Abstract
Objectives
Although coronavirus disease 2019 (COVID-19) prognosis is mostly good in pediatric patients with no underlying diseases, there are a few reports on children with oncological underlying malignancies. This study aimed to describe the clinical and laboratory features of 20 children with COVID-19 who had underlying malignancies in an Iranian referral pediatrics hospital.
Methods
All children under 15-year-old of age with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positive real-time polymerase chain reaction (PCR) and presence of an underlying malignancy were included in the study.
Results
In this study, among 20 patients, 11 were male (55%). The mean age of the patients was 6.0 ± 4.1 years. Twelve patients (60%) had acute lymphocytic leukemia, two had acute myeloid leukemia (10%), and six had solid organ tumors (30%). The most common symptoms were fever (65%) and cough (65%). We reported severe pneumonia in seven hospitalized patients (35%) and three patients (20%) required intensive care unit admission and mechanical ventilation. Procalcitonin was normal in 73% of the cases (11 out of 15), but it was highly elevated in four cases (27%). Five patients (25%) had positive blood cultures and a mortality of 20% was reported.
Conclusions
This is the largest study on SARS-CoV-2 infected pediatric patients with underlying malignancies in Iran. Since the risk of exposure to SARS-CoV-2 and even death in children with malignancy, either in the hospital or community setting during the pandemic is high, special precautions to reduce the risk of transmission are highly suggested.
Background
Severe acute respiratory syndrome coronavirus 2 (SARS- CoV-2) which was first discovered and described in Wuhan, China, has spread rapidly around the world and infected more than two million people in 185 countries [1].
Although the numbers of pediatric patients with coronavirus disease 2019 (COVID-19) are increasing, a majority of the cases show mild disease [2], [3]. Children have represented 5% of SARS-CoV-2 positive cases in the USA, 2% of diagnosed cases in China, and 1.2% of cases in Italy [3]. According to the Chinese Center for Disease Control and Prevention’s report on 44,500 confirmed cases, 81% of the patients showed mild symptoms and severe infection with dyspnea, respiratory distress, hypoxia, and lung involvement was found in only 14% of the cases. The total mortality rate was of 2.3% and none of the deceased patients were from the noncritical group [4], [5], [6], [7]. However, the disease severity and mortality might vary according to geographic distribution and some atypical presentations might observe [8], [9], [10], [11], [12], [13], [14].
COVID-19 prognosis is mostly good in pediatric patients with no underlying diseases but it might pose an increased risk in cancer patients, particularly in those who have recently undergone chemotherapy, radiotherapy, or immunotherapy, leading to the deterioration of the patients [15]. According to a previous report, the prevalence of COVID-19 infection among children with cancer in Madrid was of 1.3% [16].
There are a few reports on children with oncological diseases [17], [18]. This study aimed to to describe the clinical and laboratory features of 20 children with COVID-19 who had underlying malignancies in an Iranian referral pediatrics hospital.
Methods
This study was approved by the Ethics Committee of Tehran University of Medical Sciences, Tehran, Iran (IR.TUMS.VCR.REC.1399.060), and signed informed consent was obtained from all patients who participated in the study or their parents/legal guardians.
This study’s inclusion criteria were children under 15-year-old of age who had an underlying malignancy and SARS-CoV-2 positive reverse transcription-polymerase chain reaction (rRT-PCR) and were admitted to Children’s Medical Center, an Iranian referral hospital, between March and June 2020. A confirmed case of COVID-19 was defined as a positive result of SARS-CoV-2 rRT-PCR using a nasopharyngeal swab. The RNA of collected samples on the swab was then extracted using SinaPureTMViral kit (Sinaclon, Iran) and cDNA template synthesis was performed using PrimeScript™ RT reagent Kit (TaKaRa, Japan). The rRT-PCR was performed according to our previous report using the regions of the virus nucleocapsid gene and RNase P (RP) as an internal control [19].
Epidemiological, clinical, laboratory, and treatment data were obtained from medical records. Demographic characteristics, clinical data, baseline symptoms, and physical signs, treatments ant outcome, and laboratory findings including blood cell counts, hemoglobin level, absolute neutrophilic and lymphocytic count, inflammatory markers (i.e. Ferritin, C-Reactive protein (CRP) and Erythrocyte sedimentation rate (ESR), liver enzymes, coagulation factors (prothrombin time (PT), partial thromboplastin time, and international normalized ratio), electrolytes (calcium, sodium, magnesium, phosphorus, and potassium) and kidney function tests (blood urea nitrogen and creatinine) were collected. Severe pneumonia was defined by the presence of any of the following conditions: hypoxia: SpO2≤93% (<90% in premature infants), increased respiration rate: RR≥70/min (≤1 year), and RR≥50/min (>1 year), blood gas analysis: PaO2<60 mmHg, PaCO2>50 mmHg, or other manifestations [19].
Statistical analysis
All statistical analyses were performed using SPSS (Statistical Package for the Social Sciences) version 13.0 software (SPSS Inc). Categorical variables were described as frequency rates and percentages, and continuous variables were described using median and interquartile range (IQR) values.
Results
Between March and June 2020, a total of 269 patients less than 15 years of age with underlying malignancies were hospitalized in our hospital. Among them, 20 patients (7.4%) with confirmed SARS-CoV-2 infection were included in the study. Nine patients were female (45%) and 11 were male (55%). The median age of the patients was 6.0 years (IQR: 3–10 years). Twelve patients (60%) had acute lymphocytic leukemia (ALL), two had acute myeloid leukemia (AML) (10%) and six had solid organ tumors (30%). None of these patients had received a hematopoietic stem cell transplantation. Six patients (30%) had contact with a family member with confirmed SARS-CoV-2 infection (Table 1).
n | % | |
---|---|---|
Sex | ||
Female | 9 | 45 |
Male | 11 | 55 |
Age | ||
<1 years | 1 | 5 |
1–5 years | 8 | 40 |
6–10 years | 6 | 30 |
11–15 years | 5 | 25 |
Underlying malignancy | ||
Acute myeloid leukemia, AML | 2 | 10 |
Acute lymphoblastic leukemia, ALL | 12 | 60 |
Solid tumors | 6 | 30 |
COVID-19 positive family member | 6 | 30 |
Positive blood culture | 5 | 25 |
Presenting symptom and signs | ||
Fever | 13 | 65 |
Cough | 13 | 65 |
Tachypnea | 9 | 45 |
Respiratory distress | 8 | 40 |
Chest pain | 1 | 5 |
Vomiting | 5 | 25 |
Abdominal pain | 1 | 5 |
Diarrhea | 3 | 15 |
Headache | 2 | 10 |
Myalgia | 3 | 15 |
Treatment | ||
Oseltamivir | 3 | 15 |
Hydroxychloroquine | 9 | 45 |
Azithromycin | 10 | 50 |
Third-generation cephalosporin | 9 | 45 |
Vancomycin | 5 | 25 |
Meropenem | 3 | 15 |
Amphotricine liposomal | 2 | 10 |
Colistin | 1 | 5 |
Linezolide | 1 | 5 |
Kaletra | 2 | 10 |
Corticosteroid | 3 | 15 |
Outcome | ||
Death | 4 | 20 |
Overall, 19 patients were on chemotherapy at the time of developing SARS-CoV-2 infection and only one case was SARS-CoV-2 positive before initiation of the chemotherapy.
All the patients were symptomatic. The most common sign and symptoms were fever (65%) and cough (65%). Forty-five percent of the patients had tachypnea and 40% suffered from respiratory distress. Myalgia and diarrhea were reported in 15%. One-fourth of the cases had nausea and vomiting and only one patient presented with symptoms like chest and abdominal pain. We reported severe pneumonia in seven hospitalized patients (35%) and three patients (20%) required intensive care unit (ICU) admission and mechanical ventilation. Unfortunately, four cases (20%) died (three cases with ALL and one case with AML) (Table 1).
The laboratory results of the patients are shown in Table2. The median level of lymphocyte count was 0.83 × 109 cells per L (IQR: 0.33–2.3) which shows lymphopenia in the majority of patients. The median of the neutrophil count was 2.95 × 109 cells per L (IQR: 0.25–6.6). Hemoglobin levels ranged between 6.9 and 14.2 g/dL with a median of 9.7 (IQR: 8–11).
Median | Interquartile range | |
---|---|---|
White blood cell count (×109 cells per L) | 5.9 | 0.75–9.6 |
Red blood cell count (×109 cells per L) | 3.4 | 2.9–4.2 |
Haemoglobin, g/dL | 9.7 | 8–11 |
Platelet count (×109 cells per L) | 140 | 52–350 |
Lymphocyte count (×109 cells per L) | 0.83 | 0.33–2.3 |
Neutrophil count (×109 cells per L) | 2.95 | 0.25–6.6 |
PH | 7.42 | 7.39–7.48 |
Partial pressure of carbon dioxide (PaCO2), mmHg | 26 | 23.5–29.8 |
Partial pressure of oxygen (PaO2), mmHg | 87 | 50–95.25 |
Bicarbonate (HCO3), mEq/L | 17.5 | 14.9–19.8 |
O2 saturation, % | 97.2 | 88.8–98 |
Blood sugar, mg/dL | 105 | 90–124 |
Blood urea nitrogen, mg/dL | 13 | 10.25–16.75 |
Creatinine, µmol/L | 0.5 | 0.5–0.7 |
Potassium, mmol/L | 4 | 3.97–4.3 |
Sodium, mmol/L | 134 | 131–137 |
Calcium, mg/dL | 8.9 | 8.5–9.5 |
Magnesium, mg/dL | 1.7 | 1.47–1.95 |
Phosphorus, mg/dL | 4.7 | 3.8–5 |
Creatine phosphokinase, U/L | 27 | 22.25–35 |
C-reactive protein, mg/dL | 62 | 8.5–63.5 |
Erythrocyte sedimentation rate, mm/h | 67 | 26–89 |
Ferritin, ng/mL | 8,488 | 252–12,424 |
Prothrombine time, s | 12.5 | 12.5–14.1 |
Partial thromboplastin time, s | 31 | 30–36 |
International normalized ratio | 1 | 1–1.2 |
Lactate dehydrogenase, U/L | 680 | 407–995 |
Procalcitonin, ng/mL | 0.025 | 0.1–1 |
Alanine aminotransferase, U/L | 25 | 11.5–59 |
Aspartate aminotransferase, U/L | 22 | 18–41 |
The median for CRP and ESR was 62 mg/dL (IQR: 8.5–63.5) and 67 mm/h (IQR: 26–89), respectively. Procalcitonin was normal in 73% of the cases (11 out of 15), but it was highly elevated in four cases (27%). Five patients (25%) had positive blood cultures; among them, two patients died.
Lactate dehydrogenase was significantly elevated at admission for deceased patients compared to the discharged patients (1,193 (U/L); IQR, 756–1754 U/L vs. 457 U/L; IQR, 367–883 U/L; p=0.033). The level of procalcitonin (4.5 ng/mL [IQR, 0.02–9.7 ng/mL] vs. 0.02 ng/mL [IQR, 0.01–0.05 ng/mL]), PT (13.9 s [IQR, 12.7–21 s] vs. 12.5 s [IQR, 12.5–14 s]), and CRP (89.5 mg/L [IQR, 15.2–155.5 mg/L] vs. 48 mg/L [IQR, 10–60 mg/L]) was higher in children who are now deceased compared to those who were discharged; however, the differences were not significant (p >0.05).
Discussion
To our knowledge, this is the first report of pediatrics with underlying malignancy and SARS-CoV-2 infection in Iran. According to the previous reports, symptomatic SARS-CoV-2 infection was rarely reported among heavily immunocompromised children [20]. Although it has been reported that the COVID-19 may have a mild course even in children receiving anticancer chemotherapy [20], in our study, 35% of the patients showed severe pneumonia, 20% required ICU admission and mechanical ventilation, and four cases (20%) died. In a recently published systematic review, 9.6% of the patients showed severe COVID‐19 [21]. According to the American Society of Hematology registry, among 146 cases of COVID-19 with hematologic, 26% died and ALL was the commonest malignancy (30%) [22], [23].
In contrast to previous studies [3], [21], children with underlying malignancies were more likely to have severe disease. The possibility of immunosuppressive treatments causing patients to develop a more serious type of COVID-19 should not be underestimated [24]. Moreover, the risk of exposure to the COVID‐19 infection in hospitals is high.
In this study, 45% of the patients were female and 55% of the patients were male. Our findings are in consistent with other published studies, showing that there are no significant differences between sex and age in pediatric patients [19], [25].
All of our patients had underlying malignancies before the diagnosis of COVID19. Sixty percent of our cases had ALL, 30% solid tumor malignancies, and AML was present in 10% of the cases. So, the most common underlying malignancy in children with COVID-19 was ALL. This result could be affected by the fact that leukemias are the most common malignancy in pediatric patients. However, there are rare reports on the impact of the COVID‐19 pandemic on pediatric cancer patients is available [26].
In the study of Carlotti et al., severe COVID-19 was found higher in patients with hematologic cancer, lung cancer, or metastatic cancer (stage IV) compare to the patients without these conditions [27], [28].
In a previous report conducted in Madrid, the median age of pediatrics with malignancy and COVID-19 was 10.6 years; 73% of the patients had hematologic malignancies and 21% of the patients had solid tumors which are in consistent with our report [16]; however, the age of our patients was lower.
In our study, 36% of the patients had a COVID-19 confirmed family member. In the study of Qiu et al., the most common route of transmission for pediatric patients was close contact with family members with COVID-19 (89%) [6].
In this repot, 25% of the patients had positive blood cultures. Previous studies suggested that bloodstream infections are very rare in patients with COVID-19 [29], but there are no studies available in pediatric patients. However, this finding might be due to the fact that cancer patients are more susceptible to bacteremia because of their reduced immunity. On the other hand, cytotoxic therapies for hematological malignancies may lead to the reduction of lymphocyte subsets, making the patients more vulnerable to infection [30], [31].
Unfortunately, 20% of our patients died during the course of treatment which is significantly higher than the reported mortality in healthy children with COVID-19 [3].
The most common symptom in our patients was fever (65%) and cough (65%) that was similar to previous reports [16], [19], while chest pain and abdominal pain was only reported in 5% of the cases.
The most common treatment used in our patients were hydroxychloroquine (45%), azithromycin (50%) and third-generation cephalosporins (45%) which were chosen based on the underlying disease, accompanying neutropenia, and the presence of bacteremia and the antibiotic susceptibility test. Hydroxychloroquine and azithromycin were the most widely used treatments in other studies as well [16, 19, 27]. In some pediatric cases in China, lopinavir, ritonavir, and inhaled recombinant human interferon-alpha have been applied [32]. However, the World Health Organization discontinues hydroxychloroquine and lopinavir/ritonavir because they have little or no reduction in the mortality of hospitalized COVID-19 patients. Moreover, the guidelines for the medical management of COVID-19 have changed over time which could explain the differences in various studies [32].
According to the laboratory results, lymphopenia was found in the majority of patients that was higher than previous reports [19], [33]; however, the effects of the underlying malignancy and immune dysregulation should not be forgotten [34].
Since a risk of exposure to SARS-CoV-2 both in the hospital or community setting resulting in extensive anxiety among families of children with cancer [35], standard precautions for basic and respiratory hygiene to reduce the risk of transmission are highly recommended.
Conclusion
This is the largest study on SARS-CoV-2 infected pediatric patients with underlying malignancies in Iran. Since the risk of exposure to SARS-CoV-2 and even death in children with malignancy, either in the hospital or community setting during the pandemic is high, special precautions to reduce the risk of transmission are highly suggested.
There are some important issues that were not discussed in our study. First, the outbreak of COVID-19 started in December 2019, so detailed case descriptions and clinical courses are limited and the long-term outcome and sequelae may need further follow-up; second, the treatment strategy in children may need additional debate and caution and more studies on this topic to learn more about this virus as well as better treatment options and care for pediatric patients with malignancy is highly needed. And third, the emotional burden and the high-stress levels these patients are experiencing in this pandemic should not be ignored.
Funding source: Tehran University of Medical Sciences and Health Services
Award Identifier / Grant number: 99-1-149-47172
Acknowledgment
This study was taken from Dr. Amene Navaeian’s postgraduate thesis.
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Research funding: This study was supported by a grant (grant number: 99-1-149-47172) from Tehran University of Medical Sciences to Dr. Setareh Mamishi.
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Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.
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Competing interests: The authors did not have any conflicts of interest relevant to this article.
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Informed consent: Informed consent was obtained from all individuals included in this study.
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Ethical approval: This study was approved by the Ethics Committee of Tehran University of Medical Sciences, Tehran, Iran (IR.TUMS.VCR.REC.1399.060) and signed informed consent was obtained from all patients who participated in the study or their parents/legal guardians.
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