EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Key words : Antiviral drug therapy, Azithromycin, Chronic allograft dysfunction, Coronavirus 2019, Hyperinflammation, Pneumonia

COVID-19 is rapidly infecting people worldwide, and lung transplant (LTx) recipients are also becoming infected. Currently, acute respiratory distress syndrome (ARDS) remains the leading cause of death.¹ In patients with severe COVID-19 and hyperinflammation, immunomodulators such as corticosteroids might be beneficial against the disease-related cytokine storm.² Nevertheless, an unfavorable risk-benefit balance of corticosteroids in COVID-19-related ARDS was initially suggested.³

In LTx recipients, data on disease presentation and evolution are scarce, and the benefit of high-dose corticosteroids remains uncertain. Here, we report life-threatening COVID-19-related ARDS in 2 LTx recipients who recovered with high-dose corticosteroids that were initiated immediately after ARDS onset.

A 46-year-old male LTx recipient was admitted to hospital in March 2020, for fever and dyspnea. The patient had previously received a double LTx for cystic fibrosis. Graft function at 9 years post-LTx was stable with long-term azithromycin treatment. A lung computed tomography (CT) scan showed bilateral ground-glass opacities (Figure 1), but an initial reverse transcriptase-polymerase chain reaction (RT-PCR) nasopharyngeal swab test for SARS-Cov-2 was negative. A regimen of piperacillin/tazobactam combination (Tazocilline) with spiramycin (Rovamycine) was initiated, and baseline immunosuppression remained unchanged. No antiviral treatment was administered (Table 1). On day 7 after hospitalization, admission to the intensive care unit (ICU) was required in response to progressive decline of respiratory conditions, and mechanical ventilation was started for ARDS, with severe hypoxemia and relatively preserved compliance (Table 1). Bronchoalveolar lavage fluid tested by RT-PCR for SARS-Cov-2 was shown to be positive. Within the next 3 days, the respiratory condition deteriorated despite protective ventilation (fraction of inspired oxygen [F?o₂] = 100%), prone position sessions, and hemodialysis sessions. Hyperinflammation was observed, with an increase in C-reactive protein (273 mg/L). On day 3 after ICU admission, methylprednisolone (2 mg/kg/d) was started after bronchoalveolar lavage fluid culture showed no other infectious agent. Within 3 days after the start of the corticosteroid regimen, chest radiograph findings showed significant improvement (Figure 1) and the ratio of Pao₂ to F?o₂ increased to >250, which allowed the patient to be weaned from mechanical ventilation on day 6. The dosage of methylprednisolone was progressively tapered to the daily maintenance dose (5 mg/d) within a 2-month period. Presently, at 8 months post-ARDS, the patient has no need for supplemental oxygen. Although the CT scan pattern on day 28 showed mild bronchiectasis and subpleural reticulations, the follow-up CT scan showed complete resolution of radiological lesions.

A 49-year-old female LTx recipient was admitted to hospital in April 2020, for fever, dyspnea, and diarrhea. The patient had previously received a double LTx to treat bronchiectasis. Lung function at 8 years post-LTx was stable with long-term azithromycin treatment. A lung CT scan showed ground-glass opacities (Figure 1), and a nasopharyngeal swab tested with RT-PCR was positive for SARS-Cov-2. A regimen of cefotaxime with sulfamethoxazole/trimethoprim (Bactrim) was initiated empirically, and baseline immunosuppression remained unchanged. Hydroxychloroquine was administered (Table 1). The patient was admitted to the ICU to treat rapid deterioration of respiratory conditions within the first 24 hours, and mechanical ventilation was started for COVID-19-related ARDS. The patient’s respiratory condition continued to deteriorate despite protective ventilation (F?o₂ = 100%), prone position sessions, and hemodialysis sessions. Hyperinflammation was observed, with an increase in ferritin to 13?232 ng/mL. On day 5 after initiation of mechanical ventilation, methylprednisolone (2 mg/kg/d) was started after a new bronchoalveolar lavage fluid culture showed no other respiratory pathogens. Within 3 days after the start of the steroid regimen, chest radiograph opacities showed respiratory improvement (Figure 2), and the patient was weaned from mechanical ventilation on day 8 postintubation. The dosage of methylprednisolone was progressively tapered to the daily maintenance dose (5 mg/d) within 2 months. The patient was discharged from the ICU after 1 month but still required partial pressure support ventilation (F?o₂ at 25%) to treat severe ICU-acquired weakness. Respiratory status progressively improved thereafter, with no need for supplemental oxygen at 4 months post-ARDS.

Here, we have reported life-threatening COVID-19-related ARDS in 2 LTx recipients and the efficacy of a regimen of high-dose corticosteroids initiated immediately after ARDS onset. Currently, we still do not know whether COVID-19 is more severe or is mitigated as a result of the effects of immunosuppression on virus replication after LTx.

Our cases highlight the following 3 findings. First, LTx recipients may present with severe COVID-19 that may require mechanical ventilation despite long-term azithromycin treatment, which has been proposed to be protective against the disease.⁴

Second, our results suggest that a regimen of corticosteroids is beneficial for immunomodulation in cases of severe COVID-19 pneumonia with hyperinflammation, which supports a similar hypothesis from a recent study that reported both pulmonary and inflammatory phases in native and immunosuppressed states.² This benefit of corticosteroids was also suggested in nontransplant patients with COVID-19-related ARDS,¹ and the hypothesis of anti-inflammatory effects directed against the cytokine-induced storm was confirmed in a randomized trial.⁵ Our cases of severe COVID-19-related ARDS confirm the potential benefit of corticosteroids as immunomodulators at this inflammatory phase in patients with long-term immunosuppression such as LTx recipients. A recent study has hypothesized that the main site of COVID-19 is the allograft, which is susceptible to a major influx of inflammatory cells.²

To date, the outcomes of COVID-19-related ARDS in LTx recipients with mechanical ventilation in the ICU have been sparsely described,^6-14 either as clinical cases or in a series of LTx or solid-organ transplant recipients. The outcomes were poor in this selected population, with a mortality rate of 75% among identified cases^6-14 (Table 2). Antiviral and immunomodulatory therapies such as high-dose corticosteroids are not well documented for cases of COVID-19-related ARDS, and so no firm conclusions are yet possible regarding the efficacy of corticosteroids in this clinical setting. However, it is notable that high-dose corticosteroids were rarely administered to patients at the beginning of the COVID-19 pandemic; for example, only 1 of 10 patients was treated by steroid pulse in the series reported by Aversa and colleagues.¹⁴ The rarity of this treatment option may be the result of lingering uncertainty regarding the efficacy of high-dose corticosteroids in severe COVID-19 pneumonia during this period.¹⁶

Acute kidney injury, which is considered a marker of disease severity,¹⁷ required repeated hemodialysis sessions in both patients in our case report. In addition, patient 1 exhibited particular features specific to other reported cases of COVID-19-related ARDS, with severe hypoxemia associated with near-normal respiratory compliance.¹⁸

The third important finding in our study was the consistency of the CT pattern compared with early-stage lung fibrosis on day 28 for patient 1, as previously reported for COVID-19 cases. These early CT scan patterns might sometimes progress toward severe fibrosis¹⁹ or completely resolve, as in our patient during subsequent follow-up.

In summary, our findings suggest the possible benefit of an early regimen of high-dose corticosteroids for COVID-19-related ARDS with hyperinflammation in patients with long-term immunosuppression such as LTx recipients. The respective indications of other immunomodulators for severe COVID-19 pneumonia,²⁰ including monoclonal antibodies, remain subject to further evaluation to discover optimal timing of treatment regimens in patients with immunosuppression.

Volume: 19 Issue: 7 July 2021

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