key: cord-0957620-txkzxn2u
authors: Bhayana, Swati; Kalra, Manas; Sachdeva, Anupam
title: Covid-19 in pediatric hematology-oncology and stem cell transplant patients –The spectrum of illness, complications and comparison of first two waves
date: 2022-05-11
journal: nan
DOI: 10.1016/j.phoj.2022.05.003
sha: 15412ec24e9dc596db35985c05ecee9dbb177b6a
doc_id: 957620
cord_uid: txkzxn2u

Introduction Indian subcontinent witnessed first wave of COVID-19 around March 2020 and second wave in April 2021. The mutant delta variant was ≈2.5 times more transmissible and led to the severe second wave. We compared the impact of two waves on pediatric hematology and oncology patients at our tertiary care centre that was at heart of managing COVID-19. Methods Children between 0–18 years, who were treated for a haematological illness, malignancy or stem cell transplant with confirmed COVID-19 infection or who developed multisystem inflammatory syndrome in children were included. Results A total of 48 (22-first, 26-second wave) children were evaluated. Despite better understanding of disease and standardised management algorithms, we found a trend towards younger age, increased requirements of oxygen, severe pneumonia and other post-covid complications in admitted patients during the second wave. We observed early RTPCR negativity in second wave. Invasive aspergillosis, disseminated candidiasis, reactivation of tuberculosis HLH and MISC were the main complications. No child died of COVID-19. Conclusion The second wave hit pediatric hematology and oncology patients harder than the first wave.COVID-19 infection in these patients may lead to significant morbidity and complications that interfere with treatment of their primary illnesses. They need close monitoring for development of life threatening infections. Early recognition and prompt therapy can optimise outcomes.

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has had a devastating effect on the world's population resulting in more than 281 million cases and 5.4 million deaths worldwide and emerged as the most significant global health crisis since the influenza pandemic of 1918 as of February 2022 [1] .

COVID-19 was first reported in Wuhan, China at the end of January 2020 and declared a pandemic by World Health Organization (WHO) in March 2020 [2] . Like the Spanish flu, COVID-19 has also affected the globe in tsunami like waves. Despite the phenomenal pace at which mass vaccination efforts have been carried out across the world, the emergence of new variant strains of SARS-CoV-2 threaten to overturn the progress made so far and the concern of future waves still looms around.

Patients affected by cancers are at higher risk of SARS-CoV-2 infection owing to the immunocompromised status [3] . Adult cancer patients with COVID-19 have had worse outcomes and higher fatality [4] [5] as compared to the normal population [6] [7] . Children with cancer are a vulnerable population for severe COVID-19 owing to the primary illness, chemotherapy related immunosuppression, frequent exposure and repeated visits to the hospital.

Indian subcontinent witnessed 2 peaks, first wave hit around March 2020 and peaked until September 2020 and second wave hit by April 2021. The rise in case load during the second wave was astronomical and saturated the health care facilities within no time [8] . The culprit of the second wave was a delta strain (B.1.617.2 ) that was ≈2.5 times more transmissible than the strain of the first wave [9, 10] . Since the emergence of variants, their spread across the globe has been fast and studies highlight that they are more severe with higher risk of J o u r n a l P r e -p r o o f mortality, hospitalizations and Intensive care unit (ICU) admissions [11] . Other reasons contributing to the further outbreak are lack of covid appropriate behaviour by the public and vaccination coverage that still doesn't cover the majority of pediatric population and adults completely. Data suggests that higher age, requirements of oxygen and ventilation, ICU admission, and organ impairment were more prevalent in the admitted COVID-19 cases during the second wave [12] .

We have previously reported data of our patients with COVID-19 infection during the first wave [13] . We further studied the clinical profile and outcomes of the children with haematological illnesses, cancer and recipients of hematopoietic stem cell transplant (HSCT) who developed COVID-19 infection during the second wave in 2021. The study intends to compare the two waves, describe the complications of COVID-19, help formulate the baseline data to compare with future waves of SARS-CoV2 and aid in policy/strategy making.

Study design, duration -This is a retrospective study from a tertiary care centre in North India conducted during the first and second wave of the SARS-CoV-2 pandemic. The first wave included cases between March and December 2020 and the second wave included cases between March 2021 and June 2021 with a follow up till mid-October 2021.

• Children between 0-18 years, who were treated for a hematological illness, malignancy or those who underwent HSCT regardless of the current treatment status The institutional protocol and the Delhi government policy suggested COVID-19 testing for patients with malignancies prior to administering chemotherapy, regardless of their symptoms. We therefore tested asymptomatic patients on fortnightly basis and symptomatic patients at presentation. The patients underwent antigen testing (Antigen standard Q COVID-19 antigen kit) or RT-PCR testing (Argene kit) or rapid real-time PCR test (GeneXpert/BioFire-Xpert kit) based on urgency of admissions, kit availability in the hospital. Repeat testing was performed every 5 days for the hospitalized patients during the first wave and every 7 days during the second wave and after 2 weeks for patients in home quarantine. Baseline blood investigations for all admitted patients included complete blood counts, liver and kidney functions, IL-6, serum ferritin and N-terminal pro b-type natriuretic peptide (NT-pro BNP). Children with mild symptomatology and normal oxygen saturation were managed at home and tele-consultation service was provided twice a day. A 24-hour helpline service was provided to all patients on home quarantine. Patients received treatment for COVID-19 as per the institutional protocol and in accordance with the national guidelines for the management of COVID-19, issued by the government from time to time. Patients presenting with clinical features suggestive of MISC and fulfilling the WHO criteria were included. Patient underwent antibody testing as per XX.

Exclusion criteria -Patient suspected to have COVID-19 infection without definitive evidence of positive antigen/PCR test report.

Data was described in percentages for categorical variables and as the mean ± standard deviation and median for continuous variables. No sample size calculations were performed as all cases with COVID-19 positivity were enrolled. Percentage of children were compared J o u r n a l P r e -p r o o f using chi square tests. Demographic and clinical profile in the two groups were compared using chi-square for qualitative data and t test for quantitative data.

To compare the prevalence, clinical , laboratory parameters and outcomes of COVID-19 infection during the two waves of the pandemic in pediatric hematology oncology and HSCT patients during the first and second wave of SARS-CoV2 pandemic. Amongst the symptomatic cases, most common symptom was fever (first wave, n=7/22; second wave n=5/26) and cough (first wave, n=7/22; second wave n=4/26). Table 2 shows details of symptomatic patients in two waves (First wave, n=10/22; second wave n=7/26) Table 3 shows laboratory parameters (mean/median) during the first and second wave However, the median time to delay (First wave -14 days , second wave -9 days ) reduced and the maximum delay period was kept as minimal as possible. We did not routinely add metronomic/ oral chemotherapy to our patients facing delay in receiving the next cycle as the delay was minimal. The maintenance chemotherapy was withheld for a maximum of 7 days and restarted once the child was afebrile, free from symptoms and stable at home. We did Not only children with haemato-oncological illnesses had to face significant interruptions in treatment and logistic challenges that COVID-19 bestowed, it also lead to increased morbidity and financial burden. The first wave witnessed usage of many therapeutic strategies , mostly out off desperation without adequate scientific proof of the benefit.

Emergence of new mutations and rapidity of its spread exhausted the health care facilities and personnel. We looked at the extent of damage the virus did to pediatric hematology, oncology and HSCT patients on regular follow up with our unit.

Mean positivity rate during the first wave was 12.1 % and during the second wave was 17.4 %. The absolute incidence of COVID-19 amongst pediatric cancer patients continues to be low in first wave as well as second wave.

Median age at diagnosis showed a decreasing trend in our study from first wave to second wave. The trend to younger population involved is seen among children as well as adults during the second wave. [14, 15, 16, 17] .

Similar to general population who were affected with COVID-19 , majority of our patients during the second wave were asymptomatic [16, 18] . There is also decreasing trend of fever and cough as the presenting symptom as observed in our study. Though studies showed more gastrointestinal symptoms during the second wave in general population, our cohort had lesser such symptoms when compared to the first wave [19] . Two of our patients during the first wave had neurological symptoms. One was encephalopathy of unknown origin and other child presented with PRES. The causal relationship with COVID-19 could not be established.

However, literature does support that COVID-19 may precipitate neurological events in children [20, 21] .

We observed a higher median ferritin and median Interleukin 6 (IL6) levels during the second J o u r n a l P r e -p r o o f wave similar to other studies thereby explaining severity of cytokine storm and indirectly the cellular damage and organ dysfunction [22] .

CT chest was extensively used during the second wave in diagnosing and prognosticating COVID-19 cases. CT severity score is used as a semiquantitative imaging tool and studies show the cut-off of 6.5/20 (with about 32.5% lung involvement) had 90.9% sensitivity and 69% specificity for identification of severe cases [23] . The most widely used method is based on scoring of percentage of involvement of each lobe and total score of 0 to 25 [24] . The CT findings of COVID-19 ranged from consolidation patches with air bronchogram, pulmonary nodules and atelectatic fibrous bands to extrapulmonary findings in the form of pleural effusion and pericardial effusion. Two of our patients from second wave had CTSS >7 and bilateral lung involvement. Both of these required oxygen support. Follow up scans in one patient with Pre B ALL showed invasive pulmonary aspergillosis.

Duration to negative RTPCR is variedly found in studies from 10 days to 5 weeks. Studies have reported unfavourable outcome in persistent positive cases [25] . We observed that the time to negativity decreased during the second wave. The maximum persistent positivity during the first wave was 63 days in a child with HLH post haploidentical transplant who required intensive care whereas the maximum duration during the second wave was 14 days.

Although scarce, some studies have supported that patients with haematological malignancy mount a good antibody response and high rate of seroconversion [25, 27] . Eight out of 10 (80%) and 11 out of 14 patients (73.5 % ) had positive antibody titres during the first and second wave respectively. Prospective studies are needed to analyse if these antibodies are sustained in the system and rise in titres once again if exposed to the virus. These patients should also be considered for clinical trials on safety and efficacy of vaccination [28] .

The unique syndrome of MIS-C can also bring additional challenges in managing children J o u r n a l P r e -p r o o f with compromised immunity. We encountered 3 children with MISC based on WHO criteria [29] . Two children needed intensive care therapy including one child with medulloblastoma requiring high frequency oscillatory ventilation. Two of these patients developed coronary artery dilatation. These dilatations resolved on follow up and none had residual cardiac sequelae.

Some of our patients who developed COVID-19 illness were later found to have secondary complications, mainly in form of infections. One of the our patients had CMV infection one month post recovery from MISC. There has been case reports of COVID-19 and CMV coinfection in critically ill patients caused by the increasingly widespread use of anti-IL-6 and anti-IL-1 biological therapies in COVID-19 [30] . However, underlying immunocompromised status, primary illness and prolonged steroids for MISC may explain CMV reactivation in our patient even though anti-IL therapies were not used.

Another child with Pre B ALL had pulmonary tuberculosis during the induction chemotherapy with MISC. Studies have postulated that COVID-19 infection may boost the development of active TB [31] . Prolonged T cell depletion post COVID infection, excessive usage of steroids, malnutrition and general debility may cause reactivation of latent TB in our patients [32] .

Viruses have been traditionally associated with precipitation of HLH. COVID-19 triggered severe hemophagocytosis in a child with primary HLH has not been reported. During the second wave, a patient presented with life threatening hemophagocytosis triggered by COVID-19 and she was found to have compound heterozygous PRF1 mutation. This child needed extensive supportive therapy in ICU. She was given etoposide, steroids and cyclosporine based chemotherapy. After 10 weeks of treatment and control of inflammatory state, she successfully underwent haploidentical transplant with TCR alpha beta depletion.

Reinfection by SARS-COV-2 is rare but has been documented. Surveys have identified a reinfection proportion of 4.5% from a pool of 1,300 participants infected between January 2020 and October 2020. [8] . Case report from pediatric oncology pool have reported reinfection as well [33] .In our study we found reinfection in one patient. This was a case of Burkitt leukaemia who received 3 rituximab doses prior to his infection during the first wave. We withheld rituximab doses in the immediate post recovery chemotherapy due to poor outcomes of COVID-19 in patients with cancer and connective tissue disorders who have been treated with rituximab, [34] . The child had low titre antibody positivity (3.41 IU/ml) during the first wave but negative antibody response during the second wave. This could be explained by rituximab mediated humoral depletion which could compromise antiviral immunity, including development of SARS-CoV-2 antibodies, increase the risk of reinfection, and impair vaccine efficacy [35] . His clinical course was uneventful both times and recovered without any hospitalization.

The absolute number of patients with alteration in chemotherapy was less during the second wave. The median delay time was less and the maximum delay time was also kept as minimum as possible. This is because of the building evidence and confidence in continuing therapy in patients who are not unwell, and monitoring lessons learnt from first covid wave.

The threat of cancer and relapse in these children is more than what a mild covid-19 disease could do. Most of pediatric guidelines have supported continuation of chemotherapy as comparison to adult guidelines who often need interruption due to co morbidities and complications of the viral infection [36] .

We understand that the research was limited to patients from a single centre in North India. J o u r n a l P r e -p r o o f

As it was a retrospective study, waiver of consent was taken from Institutional Ethics committee. 

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