A case series of pediatric COVID-19 with complicated symptoms in Iran

People in different age groups are susceptible to SARS-CoV-2 infection as a newly emerging virus. However, the clinical course, symptoms and disease outcome vary from case to case. Although COVID-19 is usually milder in children than adults, some studies reported nonspecific symptoms. Here, we report eight pediatric cases of COVID-19 admitted in the Taleghani Children Hospital in Gorgan city, north of Iran, with complicated symptoms. The current case series poses several challenges to the pediatricians regarding the pediatric cases of COVID-19. As most literature relating to adults are not always transferable to children, clinicians should be warned about such presentations among children with COVID-19.

. Clinical and laboratory findings of all cases at admission.   situation has not improved, and he got cerebral palsy. More details of this case have been published in our earlier work as a case report article [9].

Case 2
A 12-month-old male was referred because of fever, seizure and anemia while suffering from fever and diarrhea for 3 days. The seizure was upward gaze with generalized tonic-clonic movement in a few seconds. In the initial examination, abdominal distention and hepatosplenomegaly were observed. At admission, laboratory findings showed leukocytosis with lymphocytosis and decreased hemoglobin. The main findings of LP were pleocytosis with 90% lymph and negative for bacterial growth. The molecular test for SARS-CoV-2 and HSV-1 and 2 in CSF was negative. With suspicion of meningoencephalitis, wide-spectrum antibiotics were used. CT scan showed peripherally located patchy consolidations and ground-glass opacities in the basal segments of the right-lower lobe and inferior aspects of the right-middle lobe and lingula ( Figure 1). SARS-CoV-2 and TB tests in respiratory samples were negative. Because of the reverse in CD4/CD8 ratio, an HIV test was ordered and reported as negative. The molecular test for SARS-CoV-2 again was negative. Abdominal sonography and CT scan showed hepatosplenomegaly and lymphadenopathy in the para-aorta and celiac trunk. Although his brain CT scan and MRI findings were normal, bone marrow aspiration revealed mild erythroid hyperplasia. Nasopharyngeal swab became positive for SARS-CoV-2 on day 18. Treatment was started with hydroxychloroquine, and the patient became well and was discharged.

Case 3
A 33-month-old male was admitted due to unilateral massive pleural effusion, respiratory distress and fever. Both a microbial examination in pleural fluid and the SARS-CoV-2 test in nasopharyngeal swab were negative. The main laboratory finding was leukocytosis with polymorphonuclear dominance. Pleural biopsy and bone marrow aspiration revealed acute lymphoblastic leukemia T cells. The patient was referred to the oncology department, and chemotherapy was performed for 3 weeks. One week later with sustained fever, lethargy and cough, the SARS-CoV-2 test was done, and the result was suspicious. His CT scan revealed peripherally located patchy consolidation 10.2217/fvl-2021-0091 Future Virol. (Epub ahead of print) future science group in the right-lower lobe and centrilobular ground-glass opacities in both lungs ( Figure 1). Treatment was started with cotrimoxazole, meropenem, vancomycin, nystatin, hydroxychloroquine, dexamethasone, pantoprazole and albumin. Four days later, the SARS-CoV-2 test became positive. Before receiving the RT-PCR result, the patient was transferred to the pediatric intensive care unit (PICU) because of respiratory distress and decreased O 2 saturation, and he expired due to severe illness and anemia.

Case 4
An 8-month-old male was referred to the pediatric emergency department with fever, productive cough, tachypnea, vomiting and diarrhea. At admission, bilateral whizzing and respiratory distress were heard with a stethoscope. He was born preterm and had normal delivery and development. The patient had a history of 33 days of hospitalization at birth and two-times due to pneumonia at 5 and 7 months. On arrival, the child had a respiratory rate of 61 per minute, a heart rate of 150 and O 2 saturation of 75%. The level of total IgM and IgG was lower, which indicated humoral immune deficiency. Collapse consolidations in the posterior aspects of both lungs and patchy ground-glass opacity in the right-upper lobe were observed in the CT scan (Figure 1). TB and influenza tests were negative. The patient was transferred to the PICU, and treatment started with meropenem, vancomycin and cotrimoxazole. Nasopharyngeal swab became positive for SARS-CoV-2 RNA on day 4. He received IVIG and linezolid during the hospitalization, and hydroxychloroquine and ciprofloxacin were also added to the treatment. On day 20, the patient had a bilateral pneumothorax, and a chest tube was implanted, but the patient expired 2 days later.
Case 5 A 4.5-year-old male was hospitalized because of fever, severe weakness, lethargy, anorexia and abdominal pain.
In the initial examination, the patient had a little edematous and tachypnea. At admission, the main laboratory findings were severe thrombocytopenia, anemia with hemoglobin of 7, leukocytosis with 90% polymorphonuclear and albumin of 2.2. His lung CT scan revealed peripherally located patchy consolidations along with interlobular septal thickening (Figure 1). With suspicion of COVID-19, the physician ordered the SARS-CoV-2 RT-PCR test. Due to the patient's condition, albumin and caltra drugs were prescribed. Later day, the nasopharyngeal swab became positive for SARS-CoV-2 RNA. With the start of treatment, his condition improved, and he was discharged 6 days later in good condition.

Case 6
A 7-month-old female was admitted due to whizzing, fever and food intolerance. She weighed 1.5 kg at birth and 3 kg at the time of admission, but the development was normal. In previous hospitalizations, there was no found reason for her failure to thrive. Initial physical examination showed a little tachypnea with normal O 2 saturation. At admission, laboratory findings were normal. In CT scan, ground-glass opacities created regions of differing pulmonary attenuation (mosaic attenuation pattern) along with mild peribronchial wall thickening were observed ( Figure 1). Thus, COVID-19 was proposed by the attended physician, but the primary SARS-CoV-2 RT-PCR test was negative. Cefotaxime was used for the first 3 days of hospitalization, and the respiratory condition relatively improved. On the fourth day of hospitalization, she suddenly developed apnea, was transferred to the PICU and was intubated. Treatment was started with hydroxychloroquine, IVIG, meropenem and vancomycin. Later day, the nasopharyngeal swab became positive for SARS-CoV-2 RNA. Unfortunately, the patient expired 3 days later.

Case 7
A 2-month-old male was hospitalized with symptoms such as tachypnea, heart murmur, crying, lethargy, poor feeding and no weight gain. His mother reported that she had been wheezing and restless for about a month. The main finding of initial laboratory findings was anemia. The patient chest x-ray proposed bronchopneumonia, so antibiotic therapy started. There was no COVID-19 history in his family, and his primary COVID-19 test was negative. The CT scan showed subsegmental collapse consolidation in posteromedial aspects of both lower lobes and mosaic attenuation in lungs (Figure 1). According to the CT report, the COVID-19 test was repeated, and the nasopharyngeal swab became positive for SARS-CoV-2 RNA. After 10 days of antibiotic therapy, the patient was discharged in relatively good condition.

Case 8
A 6-year-old male was referred with symptoms and signs such as fever, cough and respiratory distress that started about 10 days prior. The patient was asthmatic and under treatment with salbutamol spray and corticosteroids. He had a history of hospitalization due to pneumonia last year. His body temperature reached over 40 • C, O 2 saturation was under 91%, and he had respiratory distress even while resting. The patient had no history of travel or contact with COVID-19 cases. The main laboratory findings were thrombocytosis and erythrocyte sedimentation rate of 101. The CT scan showed diffuse centrilobular ground-glass opacities and mild peribronchial wall thickening in both lungs (Figure 1). The patient was reported to be positive in the SARS-CoV-2 RT-PCR test. Treatment started with ceftriaxone, hydroxychloroquine and oxygen therapy. Finally, he was discharged in relatively good condition.

Discussion
The notifiable COVID-19 cases mainly were among adults, and pediatric patients were rarely reported. Importantly, preliminary clinical findings showed that children usually presented with mild or asymptomatic infections [10]. In theory, children are also susceptible to SARS-CoV-2 infection, and lower likelihood to get severe disease and death may be related to the children staying at home during the pandemic and having less contact with the source of infection. Other factors may include their still-developing immune system and having more pulmonary stem cells that can repair the injured cells. While the COVID-19 situation appears to be changing in pediatrics, its clinical profile in this population is less known [11]. This is a case series report on COVID-19 in children from Iran. These cases were in 2 months to 7 years, indicating no age group is safe from infection with SARS-CoV-2. Although with a small number of cases, we found that male children are more affected than females. This may be because of anatomical, genetic, hormonal and immunological differences. Notably, the expression level of ACE2 is found to be more in males than females [8].
The most important finding to come from the present analysis is the complicated pediatrics symptoms for COVID-19. Of the eight cases, five had respiratory symptoms, two had fever, seizures, low-level consciousness and one had edema, abdominal pain and severe weakness. Cases 1 and 2 were admitted with neurological manifestations, and this was different in that cases. While CSF analysis of case 1 was normal, the virus was detected in CSF. While the main LP findings in case 2 were pleocytosis with 90% lymph, CSF was negative for SARS-CoV-2. Neurological manifestations have been suggested as a presenting symptom or complication of COVID-19 [12], but only a few studies detected SARS-CoV-2 in the CSF [9,13]. Our case 1 represents the presence of SARS-CoV-2 in both the respiratory tract and CSF and highlights the importance of consideration of neurological complications as unknown signs of COVID-19. More studies are needed to guide the pediatricians further and confirm the CNS infection of SARS-CoV-2, neurologic manifestations and how the virus enters the CNS.
In these cases, inconsistent with the Liu et al.'s study [14], severe leukocytosis was observed in four patients, two of whom recovered and two died. The former two had polymorphonuclear, while the latter two had lymph dominance. No lymphopenia or leukopenia was seen that is inconsistent with other adult studies, indicating a different manifestation of the COVID-19 in pediatrics. The RT-PCR test was reported positive at admission only in four positive and in two cases were positive in the third test. Although the RT-PCR test confirmed all subjects as the 'criterion-referenced' for COVID-19 detection [15], we cannot rule out the potential of nosocomial infection or false-negative results, especially in cases that the test was negative for the first or second time. It is hard to determine common clinical characteristics in children with COVID-19, and it is unclear whether there is a common biomarker due to the small number of cases. Although the overall symptoms are relatively mild in children, the CT scan profiles are similar to adults.'

Conclusion
The current case series poses several challenges to the pediatricians regarding the pediatrics COVID-19. As most literature relating to adults are not always transferable to children, clinicians should be warned for such presentations among pediatrics with COVID-19. It is recommended that children with unusual clinical symptoms be screened for SARS-CoV-2 infection. Further research and reports are crucial to help us understand the clinical characteristics and natural history of COVID-19 in children. 10.2217/fvl-2021-0091 Future Virol. (Epub ahead of print) future science group A case series of pediatric COVID-19 with complicated symptoms in Iran Case Series

Summary points
• As an emerging virus, all people in different age groups are susceptible to SARS-CoV-2 infection.
• Although COVID-19 is usually milder in children than in adults, some studies reported nonspecific symptoms.
• The current case series poses several challenges to the pediatricians regarding the pediatrics COVID-19.
• Of the eight cases, five had respiratory symptoms, two had a fever, seizures and low-level consciousness, and one had edema, abdominal pain and severe weakness. • Cases 1 and 2 highlight the importance of consideration of neurological complications as unknown signs of COVID-19. • As most literature relating to adults are not always transferable to children, clinicians should be warned for such presentations among pediatrics with COVID-19.

Author contributions
A Tahamtan and F Cheraghali conceptualized and designed the study. F Cheraghali, L Barati, D Amanian, L Shahkar, M Najafinejad, S Shahabi and A Tabarraei collected data. A Tahamtan, H Naziri and F Cheraghali drafted the manuscript. All the authors evaluated and edited the manuscript and have read and approved the final manuscript.