Treatment and outcomes of pediatric patients with cancer and COVID-19 at MAHAK pediatric cancer treatment and research center, Tehran, Iran

The COVID-19 pandemic has been particularly devastating for Iran. Children with cancer are generally immunosuppressed and especially vulnerable to SARS-CoV-2 infections. We report the treatment and outcomes of pediatric oncology patients with COVID-19 at the MAHAK Pediatric Cancer Treatment and Research Center (MPCTRC) in Tehran. We enrolled pediatric oncology patients who experienced SARS-CoV-2 infections from March 18, 2020, to January 28, 2021. The COVID-19 diagnostic criteria at MPCTRC were based on imaging and clinical presentation because of specific challenges diagnosing SARS-CoV-2 infections with molecular testing, which was locally developed and conducted at centers other than MPCTRC. We enrolled nine outpatients and eight inpatients (mean age = 9 years), seven of whom had a diagnosis of leukemias, and five who had brain tumors. COVID-19 symptoms were mild in fourteen patients, and three patients were asymptomatic. Of twelve patients who received molecular testing for SARS-CoV-2 infection, eight were negative and four were positive. Of nine patients tested for IgG and IgM antibodies, one was positive. Three patients died of COVID-19, all of whom were hospitalized. Mild COVID-19 symptoms did not appear to affect the outcomes of the pediatric patients with cancer who received treatment at MPCTRC during the study period.


Introduction
Sudden acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID- 19), introduced an important public health threat in the world beginning in 2019 [1] . Originating from Wuhan, China [2] , SARS-CoV-2 can easily transmit from person to person [3] . Initial reports suggested that COVID-19 is uncommon in children [ 1 , 4-6 ]. In April 2020, however, She et al. reported a precipitous increase in the number of children infected with SARS-CoV-2 [7] . The virus primarily targets the respiratory system, which can lead to pneumonia [8] . The clinical features of children with COVID-19 are similar to those of adults but are generally milder [9] . From March 7 to March 30, 2020, SARS-CoV-2 infections were diagnosed in thirty-five children at Tehran University of Medical Sciences. Of these children, 22 were boys, and their median age was 7.5 years (range, 4 months to 15 years old). Of these 35 pediatric COVID-19 cases in Tehran, 29 resulted from family exposure to SARS-CoV-2. Nearly 86% of patients received oseltamivir, and 63% were administered hydroxychloroquine. In addition, many patients received azithromycin, cefotaxime, and/or ceftriaxone [10] .
Patients with cancer have a higher risk of morbidity and mortality than does the rest of the population because of their compromised immune status secondary to cancer or its treatment [11][12][13][14] . However, no reports of Iranian pediatric patients with cancer who experienced SARS-CoV-2 infections have been published. Therefore, we evaluated the characteristics and follow-up care of pediatric oncology patients with COVID-19 who received treatment at the MAHAK Pediatric Cancer Treatment and Research Center (MPCTRC). MPCTRC is a non-governmental charity-based organization that provides multidisciplinary care for pediatric patients with cancer. Despite administrative safety and protective controls at the time of the COVID-19 pandemic, some patients receiving care at MPCTRC experienced symptoms that met our diagnostic criteria for COVID-19. We describe the COVID-19 clinical presentation, treatment, and outcomes of these children.  Table 1 Clinical presentation of COVID-19.

Infection Severity
Carlotti et al [15] Dong et al [16] Asymptomatic Absence of clinical signs and symptoms of the disease and normal  chest X-ray scan associated with a positive test for SARS-CoV-2   Without any clinical symptoms and signs, and the chest imaging  results normal, whereas the 2019-nCoV nucleic acid test result is  positive  Mild  Upper airway symptoms such as fever, fatigue, myalgia, cough,  Patients can quickly deteriorate to acute respiratory distress syndrome or respiratory failure and may present shock, encephalopathy, myocardial injury or heart failure, coagulopathy, acute kidney injury, and multiple organ dysfunction Children can quickly progress to acute respiratory distress syndrome or respiratory failure and may also have shock, encephalopathy, myocardial injury or heart failure, coagulation dysfunction, and acute kidney injury. Organ dysfunction can be life-threatening

Study design and patients
We performed a cross-sectional, retrospective study of children with cancer who received treatment at MPCTRC from March 18, 2020, to January 28, 2021, and met our diagnostic criteria for SARS-CoV-2 infection. Two children with COVID-19 who were referred to other Iranian centers for treatment were excluded from the study. These two patients had newly diagnosed cancer, and their parents elected for treatment at pediatric cancer units closer to their homes. The data collected included patient sex, age at the time COVID-19 diagnosis, and cancer type. We also evaluated laboratory test findings, imaging studies, types of cancer-directed therapy, and patient status at their last follow-up visits. The study was approved by the MAHAK ethical committee (IR. MAHAK.RESEARCH.1399.230)

Clinical presentations
We used the COVID-19 clinical presentations described by Carlotti et al. and Dong et al. [ 15 , 16 ] to divide the clinical symptoms of our patients into five categories: asymptomatic, mild, moderate, severe, and critical ( Table 1 ). All patients with cough, fever, and/or respiratory symptoms (with or without digestive symptoms) were screened for SARS-CoV-2 infection.

Laboratory tests
At the time of admission, patients had laboratory testing performed for white blood cell count, absolute neutrophil count, absolute lymphocyte count, and C-reactive protein level [17] .

Imaging evaluation
Chest computed tomography (CT) scans were performed for all patients with suspected COVID-19 at the time of their first reported symptoms to evaluate the severity of SARS-CoV-2 infections because children with severe infections exhibit bilateral multiple lobar lesions [17] .

Detection of SARS-CoV-2 infections
Real-time reverse transcriptase polymerase chain reaction (RT-PCR) can detect the presence of SARS-CoV-2 nucleic acids in infected tissues [18] . Therefore, nasopharynx or nasal swabs were  collected from the patients at the time of reporting their first symptoms. Because of global shortages of RT-PCR test reagents at the beginning of the COVID-19 pandemic, RT-PCR was performed only in patients with severe or critical COVID-19 symptoms [ 15 , 19 ].

Diagnosis of COVID-19 at MPCTRC
The COVID-19 diagnostic criteria at MPCTRC were based on clinical symptoms, known exposure to SARS-CoV-2, and CT imaging findings. RT-PCR was not performed for all suspected cases because it was developed locally at other hospitals and its quality assurance could not be confirmed or validated at the time of diagnosis. CT imaging was performed at the time of diagnosis and at 14 days after treatment or supportive care. Fig. 1 depicts a schematic diagram of the diagnostic and treatment workflow for the patients who were referred to MPCTRC during the study period.

Treatment of COVID-19 at MPCTRC
Treatment of SARS-CoV-2 infections at MPCTRC was based on CT findings and clinical symptoms rather than nasal swab/RT-PCR results. The inpatient cohort (n = 8, all symptomatic) consisted of patients who were hospitalized and received oseltamivir, an antiviral medication used to treat influenza, and hydroxychloroquine, in consultation with a pediatric infectious diseases specialist [20] , in addition to azithromycin [15] . The outpatient cohort (n = 9, three asymptomatic and six symptomatic) consisted of patients who were observed at home and received supportive care (ie, intravenous fluids) with azithromycin (10 mg/kg on the first day, then 5 mg/kg per day for 4 days) [15] .
Oseltamivir was administered for 5 days according to body weight for patients older than 12 months: 15-23 kg received 45 mg twice per day; 24-40 kg received 60 mg twice per day; and ≥40 kg received 75 mg twice per day [20] . Hydroxychloroquine (5 mg/kg per day) was administered for 10 days, and 10 mg/kg azithromycin was administered on the first day of treatment followed by 5 mg/kg per day for 4 days [15] . Hospitalization and treatment were offered for the six symptomatic patients in the outpatient cohort, but the parents refused. Therefore, these six patients were treated at home with intravenous fluids and oral azithromycin. Cancer-directed therapies (radiation and chemotherapy) were suspended for all patients until recovery from COVID-19 symptoms, except for two patients who had finalized their treatment and were receiving follow-up examinations.

Statistical analysis
Statistical analyses were performed with SPSS software, version 23. Parametric and nonparametric analyses were performed, as appropriate.

Patients
From March 18, 2020, to January 28, 2021, 637 pediatric patients were admitted to or visited MPCTRC for cancer diagnoses and treatment. Of these, 356 had newly diagnosed neoplasms. COVID-19 was suspected in two of these new cases at the time of admission. However, the parents of these children preferred treatment at other centers closer to their homes and were therefore excluded from our analysis.
A total of 17 patients who received treatment at MPCTRC were eligible for our study. All 17 patients had previous exposure to a person with COVID-19. Fourteen patients exhibited clinical symptoms consistent with COVID-19, and three were asymptomatic. All 17 cases had CT findings consistent with COVID-19. The most common cancer diagnoses in our cohort included leukemia (n = 7), brain tumors (n = 5) and lymphoma (n = 3). The patients with leukemias had acute lymphoblastic leukemia (ALL, n = 4) and acute myeloid leukemia (AML, n = 3). The patients with brain tumors had pilocytic astrocytoma (n = 2), ependymoma (n = 1), optic pathway glioma (n = 1), and medulloblastoma (n = 1). The patients with lymphoma diagnoses comprised Burkitt lymphoma (n = 1), Hodgkin lymphoma (n = 1), and non-Hodgkin lymphoma (n = 1). Finally, the two remaining cases had rhabdomyosarcoma (n = 1) and osteosarcoma (n = 1). The clinical characteristics of the two patient cohorts (ie, inpatient and outpatient) are summarized in Table 2 .

Clinical presentations
All COVID-19 symptoms were mild in the 14 patients who exhibited symptoms. Of these patients, 71.4%, 42.9%, and 28.6% had fever, upper airway symptoms, and cough, respectively. All eight patients in the inpatient cohort had mild symptoms (fever, 62.5%; upper airway symptoms, 50%; and cough, 37.5%). Of the six symptomatic patients in the outpatient group, all had mild clinical symptoms and were referred with fever (83.3%), and only two cases exhibited upper airway symptoms, with one experiencing cough.

Laboratory tests
Laboratory test findings in the all patients and the inpatient and outpatient cohorts are provided in Table 3 . The laboratory test findings were unremarkable for the total patient population and each cohort.

Imaging evaluations
Chest CT imaging findings are summarized in Table 4 . These findings were based on chest axial spiral CT scans without con-     trast. Representative CT images from cases 2 and 3 (inpatient cohort) and case 10 (outpatient cohort) are shown in Fig. 2 . >

Molecular detection and treatment of COVID-19
SARS-CoV-2-specific IgG and IgM antibody levels were evaluated in nine patients, and were negative in all patients except for case 13 (IgG: 6.78; IgM: 3.78). Twelve patients had RT-PCR screening for SARS-CoV-2 performed, and four were positive (cases 12, 16, 17, and 18). Five patients did not undergo RT-PCR screening for SARS-COV-2 infection.
Before the COVID-19 pandemic, all patients were receiving active cancer therapy, with the exception of cases 16 and 18 who were receiving follow-up examinations. Nine patients were receiving treatment for relapsed neoplasms. Case 7 was receiving treatment for a second ALL relapse, and case 4 was receiving chemotherapy for relapsed AML after having undergone a bone marrow transplant. The remaining thirteen patients were receiving various phases of chemotherapy treatment at the time of COVID-19 diagnosis ( Table 5 ).
At the time of this writing, three patients in our study had died of COVID-19, and all other patients had recovered. The deceased patients were a 16-year-old male with Burkitt lymphoma who was receiving chemotherapy for recurrence, a 13-year-old male with osteosarcoma who was receiving chemotherapy after surgery, and a 10-year-old male with ALL who was in a subsequent maintenance phase of chemotherapy after relapse. All three patients died because of respiratory failure, despite hospitalization and treatment with hydroxychloroquine, oseltamivir, and azithromycin.

Discussion
Despite the devastation of the COVID-19 pandemic, we still know very little about its biology in children with cancer. Some studies have reported that patients with cancer have an increased risk of contracting COVID-19 [21][22][23] . Our study is the first report of COVID-19 in children with cancer referred to a cancer center in Iran. During the period of our study, 17 of 637 patients contracted COVID-19, according to our institutional criteria,. Unfortunately, three of these patients who were hospitalized and received oseltamivir, hydroxychloroquine, and azithromycin therapy died of COVID-19. Because nine children in our study refused hospitalization but recovered at home with only supportive care, we cannot draw meaningful conclusions as to the benefit of hospitalization coupled with antiviral/hydroxychloroquine therapy on the outcomes of our patients.
In April 2020, Ruggiero et al. systematically reviewed published reports of pediatric patients with cancer who contracted COVID-19 [24] . At that time, information on only one pediatric oncology patient with COVID-19 had been published [25] . Chen et al. reported the experience of an 8-year-old male patient with ALL in Wuhan, China, who contracted COVID-19 6 days after completing his maintenance chemotherapy regimen. The authors suggested that SARS-CoV-2 was transmitted to the patient from his attending physician at the hospital [25] .
To date the literature describing COVID-129 in pediatric patients with a diagnosis of cancer remains very sparse ( Table 6 ). Hrusak et al. conducted a web-based survey characterizing COVID-19 cases in pediatric hematology-oncology centers. Thirty-two countries participated in the survey, and of 200 cases who received SARS-CoV-2 testing, only eight were positive. Moreover, the severity of COVID-19 symptoms was mild in these cases [26] . The Memorial Sloan Kettering Cancer Center established a program for screening COVID-19 in pediatric oncology patients ( Table 6 ). Over a brief onemonth period from March 10 to April 12, 2020, 20 of 178 patients who were screened for SARS-CoV-2 infections were positive. The mean age of these patients was 15.9 years, and only three were female. One of the patients was hospitalized for a noncritical condition, three asymptomatic patients were hospitalized because of their cancer comorbidity, and the remaining 16 experienced mild COVID-19 symptoms and recovered at home [27] . Finally through March 18, 2020, only five pediatric oncology cases exhibiting mild COVID-19 symptoms were reported in the Lombardy region of Italy. These cases included patients with ALL in second remission, osteosarcoma, hepatoblastoma, and rhabdoid tumors. Three patients recovered at home, and two were hospitalized without any antiviral medications [28] .
Our findings and those of others suggest that treatment in the outpatient setting without antivirals or antibiotics is a viable option for pediatric oncology patients with COVID-19. Indeed, all of the patients in our study with mild COVID-19 symptoms who refused hospitalization recovered at home. However, our experience also demonstrates that COVID-19 can be fatal in a meaningful fraction of infected pediatric patients, and it is hoped that going forward when these cases are recognized, the availability of novel therapeutics and our greater understanding of the management of this disease may help in their management.

Conclusion
We suggest that a majority of pediatric patients with cancer who experience mild COVID-19 symptoms can most likely receive supportive care at home without hospitalization helping to prevent further SARS-CoV-2 transmission. Finally, the quality of molecular diagnostic testing for SARS-CoV-2 infections in Iran should be improved.