EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Key words : Acute kidney injury, Coronavirus, Encephalopathy, Graft-versus-host disease, Immunosuppression, Thrombotic microangiopath

Coronaviruses belong to a large family of viruses that cause illness that ranges from upper respiratory infection (eg, to resemble a common cold) to severe respiratory disease.¹ A novel virus was first reported in Wuhan, Hubei Province, China, on December 26, 2019.² The COVID-19 virus is one of the RNA betacoronaviruses that has crossed over from animals, mostly bats, into humans. COVID-19 has spread rapidly from human to human, causing a pandemic around the world.1 Many reports demonstrated that the severity of COVID-19 in children is less than in adults.^1,3 However, those children with underlying disease are more likely to develop a serious infection and life-threatening complications.^4,5 The clinical effects of COVID-19 on immunosuppressed patients, particularly hematopoietic stem cell transplant (HSCT) recipients, are unknown because of the few number of cases.⁶ There are concerns for severe systemic disease in this population, given their immunocompromised state, alloreactivity, and other medical comorbidities.⁶ Therefore, here we share our experience of 4 confirmed cases in pediatric HSCT recipients who were hospitalized in the Children’s Medical Center at the Tehran University of Medical Sciences.

By August 30, 2020, we confirmed 4 cases of COVID-19 among pediatric HSCT recipients by real-time polymerase chain reaction (RT-PCR) test of SARS-CoV-2 in respiratory tract samples. Transplant characteristics, laboratory tests, and treatment are summarized in Table 1, Table 2, and Table 3, respectively.

Patient 1
A 10-year-old girl with acute myeloid leukemia presented with fever (40 °C), chill, cough, and headache on day +18. Two days later, she developed generalized tonic-clonic seizures that lasted for 2 minutes. There was no previous history of seizure. Clinically, there was no neck stiffness or focal neurological deficit. Brain computed tomography (CT) scan ruled out intracranial hemorrhage. There were no specific findings in brain magnetic resonance imaging. After 24 hours, she developed increased frequency and severity of cough with dyspnea and wheezing on auscultation. Arterial oxygen saturation was 95%, and she did not need oxygen therapy. Chest CT scan showed patchy consolidation with halo signs in both lungs (Figure 1). Real-time polymerase chain reaction test for SARS-CoV-2 was positive. The fever stopped 4 days after treatment. No other seizure occurred. The patient was discharged in a stable clinical condition after 10 days. She remained in good condition 3 months after discharge, but then she developed liver graft-versus-host disease (GVHD). At the time of this writing, she was at 6 months posttransplant under multiple immunosuppressive drugs.

Patient 2
A 3-year-old boy with severe aplastic anemia at 15 months posttransplant presented to the emergency department with high-grade fever, chill, tachypnea, and cough. His condition worsened with time. Blood oxygen saturation level dropped below 85% and required admission to the intensive care unit (ICU), and he was started on oxygen supplement with a noninvasive ventilator. Chest CT scan showed bilateral patchy consolidations (Figure 2). His recent history revealed exposure to a household with diagnosed COVID-19 infection. Real-time polymerase chain reaction test for SARS-CoV-2 was positive on the nasopharyngeal swab. Although antiviral therapy was initiated (Table 3), his respiratory distress deteriorated over the course of 25 days and required endotracheal intubation. A new CT scan showed bilateral atelectasis (Figure 2). A bronchoalveolar lavage specimen showed negative results for bacterial and fungal cultures but remained positive for COVID-19. A course of ribavirin was started. Although he underwent extubation and 2 consecutive bronchoalveolar lavage swabs were negative for SARS-CoV-2, dyspnea was still present. He was transferred from the ICU but remained at the hospital under oxygen therapy until he was discharged 74 days after admission. At the time of this writing, 2 months after discharge, he had pulmonary hypertension and mild cardiomegaly under captopril, acetazolamide, and intermittent oxygen supplement.

Patient 3
A 4-year old boy with X-linked lymph proliferative disease was in treatment for skin GVHD when he was admitted for treatment of severe diarrhea and rectorrhagia on day 32 posttransplant. Mycophenolate mofetil was added to control the symptoms. After 5 days of hospitalization, he developed cough, shortness of breath, and wheezing with no fever. Hypoxia developed later and required noninvasive ventilation. A lung CT scan revealed bilateral pneumonia (Figure 3). Real-time polymerase chain reaction assay on nasopharyngeal swab confirmed COVID-19 infection. The initial sepsis workup was negative. Although the tests for SARS-CoV-2 were negative in 3 consecutive swabs, the clinical condition of the patient continued to worsen. Noninvasive ventilation failed to maintain adequate oxygenation, and intubation was indicated. A new chest CT scan revealed cavitation lesions (Figure 3). Blood culture and bronchoalveolar lavage cultures showed resistant Pseudomonas infection. Although broad-spectrum antibiotics and antifungals were given to this patient (Table 3), there was no significant clinical or radiological improvement. He underwent unsuccessful attempts for extubation and remained intubated for more than 1 month. Finally, he died as a result of refractory hypercarbia and uncontrolled hypoxemia after 46 days of hospitalization.

Patient 4
A 7-year-old boy with Fanconi anemia was admitted on day 24 posttransplant for treatment of acute skin and gastrointestinal (GI) GVHD. Intravenous methylprednisolone was administered. The skin manifestation improved, whereas GI symptoms did not improve, and severe rectorrhagia ensued. Therefore, mycophenolate mofetil was initiated. Three days later, he suddenly developed myoclonic jerks in the eyelid followed by altered mental status and abnormal vision with hallucinations. There was no history of seizures. The neurological examination showed a focal deficit. An urgent brain CT scan showed intracranial hemorrhage. Magnetic resonance imaging revealed extensive signal changes in white matter in favor of meningoencephalitis or posterior reversible encephalopathy syndrome (Figure 4). Cerebrospinal fluid analysis was normal. A PCR panel virus screen for encephalitis in cerebrospinal fluid was negative, as were fungal and bacterial cultures. He was intubated and admitted to the ICU to mitigate a low level of consciousness. Although a chest radiograph ruled out pneumonia, a nasopharyngeal swab was performed because there appeared to be no other possible reason for his situation, and the tested swab was positive for SARS-CoV-2. Three days later, laboratory studies demonstrated a rapid drop in hemoglobin level and platelet count, as well as schistocytes on peripheral blood smear with a high level of D-dimer and lactate dehydrogenase, followed by acute kidney injury (Table 2). Low C3 level (68 mg/dL; normal, 88-155 mg/dL) and C4 at the lower reference limit (13 mg/dL; normal,12-32 mg/dL) were also reported. Peritoneal dialysis was planned. However, the neurologic condition dramatically deteriorated to brainstem death. He died within 17 days of admission.

As of August 30, 2020, the COVID-19 pandemic has caused 371 816 cases and 21 359 deaths in Iran.7 Until this date, we reported 4 cases among pediatric HSCT recipients at Children’s Medical Center, which represented an incidence of 4.2% of total pediatric HSCT performed annually. This number is relatively small compared with the actual number of patients who are usually admitted to the hospital and visit the clinic. This is probably because HSCT patients are well cared for according to recommendations for rigorous hygiene and limited socialization, which may contribute to the HSCT patients’ relatively low vulnerability to pathogens and social exposure. These conditions may also explain the negative history of exposure in most patients, which impedes the determination of the incubation period.

Our patients were 3 boys and 1 girl with a median age of 6 years (range, 3-10 years). Two patients presented with fever. Three patients presented with lower respiratory tract symptoms. Two patients had seizures. One patient developed severe encephalopathy with no fever or pulmonary involvement. Presentation with extrapulmonary symptoms has been reported in atypical cases, which has led to underdiagnosis of COVID-19, especially in immunocompromised patients.⁸ The neuroinvasive propensity of COVID-19 has been attributed to immune-mediated central nervous system injury and the ability of the virus to penetrate the glial, neural, and microvascular endothelial cells, which may cause hemorrhagic necrotizing encephalopathy, acute disseminated encephalomyelitis, or demyelination.⁹ Acute kidney injury also has been observed in cases of COVID-19 as an extrapulmonary complication.⁹ Banerjee and colleagues reported a case of a 67-year-old woman with COVID-19 who, after a kidney transplant, developed acute kidney injury and a marked increase in D-dimer and lactate dehydrogenase without evidence of a thromboembolic event, which suggested microvascular thrombosis. She died within 12 days as a result of possible ischemia in the gut.⁹ Similarly, laboratory results for our patient 4 indicated microangiopathic anemia and coagulopathy coincident with low C3, acute kidney injury, and neurologic impairment. This picture is most compatible with transplant-associated thrombotic microangiopathy, which is endothelial damage by circulating cytokines and is caused by multiple factors such as GVHD, calcineurin inhibitors, and active infections, and may lead to activation of the coagulation pathway and complement system.⁹ This suggests that COVID-19 may directly or indirectly affect endothelial cells and may trigger severe transplant-associated thrombotic microangiopathy. COVID-19 has been detected in children’s feces with prolonged virus shedding, which suggests that the gut is the other viral replication site.³ Remarkably, we realized that 2 patients experienced severe rectorrhagia when they became infected with COVID-19, which was likely related to GI GVHD. However, the possible involvement of the virus on both endothelial cell damage of the GI tract and the increase in the severity of GI GVHD is not excluded. It is important to note that COVID-19 may increase cytokines and chemokines such as tumor necrosis factor α and interleukins 2R, 8, 6, and 10 and may lead to exhaustion of regulatory T cells, which play an essential role in regulation of immune responses, all of which may result in an uncontrolled cytokine storm and aggravated tissue damage.^5,10 However, GVHD is known to be caused by a reaction between donor T cells against host tissues mediated by interleukins and proinflammatory cytokines and may lead to donor T-cell activation, which subsequently differentiate and stimulate cytotoxic T lymphocytes and natural killer cells that mediate tissue damage. This also leads to consumption of regulatory T cells, which may cause an excessive inflammatory response in critical cases.¹¹ Therefore, the participation of GVHD to disturb the internal environment may indicate that it is a high-risk factor for severe inflammation and comprehensive damage in the COVID-19 infection; this, in turn, may explain the severity of disease in 3 patients who were diagnosed with active GVHD. These 3 patients required ICU admission and a longer hospital duration even after negative swabs. In contrast, patient 1, who had no GVHD, recovered and was discharged after 10 days without complications.

All patients in this report received symptomatic and respiratory support with broad-spectrum antibiotics and antifungal agents; despite this treatment, 3 patients developed cytomegalovirus reactivation and 1 died with a bacterial infection. Simultaneous coinfection with 2 or more pathogens has been reported in about 40% of pediatric patients without underlying disease by Xia and colleagues.¹² Hematopoietic stem cell transplant recipients receive immunosuppressive drugs that impair their immune response and make them more vulnerable to opportunistic infections.¹³ Vicent and colleagues reported that high immunodeficiency score and low CD4/CD8 ratio are associated with severe illness in pediatric HSCT recipients.¹⁴ Reports have shown that severity of COVID-19 disease is associated with lymphopenia, particularly reduction and impairment of CD4+ T cells.^7,10 It is well known that the mechanism of immunosuppressives used for prophylaxis and treatment of GVHD is inhibition of T-cell activation at various phases of proliferation and differentiation.¹¹

Reduction or cessation of immunosuppressive drugs for kidney transplant recipients has been mentioned in previous studies.^9,13,15 Banerjee and colleagues advised cessation of antiproliferative agents and continuance of steroid therapy to better mitigate the risk of rejection.⁹ Zhu and colleagues reported a successful recovery in a 52-year-old man after discontinuance of the immunosuppressive regimen, which was replaced with a low dose of methylprednisolone; they concluded that this action may reduce the complications of COVID-19.¹⁵ However, this strategy did not improve the symptoms in 2 patients who developed advanced stage of COVID-19 and died with a bacterial infection.¹³ Importantly, in HSCT recipients, a reduction of immunosuppression is often not feasible, especially with active GVHD.¹³ The decision for change or continuance of the treatment is challenging, and this should be considered on a case-by-case basis, with attention to the risks versus benefits.⁹

According to our data, there is a high risk of severe effects from COVID-19 among HSCT pediatric patients, and this risk is associated with long-term hospitalization and complications. Active GVHD, coinfections, and long-term use of immunosuppressive agents may be risk factors for poor outcomes. However, the pathophysiology is still not completely understood. The diagnosis of COVID-19 is not sufficient to assess the overall risk to HSCT pediatric patients, and the contribution of other factors should be considered. More research is needed to discover the comprehensive effect of COVID-19 on HSCT recipients.

Volume: 19 Issue: 5 May 2021

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