The coronavirus disease 2019 (COVID-19) is a severe acute respiratory disease caused by a 2019 novel coronavirus (nCoV).1 COVID-19 was first identified in China during late December 20192,3 and has since been detected in over 100 international locations.3,4 On March 11, 2020, the World Health Organization characterized COVID-19 as a pandemic.5 COVID-19 is spread through rapid transmission, generally susceptible to crowds, and is characterized with atypical clinical symptoms that can be easily missed or misdiagnosed.6–8 As of March 15, 2020, a total of 153,517 global cases have been confirmed resulting in 5735 deaths.4
People with underlying diseases are more vulnerable to COVID-19.9 Although children infected with COVID-19 only account for a small portion of the confirmed cases,9 children with tumors or autoimmune diseases are more susceptible to various infections.10 Thus, it is urgent to know whether these underlying diseases affect the clinical manifestations in children with COVID-19 infection. Leukemia accounts for nearly one-third of childhood cancer cases, and according to the International Agency for Research on Cancer and the International Association of Cancer Registry, it is the most common cancer in children.10 We report a case of acute lymphoblastic leukemia comorbid with COVID-19 in Beijing, China. The patient presented with a prolonged manifestation of symptoms and a protracted diagnosis period of viral infection of COVID-19 compared with adult patients.
Underlying Disease of Acute Lymphocytic Leukemia
The young male patient was diagnosed with acute lymphocytic leukemia (ALL) developed from the precursor B-cell (tumor cells express CD34, CD10, HLA-DR, CD19, CD56 and cyCD79α) on February 12, 2018, at the age of 1 year and 10 months. He displayed hyperdiploidy, and his common ALL fusion genes, mixed lineage leukemia, and Philadelphia-like screening were negative and clinically dangerous. He achieved complete remission with minimal residue detected in neutrophil count on day 33 (2.8 × 10−4) after a course of treatment of vincristine, daunomycin, l-asparaginase, prednisone induction chemotherapy. His minimal residue was reduced to 0.9 × 10−4 after the cyclophosphamide cytarabine 6-mercaptopurine course and shifted negative on the fourth month after his diagnosis. Afterward, he was administered chemotherapy according to the Recommendations for the Diagnosis and Treatment of Cell Leukemia: Fourth Edition.11 He received methotrexate (25 mg/m2, once per week) and 6-mercaptopurine (50 mg/m2, once per night) maintenance chemotherapy from January 7, 2019, until he was diagnosed with COVID-19.
Time Course of COVID-19
The time course of his COVID-19 infection is shown in Figure 1. The patient (3 years and 10 months) and his parents visited his grandfather in Hebei province, China, between January 22 and 24, 2020, and returned to their home in Beijing, China, on January 25. The patient developed a cough on January 23, 1 day after visiting his grandfather. His cough persisted after treatment with azithromycin, oseltamivir and Feire Kechuan oral solution. Feire Kechuan oral solution is a traditional Chinese medicine for cough relief. The ingredients include ephedra, bitter almond, gypsum, licorice, honeysuckle, forsythia, Anemarrhena, astragalus, isatis root, Ophiopogon and Houttuynia. On February 1, 2020, the patient’s grandfather was diagnosed with COVID-19. The patient was suspected to be infected with COVID-19, but results from nucleic acid reverse transcription-polymerase chain reaction were negative at the outpatient clinic of Beijing Children’s Hospital, Beijing, China, on February 8 and 9. On February 10, he developed a fever that reached a body temperature of 38.2°C, but the patient did not exhibit symptoms of chills, chest tightness or asthma. On February 11, he tested positive for COVID-19 and was hospitalized in Beijing Ditan Hospital. During his hospitalization, he received interferon aerosolized inhalation treatment, as well as oral solutions of Feire Kechuan and compound sulfamethoxazole tablets. His temperature subsided on February 12, yet his cough continued. On February 18, he tested negative for COVID-19 and was discharged home. The patient tested negative on March 7 and during re-examination on March 14.
Auxiliary Examination and Treatment
When he was admitted to the hospital on February 11, 2020, the patient exhibited lower white blood cell, lymphocyte, and CD4+ T lymphocyte counts, as well as higher alanine aminotransferase (ALT), aspartate aminotransferase (AST), C-reactive protein (CRP) and serum amyloid A (SAA) (see Table 1). These indices turned to normal level after the patient had administered recombinant human interferon α1b nebulization, Feire Kechuan oral solution, vitamin C tablets, compound sulfamethoxazole tablets and compound glycyrrhizin tablets. His lymphocyte counts, ALT, AST, CRP and SAA were in normal range. Additional tests including influenza A/B antigen, procalcitonin, myoglobin, troponin, blood coagulation, renal function, serum amylase, lipase, electrolytes and plasma levels of ammonia were all normal. His transabdominal ultrasound showed normal liver size, but his chest computed tomography (CT) revealed heavy texture in both sides of his lungs (see Fig. 2). The patient’s blood type was A RhD positive. Blood testing results including white blood cell, lymphocyte count, lymphocyte percentage, CD4+ T lymphocyte count, hemoglobin, CRP, SAA, ALT and AST are listed in Table 1.
Given that the patient was immunocompromised during the treatment of COVID-19, he did not receive chemotherapy. The patient had normal hemoglobin, normal coagulation and no tendency to bleed, resulting from no detection of skin spots, petechiae, gum inflammation or nosebleeds. A re-examination of the blood test on March 14 was normal. His CRP, SAA, ALT and AST were also normal.
This study reported the first case of childhood leukemia with COVID-19. COVID-19 is caused by 2019-nCoV, a single-stranded RNA virus from a subfamily of Coronavirus, β gene.1,12 Common signs of human infection include respiratory symptoms, fever, cough, shortness of breath and dyspnea. Severe cases combined with comorbid diseases are highly associated with pneumonia, severe acute respiratory syndrome, renal failure and even death.1,2,13,14 Children are reported to show less severe symptoms of COVID-19 compared with adults.9
Our patient had a clear history of epidemic exposure and family clustering. This is consistent with previous reports that most diagnoses in children develop from family clustering cases.9,14 Close family contact is the main epidemiologic feature of COVID-19 in children, similar to the main transmission pattern of severe acute respiratory syndrome and Middle East respiratory syndrome coronaviruses in children.6,13,14 The patient and his parents developed symptoms of fever and cough after visiting the patient’s asymptomatic grandfather during an incubation period of COVID-19. The patient may have been infected by his grandfather given the possibility that COVID-19 is contagious during its incubation period.15 The patient exhibited symptoms earlier and milder than his parents, although his father developed a similar cough.
The patient tested negative for COVID-19 on February 8 and 9, several days after the onset of his cough. Before contact with his grandfather, the patient did not present symptoms of this cough, yet after contact his cough persisted for 33 days without relief. Because his cough developed similarly to his father’s, and although he initially tested negative for COVID-19, the patient was still highly suspected to be infected by his grandfather due to the cough’s symptom presentation only 1 day after contact with his grandfather. This cough also continued for 33 days, a longer duration than adults diagnosed with COVID-19.16 This lengthened symptom presentation may be explained by the patient’s diagnosis of ALL. This disease may weaken the patient’s immune response resulting in a prolonged duration of cough induced by a low viral load. However, due to the patient’s uncollaborative responses including crying and struggling to avoid sampling during specimen collection, we cannot exclude the possibility that the result on February 8 and 9 was a false negative. These findings require validation from future studies with more cases. The 20-day lag period between the onset of cough and positive result for nucleic acid suggests that COVID-19 tests should be conducted on children who have been exposed to individuals with a confirmed diagnosis of COVID-19, especially for children with primary or secondary immune dysfunction, even if the child remains asymptomatic. On the other hand, the patient showed normal hemoglobin during the treatment of COVID-19. However, the patient did not receive chemotherapy during the treatment of COVID-19 and could be harmed by the inability to treat his ALL. Additional studies are needed to investigate the influences of COVID-19 in individuals with dysregulated immune function.
The patient tested negative for influenza A virus and influenza B virus and displayed no improvements after treatment with oral azithromycin and compound sirolimus. Therefore, these observations were unrelated to influenza A/B viruses or bacterial infection. However, we cannot eliminate the possible infection of a separate respiratory virus. Previously, we observed that children with COVID-19 usually have mild clinical symptoms (which findings are in preparation for submission; Li et al17). It is possible that children are easily infected with various respiratory pathogens, including coronavirus 229E, OC43, and NL-63 and thus gain cross-immunity protection. In addition, children may carry viruses for a longer time and become a potential source of infection, even if they remain asymptomatic.
The laboratory tests showed lower peripheral blood lymphocyte count and lower CD4+ T lymphocyte count during the early stage of COVID-19, suggesting that childhood leukemia comorbid with COVID-19 exhausts lymphocytes. For this reason, it is important to be aware of changes in T-cell subsets in children with both leukemia and COVID-19. Finding the key mechanism for pathogens to destroy lymphocytes will inspire clinicians to improve treatment by regulating the immune function of patients.9 This study speculates after 2019-nCoV infection, the virus protein phenotype that recognizes CD4+ T cells is instead modified to create CD4+ T cells during the process of replication in the host cells. Because these cells cannot recognize the virus correctly, they remain in a low activation state. To have an antiviral immune effect, the body selects other immune cells who are able to recognize the virus protein phenotype to activate and proliferate. This effectively kills the virus. At this time, the immune bias in the body is more conducive to the inhibition of CD4+ T-cell expression. For this conjecture, we need to further explore and analyze the molecular mechanism.
Multiple clinical observations report that patients with COVID-19 may have liver damage, and the proportion of liver enzymes is significantly increased in critically ill and severe patients with COVID-19.16 Human angiotensin I converting enzyme (peptidyl-dipeptidase A) 2 is the receptor related to 2019-nCoV.18 Our patient with acute lymphoblastic leukemia was in remission, and under maintenance treatment, and his previous liver enzyme tests were normal. After being infected with COVID-19, he exhibited higher ALT and AST but showed normal liver enzymes after receiving oral liver protection therapy.
The patient also showed thick and fuzzy lungs on his chest CT. This result is different from previous reports of patients with COVID-19 showing multiple subpleural ground-glass shadows and infiltrates in the lungs and even pulmonary consolidation in severe cases.9 This finding suggests that, to avoid a false negative and the delay of treatment, more attention should be provided to children exposed to COVID-19, even if they do not display significant symptoms or show expected changes on a chest CT. It is predicted that the COVID-19 pandemic may be similar to seasonal influenza (fatality rate close to 0.1%) or the pandemics of 1957 and 1968.19
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. Further attention should be provided for patients experiencing complications such as abnormal liver function, and greater active treatment should be implemented to avoid exacerbations. The findings of this case study need to be verified in a larger sample. A follow-up study of this patient may also help to understand the long-term effects of COVID-19 and its treatment on children with underlying diseases.
We thank Ms. Heather Bouchard for her polishing the texts. We also thank the anonymous reviewers.
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