Do the acute lymphoblastic leukemia and non-hodgkin lymphoma patients have a worse prognosis of COVID-19 infection in children?: a case report

Background: Coronavirus Disease 2019 (COVID-19) is a contagious disease caused by a new type of Coronavirus namely Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Children with tumors or autoimmune diseases are more susceptible, because of suppression of their immune system, chemotherapy, radiotherapy, or surgery on tumors. Case presentation: We present the clinical features 3 Acute Lymphoblastic leukemia and 1 Non-Hodgkin lymphoma patients who were infected with COVID-19 since July to August 2020 in our hospital. These were the first four cases identified as COVID-19 positive in Dr Wahidin Sudirohusodo Hospital. Case 1, 2, and 4 were diagnosed as moderate and common type of COVID-19, while case 3 was classified as severe type. They may be transmitted COVID-19 infection during hospitalization. All cases were recovered from COVID-19 after a combination therapy against virus, bacteria, and also respiratory support. Conclusion: Our case series of four pediatric cancer patients showed a good outcome after prompt treatment, suggesting that malignancy in children may not be a contributor factor for COVID-19 recovery. (Health Science Journal of Indonesia 2021;12(1):20-25)


Coronavirus Disease 2019 (COVID-19) is a contagious disease caused by a new type of Coronavirus namely
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). 1 This disease began with the emergence of unknown cases of pneumonia etiology in Wuhan, China at the end of December 2019 and has since been detected in over 100 international locations. On March 11 th 2020, the World Health Organization (WHO) characterized COVID-19 as a pandemic. 2 COVID-19 spreads through rapid transmission, generally susceptible to crowds, and is characterized with a typical clinical symptoms that can be easily missed or misdiagnosed. [3][4][5] As of July 9 th 2020, WHO reported 11,874,226 confirmed cases with 545,481 deaths worldwide (Case Fatality Rate / CFR 4.6%). Indonesia reported its first case on March 2, 2020. Cases are increasing and spreading rapidly throughout Indonesia. As of July 9, 2020, the Ministry of Health Indonesia reported 70,736 confirmed COVID-19 cases with 3,417 deaths (CFR 4.8%). 6 Children with underlying diseases are more vulnerable to  Although children infected with COVID-19 are small portion of the confirmed cases, children with tumors or autoimmune diseases are more susceptible, because of suppression of their immune system, chemotherapy, radiotherapy, or surgery on tumors. 8 Additionally children with leukemia may have depressed bone marrow due to chemotherapy. 9 Leukemia itself or its treatments could develop an immune deficiency, malnutrition, and impairment of the mucosal membrane barriers which access for endogenous microbiological flora and other opportunistic pathogens. These will lead to severe infections of SARS-CoV-2. 10 However, some papers reported the mild or asymptomatic course of COVID-19 in paediatric oncology. 11 Here, we report four patients co-infected with SARS-CoV-2 within July-August 2020 at the paediatric ward Wahidin Sudirohusodo Hospital from 195 cancer patients (2%) and describe their medical histories, clinical diagnosis, changes in clinical parameters, and outcomes.

Case 1
A 2-year and 8-month-old girl was admitted to the Department of Hematology and Oncology (HO) in our hospital on 8 July 2020 because of pale, fever, and joint pain for 5 months. She received a packed red cell transfusion two times, in February and June 2020. Physical examinations revealed pallor, hepatomegaly, splenomegaly, and lymphadenopathy. There was bleeding manifestation by petechial rash on the trunk. On admission, her laboratory results were as follows: hemoglobin, 7.1 g/dL; white blood cell count, 156.000/μL with differential count: monocytes 27.6%, lymphocytes 70.1%; platelet count, 25.000/μL. We performed bone marrow puncture with the result of Acute lymphoblastic leukemia (ALL)-L1 and the immunophenotype corresponded to a B cell population. Based on the above data, the diagnosis of this patient was ALL-L1 high-risk group and hyperleukocytosis. She received chemotherapy with the Indonesian ALL Protocol 2018 regimen and hyperleukocytosis management on 21 July 2020. During the third day at the first week of induction phase, the patient showed symptoms of fever, cough, and dyspnea. Chest retraction and rales in both lungs were discovered. A Chest CT scan showed patch infiltrates in superior right lungs, indicating a possibility of pneumonia ( Figure 1). The SARS-CoV-2 infection was confirmed by positive detection of the virus in the throat swab sample using the real-time reverse transcription-polymerase chain reaction (RT-PCR) method. The laboratory results on 20 July 2020, revealed reductions in white blood cells (WBCs) and absolute neutrophil count (ANC) in the blood. The patient was then diagnosed with COVID-19 and transferred to the isolation ward in the Department of Infectious Diseases. The symptoms were relieved after 3 days. The antibiotic of ceftazidime and amikacin were given as empirical antibacterial therapy and Oseltamivir as antiviral therapy. The patient discontinued receiving steroids due to her infection. However, the virus was sustained in the throat swab samples for several days. The patient was transferred to another isolation ward and continue chemotherapy. The SARS-CoV-2 was cleared from the patient on 10 August 2020 (Table 1).

Case 2
A 4-year and 2-month-old boy came to the emergency ward with chief complaint shortness of breath 6 days before admission and got worse 1 day before admission on August 4, 2020. Other symptoms were fever, cough, and poor appetite. He was admitted to the department of Hematology because of his past medical history of non-Hodgkin lymphoma (NHL) and routine control for chemotherapy since 19 May 2020. He has received the induction phase of chemotherapy by NHL protocol with a regimen of vincristine, cyclophosphamide, adriamycin, and methotrexate. As his clinical presentation revealed COVID-19 symptoms, we then did the chest CTscan and the result showed a ground-glass opacity (GGO) in both lungs, indicating the possibility of viral pneumonia ( Figure 1). The SARS-CoV-2 was found in a throat swab sample by real-time PCR on 6 August 2020. Blood testing showed hemoglobin 12.2 gr/dl, leukocyte 11.100/μL, platelet 434.000/ μL, reduction of lymphocyte 17.8%, monocyte 11 %. The patient was then diagnosed as having COVID-19 and transferred to an isolation ward of our department. In the isolation ward, the patient was treated with oxygen therapy by nasal catheter, antiviral therapy with Oseltamivir, levofloxacin, and amikacin. Because the patient still had minimal chest retraction, the levofloxacin antibiotic was continued until 14 days and his clinical condition gradually improved. A re-examination of the blood test on August 17th showed hemoglobin 10.5 gr/dl, leucocyte 11.100/μL, platelet 434.000/μL, increased lymphocyte 45.5%, monocyte 10.1%. The SARS-CoV-2 was cleared from the patient on 11 August 2020. (Table 1  In the isolation ward, the patient was treated with combination therapy including oxygen delivery via a non-rebreathing mask, antibiotics therapy with meropenem, amikacin, and Oseltamivir. The virus was persistent in the sample from the throat swab in this patient, so the patient remained in the isolation ward. The SARS-CoV-2 in the throat swab disappeared from the sample on 30 August 2020, about 13 days after the first time of positive detection of the virus. (Table 1)

Case 4
A 4-year and 2-month-old boy was transferred from district hospital on 10 August 2020 with the main complaint of paleness in the last 2 weeks before admission. There was fever and shortness of breath for 2 days before admission also gum bleeding 4 days before admission. On physical examination the child was conscious, increased body temperature, lymphadenopathy, the liver was palpable at 8 cm below costal arch margin and left lobe 7 cm below xiphoid process with supple, smooth surface, sharp edge with no tenderness. The spleen was palpable on Schuffner I. From the genital examination, there were palpable left testes with a size of 2x1x1cm, and right palpable testes with a size of 4x3x2cm. The laboratory results revealed leucocyte 169.000/μL, hemoglobin 3.8 gr/dl and platelet 2000/μL, differentiation: neutrophil 0 %, monocytes 54.4%, lymphocytes 60 %; NLR 0, ALC 27.937. Bone marrow puncture showed ALL-L1. We diagnosed this patient with ALL-L1 high-risk group and hyperleukocytosis. He has received chemotherapy with intrathecal methotrexate and oral dexamethasone, aggressive hydration and allopurinol. On the 5th day of hospitalization, the patient presented a cough and shortness of breath. The patient was suspected to be infected with COVID-19, and the chest CT imaging revealed multifocal consolidation in the right lobe ( Figure 1). The SARS-CoV-2 was found in a throat swab sample by real-time PCR. The patient was then diagnosed as having COVID-19 and transferred to an isolation ward of our department. The patient received meropenem and amikacin as antimicrobial therapy and Oseltamivir as antiviral therapy. However, intravenous and oral chemotherapy was discontinued. Chemotherapy is an immunosuppressant that suppresses the immune system; however, in patients with COVID-19, immunity is significantly reduced, so iv and oral chemotherapy may worsen the illness. As a result, it was decided to temporarily stop the therapy until the patient recovered from COVID-19. The delay in chemotherapy will undoubtedly have an impact on the patients' outcomes, and it has created a new problem in the management of cancer patients. The SARS-CoV-2 in the throat swab was cleared from the sample on 27 August 2020 (Table 1).

DISCUSSION
Our study reported 4 cases of pediatric cancer with SARS-CoV-2 infection in Makassar, South Sulawesi Indonesia. All children infected with COVID-19 were successfully recovered from the infection with mild to severe symptoms. They showed symptoms of SARS-CoV-2 like fever and shortness of breathiness during hospitalization. Zimmermann et al 12 described that most common symptom COVID-19 in children is fever (50%) and cough (38%). 13 In our study, we found 3 out of 4 cases had history of fever. They developed fever and other symptoms related to COVID-19 after chemotherapy, which might indicate that the SARS-CoV-2 nosocomial infection. 7,14 Early studies showed reduction in lymphocytes during SARS-CoV-2 infection, and we observed the various range of blood laboratory results in our study. Case 3 had a decreased count of lymphocytes in the blood, which may be attributed to the severity of COVID-19. The cause of wasting in cancer patients is caused by a variety of factors. it is divided into two categories; nutritional deficiencies and malabsorption, and metabolic disorders. Wasting has an effect on therapy response, complications, quality of life, and patient survival. particularly in these cases, because in addition to cancer, they were also found to be COVID-19 positive. Therefore, we have to pay a close attention to nutrition management. Yang K, et al 3 described the results of meta-analysis that lower lymphocyte count was associated with increased mortality, ARDS, and severe COVID-19.
The association seemed to be stronger in younger patients compared to older patients. In case 3, the condition of the patient classified severe COVID-19 and the need for ICU care. Case 1 and 4 had an increased count of lymphocytes in the blood, which may be attributed to their underlying disease, ALL.
In ALL patients, we usually found an increase in lymphocyte count because of increased proliferation lymphoblast in bone marrow caused by malignancy. NLR and ALC in this case could not be utilized as a parameter to assess the severity of the disease, mainly because leukocyte in leukemia patients usually increased and can sometimes be hyperleukocytosis. 15 The diagnosis of COVID-19 was based on symptoms, lung X-ray/CT examination, and detection of the virus by real-time RT-PCR in throat swab samples from the patients. 16 The main basis for the diagnosis of infections with SARS-CoV-2 is real-time polymerase chain reaction (RT-PCR) on upper or lower respiratory secretions. 17 Children with underlying diseases and suspected to be infected by COVID-19 should be observed with extended isolation time and tested with more nucleic acid detections. They should also receive early symptomatic treatment. Supportive treatment including sufficient fluid and calorie intake and additional oxygen supplementation should be used in the treatment of children infected with SARS-CoV 2. The aim is to prevent ARDS, organ failure, and secondary nosocomial infections. If a bacterial infection is suspected, broad-spectrum antibiotics such as second or third-generation cephalosporins may be used. 12 The most commonly used antibiotics in children were meropenem and linezolid. 18 And in our study, all of the cases received antiviruses like Oseltamivir and antimicrobial therapy such as ceftazidime, meropenem, and amikacin. During the observation, there were no side effects of the given medication, and the patients' tolerance was good.
Disease clusters and nosocomial infections have been reported. The proportion of nosocomial infections is high among diagnosed infections, and medical staff are at high risk of infection. One study on 44,672 patients showed that health workers accounted for 3.8% of the COVID-19 cases and five health workers died as a result of the infection. 19 Since the specific medicine for COVID-19 is still not available, the prevention of nosocomial infections will be the key. The high presence of the COVID-19 epidemic in the media is likely to improve the general public's awareness. People with symptoms indicating a SARS-CoV-2 infection should take protective measures during the hospital or clinic visit, such as wearing a mask, minimizing the time of stay in the hospital, and if possible, making remote medical consultations in advance. 20 Medical institutions should formulate infection prevention and control strategies, and strengthen the hospital's infection prevention and control efforts, such as the establishment of special departments for outpatients with fever, and a notification triage system. Triage of early identification among suspected cases can avoid excessive gathering of patients in the hospital. Isolation wards should be established for suspected and confirmed patients needing treatment. In hospitals without single isolation wards or negative pressure isolation, indoor ventilation measures should be taken timely, and the management of patients should be standardized in these wards. Using adequate disinfection procedures can reduce the possibility of hospital transmission of the virus. During the epidemic, the possibility of the outbreak of nosocomial infection, and establish an early warning mechanism. Emergency plans or measures should be developed to deal with nosocomial infections. 3,21 The report's limitation was a small sample size, so it could not be statistically analyzed. It is suggested that a larger sample size and a better study design be used. The number of COVID-19 in children is much smaller than adult. Our case series of ALL and NHL pediatric patients showed a good outcome after prompt treatment, suggesting that malignancy in children may not be a contributor factor for COVID-19 mortality. COVID-19 is a deadly disease that can lead to death. Nevertheless, in this case report,