of the disease in solid-organ transplant (SOT) recipients is unknown, for which no specific antiviral therapy is yet available. There is not sufficient literature regarding the course of SARS-CoV-2 infection, whose target organ is lung, especially in lung transplant recipients, who receive higher doses of immunosuppression therapy than other SOT recipients because of the higher rejection risk.³ There is no publication in the English literature regarding the development of acute cellular rejection or rapid chronic lung allograft dysfunction (CLAD) after COVID-19 in lung transplant recipients. In this case report, we presented a rapidly developing CLAD case after COVID-19 in a patient who underwent bilateral sequential lung transplant 60 months ago.

A 56-year-old male patient who underwent bilateral sequential lung transplant 60 months ago to resolve chronic obstructive pulmonary disease presented to our clinic with cough and dyspnea complaints. He was in treatment with tacrolimus, everolimus, mycophenolate mofetil (MMF), and steroids for immunosuppressive therapy. The patient’s body temperature was 36.1 °C, the oxygen saturation was 87% at room air, and the pulse was 93 beats/min. Bilateral heterogeneous opacities were observed in the upper zones in the posteroanterior chest radiography of the patient, with bilateral rales detected in the respiratory examination. Blood test results are given in Table 1. Blood, throat, and sputum cultures were taken from the patient. The SARS-CoV-2 reverse transcription-polymerase chain reaction (RT-PCR) test was performed with nasopharynx, oropharynx, conjunctiva, and rectal swabs, and results were negative. Empirical antibiotic therapy was initiated for the patient. SARS-CoV-2-specific antiviral therapy was not started because the potential side effects were unknown during that early stage of the pandemic. Computed tomography (CT) examination revealed patched ground-glass opacities in bilateral upper lobes (Figure 1a). In the clinical follow-up, SARS-CoV-2 RT-PCR tests were performed from the daily nasopharyngeal swab, and the results were negative. Because the patient had a fever of 38.7 °C and no regression in his complaints on the fourth day of hospitalization, fiberoptic bronchoscopy was performed for differential diagnosis, with personal protective equipment (goggles, N95 mask, protective coveralls, gloves, shoe covers) provided to the bronchoscopy team. Bronchoalveolar lavage (BAL) and transbronchial lung biopsy (TBB) were performed from the right upper lobe. Bacterial-fungal culture, acid-fast bacillus test, aspergillus PCR, respiratory viral panel test, and SARS-CoV-2 RT-PCR tests were studied from BAL fluid.

The SARS-CoV-2 RT-PCR test in BAL fluid showed a positive result, and the patient was administered favipiravir (2 × 1600 mg followed by a loading dose of 2 × 600 mg) and hydroxychloroquine (2 × 200 mg) according to the recommendations of the Scientific Committee of the Ministry of Health. Favipiravir and hydroxychloroquine were administered for 5 days.⁴ The patient, whose dyspnea regressed, was discharged on day 17 of his hospitalization after 2 negative SARS-CoV-2 RT-PCR tests performed twice with an interval of 48 hours.

Pathology examination of the TBB sample showed diffuse alveolar damage. High-density CD3⁺ lymphocyte and eosinophil infiltration in the interstitium, fibrin clusters in the alveoli, and lymphocytic endotheliitis were observed. An increase in collagen-rich connective tissue was detected in the subpleural space and septa (Figure 2a). These pathology findings were differentiated from acute cellular rejection by the diffuse distribution of CD3⁺ lymphocytes, not peribronchial and perivascular. Therefore, the pathology was compatible with lung findings reported for COVID-19.

In a clinical follow-up 2 weeks later, it was observed that the patient’s dyspnea complaint increased. A 6-minute walk test (6 MWT) was performed to evaluate the patient’s exercise capacity. The test was terminated at the fourth minute because of oxygen desaturation (So² <80%), and the patient was able to walk 250 m. Reticular densities persisted on posteroanterior chest radiography. In control thoracic CT, the ground-glass opacities in the upper lobes of both lungs decreased, but septal thickening in fibrotic pattern occurred in both upper and lower lobes. The TBB was repeated, and the SARS-CoV-2 RT-PCR test was performed from the BAL sample and was negative. Pathology evaluation showed diffuse alveolar damage and fibrosis findings in the interstitium increased, and CD3⁺ lymphocyte infiltration developed in the perivascular and peribronchial mucosa (Figure 2b). According to the International Society for Heart and Lung Transplantation (ISHLT) pathology working group recommendations, the pathology findings were consistent with A1B1 acute cellular rejection.⁵

Pulse steroid therapy (methylprednisolone, 3 × 1000 mg/d + 1 mg/kg/d, reduced to a maintenance dose in 2 weeks) was administered to the patient. Azithromycin treatment was also administered as a CLAD prevention strategy in line with the recommendation of the ISHLT CLAD consensus report (1 × 500 mg for the first 7 days, then 1 × 250 mg, 3/7 days).⁶ Clinical improvement was observed in the patient after the third day of pulse steroid therapy. One week later, he completed 6 MWT without desaturation and walked 510 m.

At the third month of follow-up, the patient demonstrated exercise dyspnea. Septal thickening had progressed, as shown in thorax CT examination (Figure 1b), and there was a significant decrease in 6 MWT (330 m). Forced expiratory volume in 1 second (FEV1) in the pulmonary function test at the third month after infection decreased from the best FEV1 value of 2.77 L (83%) (before infection, 2.47 L [75%]) to 0.92 L (28%). Forced vital capacity value decreased from 3.31 L (80%) (before infection, 3.23 L [79%]) to 1.64 L (41%). This was accepted as CLAD stage 4 according to the ISHLT CLAD consensus report because it had been 67% lower than the baseline best FEV1 value since this date.⁶

The patient was followed-up 7 months after the SARS-CoV-2 infection. At that time, his exercise dyspnea persisted. Signs of fibrosis accompanied by septal thickening continued on CT (Figure 2c), and the final 6 MWT was terminated in 3.5 minutes because of oxygen desaturation (So2 <80%) after the patient had walked 210 m. It was seen that FEV1 decreased to 0.71 L (22%) and that the forced vital capacity value decreased to 1.40 L (35%) in the control pulmonary function test at month 7 after the infection. As of this writing, the CT and pulmonary function test results were shown to be compatible with CLAD stage 4, according to the ISHLT CLAD consensus report.^6,7

In contrast to the early period of the pandemic, large case series of SARS-CoV-2 infection are now frequently encountered in patients who have undergone SOT.^8,9 Early publications that claimed prognosis of COVID-19 was worse in SOT recipients caused controversy with regard to the appropriate immunosuppressive treatment strategy in this patient group.¹⁰ Some argue that reduction or temporary discontinuance of the immunosuppressant drug doses would facilitate the patient’s immune response against SARS-CoV-2. Those who argue that immunosuppressant drugs should be used suggest that this will prevent a cytokine storm.¹¹ The ISHLT recommended discontinuation of only MMF from immunosuppressant therapy.¹² In our case, previously the dose of tacrolimus was decreased to mitigate an increase in creatinine values, and a mammalian target of the rapamycin inhibitor, everolimus, was added to the treatment. The immunosuppressive therapy included tacrolimus, everolimus, MMF, and steroids. The MMF was discontinued, to follow the ISHLT recommendations, and other immunosuppressive drugs were continued.

The course of COVID-19 in lung transplant patients can be variable. Lung transplant recipients are more vulnerable to SARS-CoV-2 infection than other SOT recipients. Coll and colleagues reported that the mortality risk for lung transplant patients was 2.5 times higher than for other SOT patients.⁸ Messika and colleagues reported 14% mortality in a lung transplant patient group with COVID-19.⁹ Although the number of cases reported in these publications is not high, it is seen that the morbidity and mortality rates of lung transplant patients are much higher than rates in the general population. Although SARS-CoV-2 infection does not show a severe clinical course in lung recipients, it can cause serious morbidities such as acute cellular rejection and subsequent CLAD. In accordance with the current treatment guidelines, the first TBB result obtained from our patient, who was initiated on favipiravir and hydroxychloroquine treatment,
was reported as diffuse alveolar damage, CD3⁺ lymphocyte and eosinophil infiltration, fibrin clumps in the alveoli, and lymphocytic endotheliitis. The findings were interpreted in accordance with lung damage shown in autopsies of patients who died from COVID-19.¹³ Acute rejection was not considered, because CD3+ lymphocytes did not demonstrate perivascular or peribronchial infiltration.

Follow-up visits in our patient showed perivascular and peribronchial CD3⁺ lymphocyte infiltration compatible with acute rejection (A1B1), and pulse steroid therapy was administered to the patient. After a short period of clinical regression, the patient’s symptoms increased again. In the thoracic CT performed 3 months later, an increase in fibrotic septal thickening was observed (Figure 1b). Some published studies have reported the effects of viral infections on the CLAD process.¹⁴ Our patient was a lung transplant recipient infected with SARS-CoV-2 who had mild symptoms during the disease process but then developed acute cellular rejection and rapidly progressed to CLAD despite pulse steroid therapy. Therefore, our present report is vital because it contains evidence that COVID-19 triggers both acute cellular rejection and CLAD.

The clinical course of COVID-19 may be variable, and a possible severe long-term effect on lung transplant recipients may be the initiation or acceleration of the CLAD process. Recipients who recovered from COVID-19 should be carefully examined in terms of both acute rejection attacks and CLAD in their subsequent follow-ups.
Further studies are needed to understand the recipients for whom the disease may be severe, to determine the anti-inflammatory treatment regimen that can control the disease course, and to achieve the best prognosis by prevention of CLAD in recipients.

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