Observed reduction in the diagnosis of acute lymphoblastic leukaemia in children during the COVID‐19 pandemic

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Abstract

To contain the spread of the new severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), which causes coronavirus disease 2019 (COVID‐19), the Norwegian government implemented lockdown restrictions from March 13, 2020: schools, day cares and after‐school activities were closed, 2‐week quarantine was required following international travel, physical distancing (2 m) was recommended, and groups were restricted to five people. 1 Simultaneously, there was great focus on personal hygiene recommendations. From the end of April, the restrictions were gradually scaled back with reopening of schools and day cares, physical distancing reduced to 1 m and groups up to 20 people allowed. The advice to stay home in case of respiratory symptoms or fever remained. New daily cases of SARS‐CoV‐2 infection fell nationally from maximum 297 in March 26, 2020, to 10‐20 in June and July. In parallel, the number of diagnosed airway infections with other pathogens fell rapidly, probably reflecting the implemented lockdown measures. Acute respiratory infection is the most common illness in children. 2 We investigated the effect of the COVID‐19 pandemic and lockdown on the diagnosis and follow‐up of paediatric cancer patients at Oslo University Hospital (OUH). All new cancer cases in patients <18 years in the south‐eastern region of Norway (~2.6 million people) are admitted and diagnosed at OUH, and a clinical pathway for cancer in children is started. In this descriptive study, we retrospectively reviewed all clinical pathways for cancer in children resulting in a cancer diagnosis January 01, 2017–July 31, 2020, at OUH. We used the Poisson distribution, which gives the probability of a given number of events occurring in a fixed time interval, given a known event rate, to calculate the probability of the observed number of events during the COVID‐19 pandemic lockdown, given the pre‐lockdown event rate. We reviewed outpatient consultations and cancellations January 01–June 30, 2020, compared to January 01–June 30, 2019. Additionally, we examined airborne infectious pathogens (see supplementary data, Data S1) found by polymerase chain reaction (PCR) analysis of deep nasal swabs in children <18 years at OUH January 01, 2017–July 31, 2020, as an indirect measure of infectious disease in the community. There were no hospitalised paediatric cancer patients diagnosed with COVID‐19 the first 6 months of 2020. In 2017, 2018 and 2019, there were 82, 99 and 92 new paediatric cancer cases, respectively (mean 7.58 cases/month, 95% confidence interval (CI) 6.80‐8.37, median 7.5 cases/month, range 3‐12). In the first 6 months of 2020, there were 35 new paediatric cancer cases (mean 5.83 cases/month, 95% CI 3.09‐8.58, median 5.5 cases/month, range 1‐11). The number of solid tumours both within and outside the central nervous system was stable; however, there was a marked reduction in acute lymphoblastic leukaemia (ALL) cases. In 2017, 2018 and 2019, there were 20, 31 and 22 new ALL cases, respectively (mean 2.03 cases/month, 95% CI 1.63‐2.43, median two cases/month, range 0‐4). In the first 6 months of 2020, there were three new ALL cases, and all were diagnosed before the lockdown (two in early March 2020) (Figure S1). In the first 4 months of the lockdown (13.03.2020‐12.07.2020), not a single paediatric ALL was diagnosed. Based on the observed rate in 2017‐2019, the probability of having no new ALL cases over 4 months is <0.001 (95% CI 0.00006‐0.001). The probability of having ≤ 3 new ALL cases over 6 months is 0.002 (95% CI 0.0003‐0.012). There were three new ALL cases in July 2020. Before 2020, the longest period with no observed ALL cases was 66 days and the lowest number of cases in a 4‐month period was four, both occurring in 2017. Numbers from the Department of Microbiology show an 82% and 76% decrease in airway pathogens found by PCR in children in April and May 2020 compared to the average for these months in 2017‐2019 while the total number of tests was stable (Figure S1). In June and July, the reduction was 43% and 37%, respectively. Cancellations of paediatric haematology and oncology outpatient clinic consultations at OUH increased by 50% in March 2020 compared to 2019, mainly due to patients/parents in quarantine or home isolation, fear of exposure to COVID‐19 and flight traffic disruption. Telephone or video consultations were quickly implemented to avoid unnecessary delays. Eighteen per cent of outpatient consultations in March and 12% in April were over phone or video, reduced to 3% by June, compared to none in 2019. Our review shows a marked reduction in paediatric ALL cases during the COVID‐19 lockdown, though the absolute numbers are small. Similarly, the Children's Hospital of Philadelphia, USA, reported no new leukaemia cases from March 02, 2020–April 06, 2020, (35 days) compared to a 5‐year average of one every 3 days, 3 and the first cases presenting in April required intensive care, indicating delayed diagnosis. The first cases of ALL at OUH in July 2020 did not show evidence of advanced disease. There have been reports of a reduction in paediatric solid tumours, both from Milano, Italy, and New York, USA. 4 , 5 New York but not Milano observed an increase in metastatic cases. During the SARS‐epidemic in Hong Kong in 2003, which also lead to a lockdown of society, a decrease in new ALL cases in young children was seen. 6 This was hypothesised to be related to common infections playing a role in ALL development. Though we have seen a decrease in airway pathogens, we do not have a direct measure of common infections in society and we are limited by small numbers of ALL cases. The drop in ALL cases was observed from the beginning of the lockdown though one might have expected some latency; however, there had already been changes in behaviour in society before the lockdown was implemented. In addition to infection, there may have been reduced contact with other environmental factors potentially involved in leukaemogenesis during the lockdown. The role of infectious disease in ALL development is not clear, but the social experiment of the COVID‐19 lockdown might give an indication when different experiences around the world are compared, for example in a large multicentre study including regions with and without lockdown. CONFLICT OF INTEREST None. Supporting information Appendix S1 Click here for additional data file.

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Epidemiology of viral respiratory infections

Arnold Monto (2002)

Acute respiratory tract infections are the most common illnesses in all individuals, regardless of age or gender. Epidemiologic surveys and community-based studies conducted since the beginning of the 20th century have determined the rates of illness and the pathogens involved in such infections. These studies have shown that rhinoviruses cause the great majority of these respiratory illnesses, and their findings have examined the means of transmission of respiratory illness. More recently, advances in diagnostic techniques have enabled more complete identification of the viruses involved in respiratory infections, which has aided in the ability to direct specific therapeutic agents at the causative pathogens.

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Delayed cancer diagnoses and high mortality in children during the COVID‐19 pandemic

Yang-Yang Ding, Sneha Ramakrishna, Adrienne H Long … (2020)

To the Editor, Although the effects of the SARS‐CoV‐2 virus on infected patients are increasingly documented, the indirect consequences for uninfected patients are less well described. 1 We report five cases of children who presented critically ill to two U.S. tertiary referral centers (Children's Hospital of Philadelphia [CHOP] and Lucile Packard Children's Hospital at Stanford [LPCH]) in April 2020. All patients tested SARS‐CoV‐2 negative and experienced delays in cancer diagnosis due to the COVID‐19 pandemic with grave consequences. Each patient required emergent life‐saving interventions shortly after presentation (Table 1), including resuscitation following cardiac arrest (N = 2), emergent intubation (N = 4), and emergent pericardiocentesis for tamponade (N = 1). Two patients died within days of presentation. Although pediatric cancers can present with severe initial findings, the clustered frequency and acuity of these recent initial presentations is striking. TABLE 1 Clinical characteristics, presentation, and outcomes of children who presented in critical condition and were subsequently diagnosed with cancer # Visits prior to diagnosis Patient Age (years) Sex Symptoms at presentation Onset of symptoms Tele‐health PMD/urgent care ED Presumed diagnosis Time from initial presentation to diagnosis Oncologic diagnosis SARS‐CoV‐2 RT‐PCR assay Notable laboratory/radiologic findings Clinical course Survival status 1 4 F Fevers, emesis, hallucinations 3 weeks 2 1 1 Viral syndrome 2 weeks B‐cell ALL Negative × 2 WBC 1,000 /μL Blasts 1.6% Hgb 2.3 g/dL Platelets 3,000 /μL Lactate 13 mmol/L Uric acid 19 mg/dL Blood culture positive for Group G strep Many clusters of bacterial organisms on BMA Presented in shock. Cardiac arrest with multisystem organ failure. Brain herniation. Hemodialysis delayed due to COVID‐19‐related staffing shortages. Deceased (HD 5) 2 16 M Fevers, cough, emesis, diarrhea, dyspnea 4.5 weeks 0 1 2 Asthma flare and acute otitis media 4 weeks B‐cell ALL Negative × 3 WBC 1,000 /μL Blasts 26% Hgb 3 g/dL Platelets 77 ,000 /μL Lactate 15 mmol/L Uric acid 11.5 mg/dL Presented in respiratory distress. Cardiac arrest with multisystem organ failure. Small cerebral hemorrhages. Alive 3 17 F Abdominal pain, cough, palpitations 2.5 weeks 4 0 1 Gastritis 2 weeks Stage III DLBCL Negative × 1 Echocardiogram: large circumferential pericardial effusion with right atrial and ventricular collapse CT chest: large anterior mediastinal mass Presented in cardiac tamponade. 1.5 L malignant pericardial fluid emergently drained. Alive 4 10 F Shortness of breath, lethargy and cyanosis 3 days Reported parental reluctance to present to care 3 days T‐cell lymphoblastic lymphoma Negative × 2 pH of 6.9 pCO2 100 Lactate of 9.2 CT chest: large anterior mediastinal mass Presented in respiratory distress and obtunded. Emergently intubated Alive 5 8 M Fevers, throat pain, pallor, bruising, vomiting, fatigue, and eye pain 4 weeks 0 2 0 Tonsillitis 4 weeks AML Negative × 1 WBC 365,000 /μL Blasts 89% Hgb 6.1 g/dL Platelets 28,000 /μL INR 1.7 Fibrinogen 191 Presented with altered mental status. Status epilepticus and emergent intubation. Intracranial hemorrhage and herniation. Deceased (HD 5) AML, acute myeloid leukemia; ALL, acute lymphoblastic leukemia; BMA, bone marrow aspirate; DLBCL, diffuse large b‐cell lymphoma; ED, emergency department; EMS, emergency medical services; HD, hospital day; Hgb, hemoglobin; PMD, primary medical doctor; WBC, white blood cell. John Wiley & Sons, Ltd. This article is being made freely available through PubMed Central as part of the COVID-19 public health emergency response. It can be used for unrestricted research re-use and analysis in any form or by any means with acknowledgement of the original source, for the duration of the public health emergency. Coinciding with the rapid rise in regional COVID‐19 cases and initiation of stay‐at‐home orders, both institutions noted significant changes in the timing and severity of new patient presentations. The first COVID‐19 case in Pennsylvania was reported on March 6, 2020. Despite a five‐year historical mean of 2.96 days between new leukemia patients, CHOP did not see any patients with a new leukemia diagnosis for 35 days (March 2, 2020, to April 6, 2020). Comparatively, the longest gap from 2015 to 2019 was 18 days. Thus, it was notable when two patients subsequently diagnosed with acute lymphoblastic leukemia (ALL) presented on consecutive days to the pediatric intensive care unit (PICU) after having cardiac arrests at local hospitals in April. Similarly, LPCH noted an increase in the percentage of patients requiring prolonged PICU care at diagnosis. In April 2020, 75% of new leukemia/lymphoma diagnoses required PICU care, compared with a historic monthly average of 12% during 2018–2019 (previous maximum 40%). Pediatric cancers are relatively rare, and thus delays in diagnosis can occur. 2 However, our experience suggests that additional factors specific to the ongoing COVID‐19 pandemic contributed to care delays and higher patient acuity. The family of one patient expressed reluctance to seek care due to fear of COVID‐19 exposure. The other four patient families had repeated contact with the healthcare system prior to ultimate diagnosis. This suggests that healthcare system factors may play a role, including decreased referrals to emergency departments or laboratories, and transition to alternative evaluation methods such as telemedicine. Diagnostic bias may also occur, since presenting signs of malignancy (fever, malaise, and respiratory symptoms) can initially be mistaken for symptoms of COVID‐19. Furthermore, endemic areas have reported that children are less likely to become critically ill from COVID‐19 disease as compared with adults, 3 which may delay referral of children for emergency services or laboratory studies. Two patients had multiple telehealth visits prior to in‐person evaluations. Telemedicine utilization among primary and acute care providers is increasing during the pandemic. 4 The limitations of telemedicine, including lack of ability to detect critical physical exam findings such as unstable vital signs, pallor, and hepatosplenomegaly, are underscored by these cases. For example, after two telehealth visits and one visual assessment outside the primary care provider's office, patient 1 re‐presented hours later to a local emergency department with overwhelming sepsis that progressed to cardiac arrest and brain death. Such an outcome is particularly difficult given the extremely favorable prognosis of childhood ALL. Indeed, the pediatric cancer diagnoses presented here are highly curable in North America with expected cure rates ranging from 67% to over 95% depending on diagnosis. 5 These cases illustrate the indirect impact of this pandemic on morbidity in COVID‐19–negative patients for whom care delays can be fatal. We highlight the unintended consequences of a pandemic‐transformed healthcare system for a vulnerable pediatric population. More work is critical to quantify these consequences and to develop solutions that protect severely ill but treatable children, while also balancing public health and the needs of those infected during this COVID‐19 pandemic. CONFLICTS OF INTEREST The authors have no conflicts of interest/financial relationships relevant to this article to disclose.

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A collateral effect of the COVID‐19 pandemic: Delayed diagnosis in pediatric solid tumors

Stefano Chiaravalli, Andrea Ferrari, Giovanna Sironi … (2020)

To the Editor: The COVID‐19 pandemic has become a huge health emergency. In the world of pediatric oncology, we have had to profoundly modify our habits regarding the management of patients and their families. We have had to focus on minimizing the risk of the virus spreading within the hospital while ensuring the best possible management of cases found positive for COVID‐19 and, above all, on assuring our children and adolescents that they will receive the oncological care they need. 1 , 2 , 3 , 4 Meanwhile, during the 8‐week lockdown imposed in Italy to cope with the peak of the epidemic, we noted a reduction in the number of pediatric tumors being newly diagnosed, probably reflecting delayed access to health care services for patients with signs and symptoms suspected of being cancer‐related. 1 Now, with the gradual decrease in the number of new coronavirus infections and related deaths, and the end of Italy's lockdown (for now), we have examined the delay in the diagnosis of patients coming to our Pediatric Oncology Unit of the Istituto Nazionale Tumori, Milan, a referral center for pediatric solid tumors not only for Lombardy (the epicenter of the COVID‐19 epidemic in Italy), but for the whole of Italy. Firstly, we found that during the lockdown period (from March 9 to May 3, 2020), we registered 16 newly diagnosed patients. It is of note that during the same period in the years 2017, 2018, and 2019, we had registered 34, 35, and 36 cases, respectively. Therefore, under lockdown, we observed only 45.7% of the expected cases (Fisher exact test P‐value .0416). We also considered our patients’ regions of provenance, bearing in mind that, judging from data collected for the whole year of 2019, we would have expected 74% of our patients to come from northern Italy, 5% from central Italy, 18% from southern Italy, and 3% from abroad. Among the 16 cases seen during the lockdown period, all but two of them were from Lombardy (the region where our center is located). Assuming that any drop in the diagnostic rate might be followed by a rebound, we then analyzed the number of new cases diagnosed in the subsequent 8‐week period (from May 4 to June 28, 2020). As shown in Table 1, in the 8‐week postlockdown period, we registered 37 new cases; eight of them (22%) coming from central and southern Italy. TABLE 1 Cases of pediatric solid tumor newly diagnosed during the 8‐week lockdown and during the subsequent 8 weeks Period March 9‐May 3, 2020 (lockdown) May 4‐June 28, 2020 Newly diagnosed cases 16 37 Age 3‐24 years (median 10 years) 1 month‐24 years (median 11 years) Region of provenance Northern Italy 14 b 29 Central Italy 0 3 Southern Italy 2 5 Tumor type b CNS tumors 5 10 Bone/soft tissue sarcomas 6 8 Lymphomas 1 2 Others 4 17 Stage: M0 13 31 M1 3 6 Abbreviations: CNS, central nervous system; M0, without metastases; M1, with metastases. From Lombardy (Milan region). a Our center only treats solid tumors. John Wiley & Sons, Ltd. This article is being made freely available through PubMed Central as part of the COVID-19 public health emergency response. It can be used for unrestricted research re-use and analysis in any form or by any means with acknowledgement of the original source, for the duration of the public health emergency. Certainly, this is only the picture for our center (a regional and national reference center for the treatment of pediatric solid tumors), and we do not know if the missing patients went elsewhere. However, it is plausible that the drop to half the number of new diagnoses may be a collateral effect of the COVID‐19 pandemic. Several publications have already reported inadequate access to care and consequent delay in the diagnosis of cancer patients (adults and children) during this emergency period. 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 The travel restrictions imposed by lockdown measures (including visits to hospitals and travel between different regions) represented a barrier to access to medical care, including access to emergency rooms and specialist visits in the event of suspicious signs and symptoms. Objective logistic difficulties were also compounded by the fear of contagion at a time when hospitals were at risk of spreading the disease. Hospitals came to be seen no longer as places offering protection and treatment, but as a possible source of infection. Assuming that families were scared of going to hospitals when mild symptoms developed under lockdown, we might have expected to see a rebound with a higher incidence of new cases, as soon as the lockdown was lifted. Albeit with the limitation of the small sample size, our analysis indicates instead that the numbers of new cases are back in line with expectations based on previous years. For the time being, there seems to have been no excessive increase in the number of cases, though it may be too early to say for sure. In fact, traveling between Italy's regions was still limited for weeks after the full lockdown measures were lifted, and the population has remained fearful of the virus even now that the situation appears to be more or less under control. As an additional evaluation, we have examined the symptom interval in the postlockdown cohort of patients, comparing the figures with those of historical studies in the pediatric oncology patient population. 13 , 14 , 15 No major findings emerged; if anything, the patient delay seems to have been longer in the postlockdown series, as if the time it took patients or families to decide to see a doctor increased (Table S1). This finding makes it important to continue monitoring the numbers of new diagnoses and any diagnostic delays (and how much this may ultimately pose a problem in terms of a disease's presentation and a patient's chances of cure). In short, albeit with all the limitations relating to the small sample size and the preliminary nature of this analysis, our study suggests that a possible collateral effect of the COVID pandemic to bear in mind is the reduced likelihood of pediatric cancer patients accessing referral centers, and their consequently worse chances of a timely diagnosis. Supporting information Supporting Information Click here for additional data file.

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Kirsten Brunsvig Jarvis:

ORCID: https://orcid.org/0000-0002-8996-1195

kirjar@ous-hf.no

Journal

Journal ID (nlm-ta): Acta Paediatr

Journal ID (iso-abbrev): Acta Paediatr

Journal ID (doi): 10.1111/(ISSN)1651-2227

Journal ID (publisher-id): APA

Title: Acta Paediatrica (Oslo, Norway : 1992)

Publisher: John Wiley and Sons Inc. (Hoboken )

ISSN (Print): 0803-5253

ISSN (Electronic): 1651-2227

Publication date (Electronic): 05 October 2020

Electronic Location Identifier: 10.1111/apa.15576

Affiliations

[ ¹ ] Department of Paediatric Haematology and Oncology Oslo University Hospital HF Oslo Norway

[ ² ] Department of Paediatric Research Oslo University Hospital HF Oslo Norway

[ ³ ] Department of Microbiology Oslo University Hospital HF Oslo Norway

[ ⁴ ] Oslo Center for Biostatistics and Epidemiology Oslo University Hospital Oslo Norway

[ ⁵ ] Faculty of Medicine Institute of Clinical Medicine University of Oslo Oslo Norway

Author notes

[*] [* ] Correspondence

Kirsten Brunsvig Jarvis, Department of Paediatric Haematology and Oncology, Oslo University Hospital HF, Rikshospitalet, Postboks 4950 Nydalen, 0424 Oslo, Norway.

Email: kirjar@ 123456ous-hf.no

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Kirsten Brunsvig Jarvis https://orcid.org/0000-0002-8996-1195

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Publisher ID: APA15576

DOI: 10.1111/apa.15576

PMC ID: 7537500

PubMed ID: 32959407

SO-VID: b948b0c7-e2f4-4d47-abf5-06a0abd43552

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This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

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Date received : 20 August 2020

Date revision received : 09 September 2020

Date accepted : 11 September 2020

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Observed reduction in the diagnosis of acute lymphoblastic leukaemia in children during the COVID‐19 pandemic

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Epidemiology of viral respiratory infections

Delayed cancer diagnoses and high mortality in children during the COVID‐19 pandemic

A collateral effect of the COVID‐19 pandemic: Delayed diagnosis in pediatric solid tumors

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