Study characteristics and quality
A total of 3077 publications were identified (Figure 2). After exclusion of duplicates and articles that did not fulfil the study inclusion criteria, one hundred and fifty-five articles were included in the qualitative synthesis of this systematic review (3, 4, 7, 8, 12-40, 57-178). The reports of one thousand two hundred and eighty-nine cases identified from these articles are presented by groups based on the 2022 updated Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms as described by the 5th edition of the World Health Organization (50, 51). The detailed characteristics of the included studies are shown in Table 1. There were 83 case report (3, 4, 17, 22, 25, 28-30, 33, 34, 36, 57, 58, 61, 63-66, 68, 71-73, 76, 77, 79-84, 86-90, 94, 95, 97-102, 105, 106, 109, 111, 112, 114, 115, 117, 118, 120-122, 124-127, 132-142, 145, 147-149, 152, 154, 156-158, 160, 164-166), 54 cohort (7, 8, 12-16, 18, 20, 21, 24, 26, 31, 32, 35, 37-40, 59, 62, 67, 69, 70, 74, 75, 91-93, 96, 103, 104, 107, 108, 113, 116, 123, 129-131, 144, 150, 155, 159, 161, 167-172, 174-176), and 18 case-series (19, 23, 27, 60, 78, 85, 110, 119, 128, 143, 146, 151, 153, 162, 163, 173, 177, 178) studies. These studies were conducted in United States (n = 27), India (n = 17), China (n = 10), Turkey (n = 9), Italy (n = 9), Iran (n = 8), Mexico (n = 8), United Kingdom (n = 6), Spain (n = 6), Poland (n = 5), Brazil (n = 5), France (n = 4), Peru (n = 3), Switzerland (n = 3), Greece (n = 3), Pakistan (n = 2), Saudi Arabia (n = 2), Russia (n = 2), Austria (n = 2), Germany (n = 2), Jordan (n = 2), Algeria (n = 1), The Netherlands (n = 1), Kuwait (n = 1), Egypt (n = 3), Oman (n = 1), Romania (n = 1), Colombia (n = 1), Israel (n = 1), Taiwan (n = 1), Canada (n = 1), Indonesia (n = 1), Argentina (n = 1), Tunisia (n = 1), Palestine (n = 1), Japan (n = 1) and Sweden (n = 1). Only two studies were made within multi-countries (n = 2) (35, 144). The majority of the studies were single centre (3, 4, 7, 8, 14-18, 21-34, 36, 37, 57-66, 68, 70-90, 92-107, 109-128, 130-143, 145-160, 162-166, 169-175, 178) and only 19 studies were multi-centre (12, 13, 19, 20, 35, 38-40, 67, 69, 91, 108, 129, 144, 161, 167, 168, 176, 177). Almost all studies included in this review were retrospective in design except few studies were prospective (n = 5) (7, 24, 67, 92, 159) and one study utilized both retrospective and prospective designs (129). All children diagnosed with blood cancer who had concurrent COVID-19 among all included studies in our systematic review were not vaccinated against SARS-CoV-2 (3, 4, 7, 8, 12-40, 57-178). Ninety-four studies were deemed to have high methodological quality, 3 moderate methodological quality, and 4 low methodological quality. Among the 54 included cohort studies, 38 cohort studies were found to be moderate-quality studies (i.e., NOS scores between 5 and 7) and 16 study demonstrated a relatively high quality (i.e., NOS scores > 7); Table 1.
Leukaemia
Leukaemia was the first most-common blood cancer in children who experienced COVID-19 (n = 1141, 88.5%) (3, 4, 7, 8, 12-15, 17-21, 23-40, 58-64, 66-82, 84-86, 89-100, 102-104, 106-129, 131-137, 139-143, 146-151, 153-163, 167-178) (see Table 1). Among them, 579 have unclassified lymphoblastic leukaemia (50.7% of all leukaemias) (3, 4, 8, 12, 13, 15, 19-21, 23, 24, 26, 29-32, 39, 40, 61, 67, 70-72, 74, 75, 81, 82, 84, 86, 92, 104, 108, 113, 116, 123, 127, 132, 150, 153, 155, 161, 162, 167-174, 177, 178), 202 have unspecified leukaemia (17.7%) (14, 18, 20, 35, 93, 96, 103, 107, 134, 147, 159, 167, 176), 185 have B-cell lymphoblastic leukaemia (16.2%) (7, 13, 27, 28, 33, 34, 36-38, 58-60, 62, 63, 66, 68, 73, 78-80, 85, 89, 90, 94, 95, 97-100, 102, 109, 112, 115, 119-122, 124, 125, 128, 129, 131, 133, 135-137, 139, 140, 142, 143, 146, 151, 154, 156, 158, 163, 175), 150 have unclassified myeloid leukaemia (13.1%) (13, 15, 17, 19-21, 23, 25, 31, 32, 37-40, 59, 64, 67, 69, 77, 78, 91, 92, 94, 104, 106, 108, 110, 111, 113, 114, 116, 117, 123, 128, 129, 141, 148-150, 153, 160, 171-175), 23 have T-cell lymphoblastic leukaemia (2%) (37, 38, 59, 76, 78, 118, 119, 126, 128, 157, 175), and 2 have biphenotypic leukaemia (a mixture of both types of lymphoblastic and myeloid leukaemias) (0.2%) (23, 99). Most of those patients had acute leukaemic conditions (n = 892, 78.2%) (3, 4, 7, 8, 13-15, 17, 19-21, 23-34, 36-40, 58-64, 66-82, 84-86, 89, 90, 92-95, 97-100, 102, 104, 106, 108-129, 131-133, 135-137, 139-143, 146-151, 153-158, 160-163, 167-175, 177, 178) and only few cases had chronic leukaemia (n = 5, 0.4%) (91, 92, 129). Reported blood cancer status for the leukaemia in children infected with SARS-CoV-2 were active (n = 258/574, 44.9%) (8, 12-15, 17, 19-21, 23, 24, 29, 31, 32, 34, 35, 37, 40, 58-60, 64, 66, 73, 74, 76, 78, 79, 81, 82, 85, 86, 90, 92, 93, 95, 97-100, 102, 103, 108-112, 114, 115, 118, 120-122, 124, 127-129, 134, 136, 140, 142, 143, 146, 148-151, 154, 156, 158-160, 167, 169, 170, 172, 174, 175, 177), remission (n = 256/574, 44.6%) (3, 4, 8, 14, 15, 21, 23-28, 30, 33, 35-37, 40, 59-62, 67-72, 74, 78, 84, 89, 91, 92, 94, 107, 126, 128, 132, 135, 137, 139, 141, 150, 155, 157, 163, 167-177), or relapsed/refractory (n = 60/574, 10.4%) (7, 13, 14, 29, 37, 63, 67, 74, 77, 80, 92, 106, 117, 125, 131, 133, 147, 150, 169, 171, 173, 174, 176, 178), however, blood cancer status in these leukaemia cases was not reported in a high percentage of patients (n = 567/1141, 49.7%) (18, 20, 21, 38, 39, 92, 96, 104, 108, 113, 116, 119, 123, 129, 153, 161, 162, 167, 174). The median interquartile range (IQR) age of this group was 96 months [48 to 156], with an increased male predominance in leukaemia patients diagnosed with COVID-19 in most of the studies (198/304 = 65.1%) (4, 7, 13-15, 17, 23, 31, 33, 34, 36, 37, 40, 59-63, 70, 72, 73, 76-78, 82, 89-92, 99, 100, 102, 109-112, 115, 118-122, 124-128, 133, 136, 137, 140, 142, 143, 146-151, 153-157, 159, 160, 163, 167, 168, 170, 177), and majority of the patients belonged to Hispanic (310/896 = 34.6%) (13, 14, 17, 18, 24, 28, 38, 39, 60, 74, 75, 77, 81, 84, 93, 104, 111, 116, 149, 154, 160, 175), White (Caucasian) (292/896 = 32.6%) (3, 8, 12, 13, 19, 25, 26, 28, 31, 32, 34, 62-64, 67-69, 73, 76, 78-80, 82, 85, 86, 89-91, 94-97, 99, 100, 102, 103, 109, 110, 112, 114, 115, 118-122, 125, 128, 129, 133-137, 141, 147, 150, 151, 153, 156, 161, 167, 176, 177), Arab (160/896 = 17.8%) (23, 29, 58, 59, 92, 123, 126, 140, 150, 171, 173, 178) and Indian (134/896 = 14.9%) (21, 27, 30, 37, 66, 117, 124, 127, 139, 142, 143, 157, 169, 172, 174) ethnicity. Many of these leukaemic children infected with SARS-CoV-2 were found to have active concurrent infections (n = 96) [including unspecified pathogens (n = 35) (19 bacteria (14, 37, 108, 151, 171-173), 12 fungi (66, 108, 172, 173), and 4 other unknown pathogens) (113); Rhinovirus (n = 6) (28, 76, 133, 153, 160); Pseudomonas (n = 6) (17, 19, 21, 31, 33, 128); Aspergillus (n = 4) (61, 71, 110, 171); Dengue virus (n = 4) (169); Influenza A virus (n = 4) (72, 133, 146, 168); Enterovirus (n = 3) (28, 76, 133); Clostridium difficile (n = 3) (19, 86, 136); Parainfluenza 1&4 virus (n = 2) (153); Epstein–Barr virus (n = 2) (17, 88, 102); Staphylococcus aureus (n = 2) (99, 158); Human adenovirus (n = 2) (19, 133); bacilli (n = 2) (66, 133); Pneumocystis jirovecii (n = 2) (112, 139); Escherichia coli (n = 2) (7, 86); streptococci (n = 2) (102, 122); Influenza B virus (n = 1) (153); Cytomegalovirus (n = 1) (61); Scopulariopsis species (n = 1) (71); Human metapneumovirus (n = 1) (95); respiratory syncytial virus (n = 1) (95); Absidia corybifera (n = 1) (171); Acinetobacter junii (n = 1) (128); Salmonella (n = 1) (132); toxoplasmosis (n = 1) (129); Rothia mucilaginosa (n = 1) (136); hepatitis C virus (n = 1) (142); Klebsiella pneumonia (n = 1) (154); Parvovirus B19 (n = 1) (169); BK virus (n = 1) (161) and Coronavirus NL63 (n = 1) (153)]. Few of those leukaemia children presented with a previous known history of hematopoietic stem cell transplantation (n = 32) [allogeneic (n = 31) (13, 19, 23, 62, 64, 74, 77, 78, 84, 106, 114, 119, 128, 129, 133, 147, 153, 160, 176, 178) and autologous (n = 1) (27)], graft versus host disease (n = 15) (13, 19, 64, 99, 114, 128, 129, 136, 153, 160, 176), immunocompromised status (n = 15) (80, 99, 104, 111, 117, 125, 127, 132, 135, 172), obesity (n = 5) (17, 104), hypertension (n = 4) (13, 19, 66), asthma (n = 3) (104), rhinitis (n = 3) (3, 76, 114), dilated cardiomyopathy (n = 3) (66, 114, 150) and Down syndrome (n = 2) (13, 63), however, a significant number of leukaemic cases who experienced COVID-19 presented with no previous medical history (n = 86, 7.5%) (4, 23, 25, 27, 29, 30, 34, 36, 58, 62, 68, 73, 79, 81, 82, 84, 85, 97, 98, 100, 104, 109, 112, 115, 118-121, 124, 126, 128, 134, 137, 140, 141, 148, 150, 151, 154-159, 163). Most common clinical symptoms from leukaemia were febrile neutropenia (n = 29) (21, 25, 31, 58, 59, 61, 66, 76, 84, 97, 111, 122, 136, 139, 148, 149, 173, 175), sepsis (n = 23) (17, 21, 37, 59, 99, 110, 114, 132, 150, 154, 172, 173), bone marrow suppression (n = 21) (3, 25, 28, 59, 60, 81, 82, 86, 90, 95, 112, 114, 122, 125, 133, 134, 149, 151, 169), multiorgan failure (n = 18) (17, 37, 59, 99, 146, 150, 154) (172, 173, 175), lymphadenopathy (n = 17) (7 cervical, 3 inguinal, 3 multiple, 2 mediastinal, 1 mandibular and 1 hilar) (58, 66, 72, 73, 81, 99, 102, 109, 118, 127, 140, 142, 143), respiratory failure (n = 14) (15, 104, 112, 150, 175), lethargy (n = 13) (3, 28, 58, 85, 94, 95, 102, 125, 132, 133, 142, 149), abdominal pain (n = 12) (14, 58, 81, 89, 111, 120, 132, 151, 156), hepatomegaly (n = 9) (58, 81, 102, 109, 127, 140, 142, 143, 156), diarrhoea (n = 9) (14, 111, 117, 120, 132, 136, 139, 149), splenomegaly (n = 8) (58, 81, 94, 98, 109, 120, 142, 143), vomiting (n = 8) (58, 89, 99, 111, 139, 149, 151), paleness (n = 8) (3, 33, 81, 85, 98, 121, 140, 142), skin rash (n = 8) (58, 61, 102, 109, 111, 136, 140, 149), tumor lysis syndrome (n = 7) (37, 118, 121, 143, 169), septic shock (n = 7) (58, 81, 136, 146, 175), acute kidney injury (n = 6) (99, 108, 149), decreased appetite (n = 5) (28, 61, 120), petechiae (n = 5) (30, 115, 134, 142, 149), hypotension (n = 5) (81, 121, 128, 136, 156), headache (n = 5) (104, 125, 126, 149), encephalopathy (n = 5) (104), thromboembolism (n = 5) (33, 108), weight loss (n = 4) (61, 109, 133, 149), isolated CNS relapse (n = 4) (59, 99, 154), seizures (n = 4) (13, 98, 104, 108), hemophagocytic lymphohistiocytosis (n = 4) (66, 119, 121, 133), fever (n = 4) (28, 132, 158), coagulopathy (n = 3) (61, 89, 99), ascites (n = 3) (59, 89, 140), bruising (n = 3) (85, 109, 149), cardiopulmonary arrest (n = 3) (17, 61, 84) and intracranial haemorrhage (n = 3) (8, 104). As expected, most prescribed therapies in these leukaemic cases infected with SARS-CoV-2 were antibiotics (n = 230) (3, 4, 13-15, 23, 28, 29, 31, 33, 34, 36-39, 58, 59, 61, 63, 66-68, 71, 72, 76, 79, 80, 84, 86, 89, 95, 97, 99, 102, 106, 108-112, 114, 117, 121-123, 128, 133, 136, 139-142, 146, 148-150, 153, 156, 158, 160, 163, 167, 169-173, 176-178), steroids (n = 147) (4, 7, 8, 14, 19, 21, 28, 30, 33, 34, 37-40, 59, 61, 64, 66, 68, 71-73, 79-82, 84, 89, 97-99, 103, 104, 106, 109-111, 115, 117-119, 121, 123, 127, 128, 132, 134, 136, 139, 140, 143, 146, 148, 150, 156, 160, 163, 167, 169, 171-173, 178), oxygen supplementation (n = 131) (13, 14, 17, 37, 40, 71, 72, 76, 80-82, 86, 89, 92, 98, 108, 110-112, 116-118, 120, 122, 123, 125, 128, 129, 136, 139, 142, 146, 149-151, 160, 163, 167, 169, 172, 175, 176), chemotherapy (n = 106) (12, 13, 17, 20, 23, 25, 31, 37, 38, 40, 58, 63, 64, 67, 73, 76-78, 80, 81, 84, 90, 99, 110, 115, 117, 118, 128, 150, 156, 157), hydroxychloroquine (n = 63) (13, 15, 17, 31, 32, 35, 38, 63, 67, 78, 80, 82, 100, 108, 109, 112, 119, 122, 141, 150, 153, 157, 160, 167, 173, 176, 178), intravenous immunoglobulin (n = 40) (7, 8, 28, 30, 31, 37, 38, 59, 66, 72, 80, 81, 89, 99, 106, 110, 111, 114, 123, 125, 133, 136, 139, 146, 156, 169, 175), antivirals (n = 46) (3, 4, 15, 27, 38, 61, 72, 95, 114, 133, 139, 146, 149, 156, 167, 173, 176), packed red blood cells (n = 29) (28, 30, 72, 77, 81, 86, 89, 109, 122, 136, 141, 142, 148-150, 156), anticoagulants (n = 25) (31, 33, 38, 63, 84, 98, 103, 104, 117, 125, 148, 150), remdesivir (n = 33) (17, 37, 61, 71, 78-80, 82, 86, 98, 103, 108, 115, 119, 125, 132, 133, 136, 148, 151, 171), antifungals (n = 43) (58, 61, 66, 71, 72, 86, 95, 106, 110-112, 114, 122, 133, 136, 139-141, 148, 149, 156, 163, 171-173), tocilizumab (n = 27) (19, 63, 64, 92, 99, 104, 108, 112, 119, 122, 125, 171), granulocyte colony-stimulating factor (n = 23) (77, 97, 126, 137, 150, 156), intravenous inotropes (n = 19) (7, 8, 37, 59, 66, 81, 82, 104, 121, 156, 175), intravenous fluids (n = 14) (34, 36, 61, 109, 118, 121, 128, 136, 140, 143, 149, 156), convalescent plasma (n = 10) (64, 79, 99, 100, 103, 111, 125, 139, 156), fresh frozen plasma (n = 9) (64, 140, 150), antiparasitic (n = 9) (39, 77), vincristine (n = 8) (40, 58, 73, 115, 118, 128, 129, 156), favipiravir (n = 8) (69, 150, 158), lopinavir/ritonavir (n = 7) (35, 67, 109, 112, 141, 163), and allogeneic hematopoietic stem cell transplantation (n = 7) (25, 67, 95, 99, 111), nevertheless, treatment for COVID-19 was not necessary in a high number of leukaemic children (n = 74, 6.5%) (19, 26, 39, 40, 59, 78, 85, 120, 123, 124, 135, 143, 151, 153, 154, 170, 175, 177). Children who suffered leukaemia and experienced COVID-19 were more likely to have high C-reactive protein (n = 111) (3, 4, 13, 14, 28, 29, 31, 33, 37, 40, 58, 63, 66, 70, 73, 76, 79-82, 84, 86, 89, 95, 98-100, 102, 106, 107, 109-112, 117, 119, 120, 122, 125, 129, 132, 133, 136, 139, 141, 142, 146, 149, 150, 154, 156, 158, 163, 166, 173), neutropenia (n = 130) (3, 13, 14, 19, 28, 31, 36, 37, 58, 59, 61, 66-68, 71, 72, 76, 79, 80, 82, 84, 94, 97, 98, 102, 111, 112, 114, 122, 124, 126, 129, 131, 134-137, 139, 142, 146, 148-151, 156-158, 167, 168, 172, 173, 175, 177), lymphopenia (n = 96) (3, 4, 13, 23, 28, 29, 31, 59, 61, 67, 68, 72, 78-80, 84, 89, 90, 97, 100, 106, 107, 111, 112, 114, 119, 124, 128, 129, 139, 146, 150, 151, 154, 157, 168, 172, 173, 175, 176), high D-dimer (n = 86) (14, 28, 33, 37, 40, 58, 66, 73, 78, 80, 84, 89, 106, 107, 110, 112, 117, 119, 125, 136, 139, 150, 175), thrombocytopenia (n = 83) (3, 7, 8, 13, 17, 28, 30, 33, 40, 58, 59, 61, 66, 72, 73, 81, 84-86, 89, 94, 98, 99, 102, 106, 109-112, 114, 115, 117, 120, 121, 132, 134, 140-143, 148-150, 154, 156, 158, 166-168, 172, 173), elevated ferritin (n = 68) (7, 13, 14, 28, 31, 40, 58, 66, 73, 76, 84, 89, 99, 100, 110-112, 117, 119-122, 125, 129, 133, 135, 136, 139, 141, 142, 149, 150, 154, 163, 166, 173, 175, 176), low white blood cells (n = 55) (3, 4, 13, 17, 28, 29, 31, 33, 36, 58, 66, 67, 72, 73, 78, 79, 81, 84-86, 98, 99, 102, 111, 112, 114, 121, 124, 129, 132, 140-143, 148, 149, 151, 154-156, 158), low haemoglobin (n = 53) (3, 4, 17, 28, 33, 36, 40, 58, 59, 63, 66, 72, 73, 79, 81, 84, 86, 89, 98, 99, 102, 109, 111, 112, 114, 115, 117, 120, 121, 132, 136, 139-141, 143, 146, 148, 149, 154-156, 158, 166), anaemia (n = 41) (28, 36, 59, 79, 85, 89, 94, 102, 109, 115, 121, 134, 150, 156, 158, 168), high interleukin-6 level (n = 36) (3, 13, 37, 61, 72, 79, 80, 84, 89, 112, 117, 119, 121, 122, 125, 141, 146, 154, 163), high erythrocyte sedimentation rate (n = 35) (28, 33, 37, 58, 73, 98, 132, 136, 150, 154), high lactate dehydrogenase (n = 25) (7, 33, 40, 79, 80, 84, 89, 102, 107, 110, 112, 120, 121, 132, 139, 141, 146, 158, 167), high procalcitonin (n = 19) (31, 63, 72, 76, 86, 95, 106, 110-112, 117, 136, 139, 142, 146, 156, 163), pancytopenia (n = 18) (3, 17, 28, 58, 73, 81, 85, 86, 99, 102, 111, 112, 140, 148, 154, 158), leukopenia (n = 13) (3, 28, 36, 68, 89, 95, 100, 102, 112, 139, 146, 157), elevated liver enzymes (n = 13) (4, 7, 13, 34, 61, 66, 68, 76, 80, 115, 125, 142, 146, 156, 166), leucocytosis (n = 10) (13, 17, 37, 81, 85, 94, 109, 134, 149, 169), high fibrinogen (n = 11) (28, 30, 33, 66, 73, 84, 111, 125, 175), high bilirubin (n = 8) (34, 61, 66, 99, 121, 142, 156, 166), high prothrombin time (n = 7) (34, 58, 61, 63, 89, 109, 111), high partial thromboplastin time (n = 7) (7, 34, 58, 61, 89, 99, 109), high troponin I (n = 7) (31, 81, 99, 156), high uric acid (n = 6) (79, 109, 120, 121, 134, 158) and lymphocytosis (n = 6) (7, 36, 40, 128). COVID-19 in leukaemic children infected with SARS-CoV-2 was asymptomatic (221/1041 = 21.2%) (12, 13, 19-21, 23-27, 31, 39, 59, 67-70, 78, 96, 99, 108, 116, 123, 124, 126, 128, 129, 135, 154, 155, 157, 160, 167, 170, 172, 174-176), mild (n = 524/1041= 50.3%) (3, 4, 8, 12-15, 17-21, 23, 24, 28-32, 35, 37-40, 59, 60, 67, 70, 71, 73-78, 84-86, 90-92, 94-97, 100, 102, 104, 106, 108-110, 113, 114, 116, 118, 119, 123, 127-129, 131, 132, 134, 137, 140, 141, 143, 150, 151, 153, 154, 159, 167, 169, 170, 172, 174-177), moderate (n = 152/1041= 14.6%) (14, 18, 33-40, 59, 60, 62, 63, 67, 74, 75, 78, 92, 104, 108, 116, 120, 123, 129, 133, 150, 153, 158, 163, 167, 169, 171, 173, 177), severe (101/1041= 9.7%) (13, 20, 21, 28, 38-40, 64, 66, 72, 74, 75, 78-80, 82, 84, 89, 92, 98, 103, 104, 107, 108, 111, 113, 115, 117, 119, 121-123, 125, 129, 139, 142, 148-151, 153, 156, 167-169, 171-175, 178) or critical (n = 43/1041= 4.1%) (7, 20, 21, 35, 37-39, 58, 59, 61, 81, 92, 99, 112, 136, 146, 150, 167, 169, 171-173, 175). Most leukaemic paediatric cases did not get multisystem inflammatory syndrome in children (MIS-C) (651/736, 88.4%) (3, 4, 8, 12-15, 17, 19, 23-38, 40, 59, 60, 62-64, 67-71, 73-79, 84-86, 90-92, 94-97, 99, 100, 102-104, 106, 109, 110, 114-116, 118-120, 123, 124, 126-128, 131-135, 137, 140, 141, 143, 150, 151, 153-155, 157-160, 163, 167, 169, 170, 173-177), however, few leukaemic children were reported to experience MIS-C (85/736, 11.5%) (7, 13, 28, 35, 37, 38, 40, 58, 59, 61, 66, 72, 74, 80-82, 84, 89, 92, 98, 99, 104, 107, 111, 112, 117, 121, 122, 125, 136, 139, 142, 146, 148-151, 153, 156, 167, 169, 173, 175, 176). Leukaemic children who tested positive for SARS-CoV-2 were admitted to the intensive care units (n = 155, 13.6%) (7, 8, 13, 18, 20, 21, 35, 37-40, 59, 61, 62, 66, 72, 74, 75, 80-82, 84, 92, 98, 99, 103, 104, 107, 108, 110-113, 115, 116, 119, 121, 123, 129, 139, 142, 146, 148, 150, 153, 154, 160, 167-169, 171-173, 175, 176, 178), intubated and placed on mechanical ventilation (n = 103, 9%) (7, 8, 13, 18, 20, 35, 37-40, 59, 61, 66, 74, 75, 81, 82, 84, 92, 98, 103, 104, 107, 108, 110, 112, 113, 116, 121, 129, 146, 148, 150, 153, 154, 168, 169, 171-173, 175, 176, 178) and suffered acute respiratory distress syndrome (n = 133, 11.6%) (7, 13, 18, 20, 35, 37-40, 59, 61, 64, 66, 72, 74, 75, 80-82, 84, 89, 92, 98, 99, 103, 104, 107, 108, 110-113, 119, 121, 125, 129, 139, 146, 148, 150, 153, 154, 168, 171-173, 175, 176, 178). Paediatric leukaemic cases with concurrent COVID-19 had a documented mortality of 99 (8.7%) (7, 8, 15, 17-21, 35, 37-40, 59-61, 74, 77, 84, 92, 93, 99, 104, 108, 110, 113, 116, 147, 150, 153, 161, 171-173, 175, 176, 178), while 1034 (90.6%) of the leukaemic children recovered (3, 4, 8, 12-15, 18-21, 23-40, 58-60, 62-64, 66-82, 84-86, 89-100, 102-104, 106-109, 111-129, 131-137, 139-143, 146, 148-151, 153-163, 167-177). Mortality was COVID-19-related in a considerable number of paediatric leukaemic cases (41/99, 41.4%) (7, 21, 35, 39, 40, 61, 74, 84, 92, 93, 99, 104, 113, 150, 153, 161, 171, 173, 175, 176), however, COVID-19 was not attributable to death in many of the reported leukaemic children (36/99, 36.4%) (8, 15, 17, 19-21, 37, 39, 40, 59, 60, 77, 92, 104, 108, 110, 116, 154, 171, 173, 175) and few studies failed to report if COVID-19 was a leading or an underlying cause of death in those leukaemic children (22/, 22.2%) (18, 38, 93, 147, 172, 178) (see Table 2).
Lymphoma
Lymphoma was the second most-common blood cancer in children who experienced COVID-19 (n = 133, 10.3%) (12-22, 31, 35, 38-40, 57, 59, 67, 78, 87, 88, 92, 93, 96, 101, 105, 108, 123, 128-130, 144, 145, 150, 152, 164, 165, 169-175, 177, 178) (see Table 1). Among them, 59 have non-Hodgkin’s lymphoma (44.4% of all lymphomas) (12, 15, 16, 18, 20-22, 32, 38, 39, 57, 59, 67, 78, 87, 101, 105, 129, 130, 144, 150, 165, 169-171, 174, 175, 177), 38 have unspecified lymphoma (28.6%) (14, 35, 92, 93, 96, 108, 172, 173, 178), and 36 have Hodgkin’s lymphoma (27.1%) (13, 15, 17, 19-21, 38, 40, 67, 88, 123, 128, 145, 150, 152, 164, 169-171, 174, 177). Reported blood cancer status for the lymphoma in children infected with SARS-CoV-2 were active (n = 46/82, 56.1%) (12-15, 17, 19, 22, 31, 35, 59, 78, 87, 88, 93, 101, 105, 130, 145, 164, 165, 169, 170), remission (n = 32/82, 39%) (16, 35, 40, 57, 128, 144, 150, 170-173, 175, 177), or relapsed/refractory (n = 4/82, 4.9%) (67, 152, 169), however, blood cancer status in these lymphoma cases was not reported in a high percentage of patients (n = 48/133, 36.1%) (18, 20, 21, 38, 39, 67, 92, 96, 108, 123, 129, 174, 178). The median interquartile range (IQR) age of this group was 180 months [141 to 199.5], with an increased male predominance in lymphoma patients diagnosed with COVID-19 in most of the studies (26/30 = 86.7%) (13, 15-17, 21, 22, 31, 40, 57, 78, 87, 88, 101, 105, 130, 144, 145, 150, 165, 170, 177), and majority of the patients belonged to White (Caucasian) (33/99 = 33.3%) (12, 13, 16, 17, 19, 22, 31, 67, 78, 87, 101, 128-130, 144, 145, 150, 152, 164, 177), Hispanic (33/99 = 33.3%) (14, 18, 38, 39, 93, 105, 175), Indian (22/99 = 22.2%) (21, 165, 169, 172, 174) and Arab (11/99 = 11%) (57, 59, 92, 123, 171, 173, 178) ethnicity. Some of these lymphomatous children infected with SARS-CoV-2 were found to have active concurrent infections (n = 9) [including unspecified fungi (n = 3) (171), Epstein–Barr virus (n = 2) (17, 88); Human immunodeficiency virus (n = 1) (101); Pseudomonas aeruginosa (n = 1) (17); cocci (n = 1) (105) and unspecified bacteria (n = 1) (152)]. Few of those lymphoma children presented with a previous known history of cardiovascular diseases (n = 7) [including superior vena cava syndrome (n = 2) (57, 170), mild mitral regurgitation (n = 1) (88), tricuspid regurgitation (n = 1) (88), pulmonary insufficiency (n = 1) (88), coronary artery ectasia (n = 1) (88) and main bronchus stenosis (n = 1) (170)], hematopoietic stem cell transplantation (n = 5) [autologous (n = 3) (152, 171) and allogeneic (n = 2) (15, 19)], immunocompromised status (n = 1) (88), inborn error of immunity (CD27 deficiency) (n = 1) (88), obesity (n = 1) (145), inherited cancer genes (n = 1) (57), secondary and central nervous system syphilis (n = 1) (101), dermatomyoscitis and myopathy (n = 1) (165) and contractures and deformity (n = 1) (165), however, a significant number of lymphomatous cases who experienced COVID-19 presented with no previous medical history (n = 13, 9.8%) (13, 14, 16, 22, 59, 105, 128, 130, 150, 164). Most common clinical symptoms from lymphoma were masses (n = 8) (2 mediastinal, 1 transverse colon, 1 nasopharyngeal, 1 adrenal, 1 groin, 1 iliopsoas and 1 parotid glands) (22, 57, 88, 105, 170), lymphadenopathy (n = 6) (2 cervical, 1 neck, 1 supraclavicular, 1 groin and 1 auricular) (57, 88, 105), bleeding (n = 3) (1 gastrointestinal, 1 central nervous system and 1 gingival) (101, 105, 145), respiratory failure (n = 3) (16, 152, 164), sepsis (n = 2) (16, 105), splenomegaly (n = 2) (22, 88), swollen neck (n = 2) (57, 164), abdominal pain (n = 2) (14, 87), multiorgan failure (n = 2) (16, 17) and acute renal failure due to methotrexate intoxication (n = 1) (105). As expected, most prescribed therapies in these lymphomatous cases infected with SARS-CoV-2 were antibiotics (n = 30) (14, 15, 22, 38, 39, 59, 67, 78, 87, 105, 110, 123, 150, 152, 169, 172, 173, 177, 178), chemotherapy (n = 15) (12, 13, 15, 17, 38, 40, 57, 78, 87, 105), steroids (n = 15) (16, 21, 22, 38-40, 59, 87, 123, 130, 150, 152, 171), antivirals (n = 10) (15, 38, 87, 145, 152, 173), oxygen supplementation (n = 11) (14, 17, 40, 59, 67, 78, 145, 150, 152, 169, 175), hydroxychloroquine (n = 8) (17, 67, 78, 108, 145, 150, 173), remdesivir (n = 6) (17, 40, 101, 108, 145, 152), intravenous fluids (n = 5) (15, 22, 145), fresh frozen plasma (n = 4) (22, 145, 150), anticoagulants (n = 4) (16, 59, 145, 175), intravenous inotropes (n = 4) (16, 59, 152, 175), tocilizumab (n = 4) (16, 78, 152, 171), radiotherapy (n = 3) (12, 101, 130), intravenous immunoglobulin (n = 3) (16, 59, 105) and lopinavir/ritonavir (n = 2) (67, 78), nevertheless, treatment for COVID-19 was not necessary in a high number of lymphomatous children (n = 17, 12.8%) (19, 31, 39, 40, 123, 128, 164, 170, 175, 177). Children who suffered lymphoma and experienced COVID-19 were more likely to have lymphopenia (n = 11) (13, 59, 67, 78, 128, 150, 152, 173), thrombocytopenia (n = 9) (17, 40, 88, 145, 150, 172, 173), high C-reactive protein (n = 8) (14, 16, 22, 88, 150, 152), high D-dimer (n = 7) (14, 16, 22, 78, 150), neutropenia (n = 7) (14, 67, 171, 173), low haemoglobin (n = 5) (17, 40, 105, 145), low white blood cells (n = 5) (17, 67, 78, 145), elevated ferritin (n = 4) (14, 16, 105, 150) and high erythrocyte sedimentation rate (n = 3) (88, 150). COVID-19 in lymphomatous children infected with SARS-CoV-2 was asymptomatic (16/115 = %) (12, 21, 31, 39, 88, 123, 129, 172, 178), mild (68/115 = 59.1%) (12-15, 17-22, 35, 38-40, 57, 67, 78, 92, 96, 101, 123, 128-130, 144, 150, 169, 170, 172-175, 177), moderate (19/115 = 16.5%) (16, 21, 35, 38, 39, 67, 87, 92, 108, 150, 169, 171, 174), severe (9/115 = 7.8%) (40, 59, 108, 129, 145, 164, 165, 170, 175) or critical (3/115 = 2.6%) (105, 152, 169). Most lymphomatous paediatric cases did not get MIS-C (78/84, 92.8%) (12-15, 17-19, 22, 31, 35, 38, 40, 57, 67, 78, 87, 88, 92, 96, 101, 123, 128, 130, 144, 150, 164, 169, 170, 173-175, 177), however, few lymphomatous children were reported to experience MIS-C (6/84, 7.1%) (16, 59, 105, 145, 152, 165). Lymphomatous children who tested positive for SARS-CoV-2 were admitted to the intensive care units (n = 16, 12%) (16, 35, 39, 40, 59, 129, 145, 150, 152, 164, 165, 170, 175), intubated and placed on mechanical ventilation (n = 5, 3.7%) (16, 39, 40, 152, 170) and suffered acute respiratory distress syndrome (n = 7, 5.3%) (16, 40, 59, 145, 152, 165, 170). Paediatric lymphomatous cases with concurrent COVID-19 had a documented mortality of 10 (7.5%) (15-17, 38-40, 93, 170), while 119 (89.5%) of the lymphomatous children recovered (12-15, 18-22, 31, 35, 38-40, 57, 59, 67, 78, 87, 88, 93, 96, 101, 105, 108, 123, 128-130, 144, 145, 150, 152, 164, 165, 169-175, 177, 178). COVID-19 was not attributable to death in many of the reported lymphomatous children (7/10, 70%) (15-17, 39, 40, 170) and few studies failed to report if COVID-19 was a leading or an underlying cause of death in those lymphomatous children (3/10, 30%) (38, 93) (see Table 2).
Myelodysplastic syndrome
Myelodysplastic syndrome was the third most-common blood cancer in children who experienced COVID-19 (n = 7, 0.7%) (38, 78, 83, 96, 119, 138, 153) (see Table 1). Reported blood cancer status for the myelodysplastic syndrome in children infected with SARS-CoV-2 were active (n = 1/7, 14.3%) (138) or remission (n = 1/7, 14.3%) (78), however, blood cancer status in these myelodysplastic syndrome cases was not reported in a high percentage of patients (n = 5/7, 71.4%) (38, 83, 96, 119, 153). The median interquartile range (IQR) age of this group was months 156 [143 to 174], with an increased male predominance in myelodysplastic syndrome patients diagnosed with COVID-19 in most of the studies (3/5 = 60%) , and majority of the patients belonged to White (Caucasian) (5/7 = 71.4%) (78, 96, 119, 138, 153) and Hispanic (2/7 = 28.6%) (38, 83) ethnicity. One of these myelodysplastic syndrome children infected with SARS-CoV-2 was found to have active concurrent infections (n = 2) [including Cytomegalovirus (n = 1) (138) and Aspergillus terreus (n = 1) (138)]. Some myelodysplastic syndrome children presented with a previous known history of allogeneic hematopoietic stem cell transplantation (n = 4) (96, 119, 138, 153), obesity (n = 2) (83, 96), diabetes mellitus (type 2) (n = 1) (96), left ventricular hypertrophy (n = 1) (96), obstructive sleep apnoea (n = 1) (96) and graft versus host disease (n = 1) (138). Two myelodysplastic syndrome children experienced the following clinical symptoms: pneumonitis (n = 1) (83), acute lung injury (n = 1) (83), macrophage activation-like syndrome (n = 1) (83), splenomegaly (n = 1) (83), hemophagocytic lymphohistiocytosis (n = 1) (83), acute renal failure (n = 1) (83), sepsis (n = 1) (83), febrile neutropenia (n = 1) (138), emphysema (n = 1) (138), pneumothorax (n = 1) (138), bronchiectasis (n = 1) (138), bronchiolitis obliterans syndrome (n = 1) (138), thoracic air leak syndrome (n = 1) (138), pulmonary aspergillosis (n = 1) (138), respiratory acidosis (n = 1) (138), and hypercapnia (n = 1) (138). As expected, most prescribed therapies in these myelodysplastic syndrome cases infected with SARS-CoV-2 were antibiotics (n = 3) (83, 138, 153), oxygen supplementation (n = 2) (83, 138), hydroxychloroquine (n = 2) (83, 153), steroids (n = 2) (83, 138), remdesivir (n = 1) (83), tocilizumab (n = 1) (83), favipiravir (n = 1) (138) and antivirals (n = 1) (138), nevertheless, treatment for COVID-19 was not necessary in two myelodysplastic syndrome children (n = 2, 28.6%) (78, 119). Children who suffered myelodysplastic syndrome and experienced COVID-19 were more likely to have high C-reactive protein (n = 2) (83, 119), high interleukin-2 and interleukin-6 levels (n = 2) (83, 119), elevated ferritin (n = 1) (83), high D-dimer (n = 1) (83), neutropenia (n = 1) (138), low haemoglobin (n = 1) (138) and thrombocytopenia (n = 1) (138). COVID-19 in myelodysplastic syndrome children infected with SARS-CoV-2 was mild (5/7 = 71.4%) (38, 78, 119, 138, 153), severe (1/7 = 14.3%) (96) or critical (1/7 = 14.3%) (83). Most myelodysplastic syndrome paediatric cases did not get MIS-C (5/7, 71.4%) (38, 78, 119, 138, 153), however, two myelodysplastic syndrome children were reported to experience MIS-C (2/7, 28.6%) (83, 96). Myelodysplastic syndrome children who tested positive for SARS-CoV-2 were admitted to the intensive care units (n = 3, 42.8%) (83, 96, 138), intubated and placed on mechanical ventilation (n = 2, 28.6%) (83, 138) and suffered acute respiratory distress syndrome (n = 3, 42.8%) (83, 96, 138). Paediatric myelodysplastic syndrome cases with concurrent COVID-19 had a documented mortality of 1 (14.3%) (138), while 6 (85.7%) of the myelodysplastic syndrome children recovered (38, 78, 83, 96, 119, 153). COVID-19 was not attributable to death in any of the reported myelodysplastic syndrome children (38, 78, 83, 96, 119, 138, 153) (see Table 2).
Langerhans cell histiocytosis
Langerhans cell histiocytosis was the third most-common blood cancer in children who experienced COVID-19 (n = 7, 0.7%) (21, 67, 166, 168-170) (see Table 1). Reported blood cancer status for the Langerhans cell histiocytosis in children infected with SARS-CoV-2 was active (n = 1/7, 14.3%) (169), however, blood cancer status in these Langerhans cell histiocytosis cases was not reported in a high percentage of patients (n = 6/7, 85.7%) (21, 67, 166-168, 170). The median interquartile range (IQR) age of this group was months 15.5 [10 to 15.5], with an increased male predominance in Langerhans cell histiocytosis patients diagnosed with COVID-19 in most of the studies (3/4 = 75%) (21, 166), and majority of the patients belonged to Indian ethnicity (4/7 = 57.1%) (21, 166, 169). One Langerhans cell histiocytosis child experienced the following clinical symptoms: lymphadenopathy (cervical and occipital) (n = 1) (166), oedemas (different part of body) (n = 1) (166), hepatomegaly (n = 1) (166), splenomegaly (n = 1) (166), ascites (n = 1) (166), rash (n = 1) (166), lesions (n = 1) (166) and icterus (n = 1) (166). As expected, most prescribed therapies in these Langerhans cell histiocytosis cases infected with SARS-CoV-2 were antibiotics (n = 2) (67, 169) and hydroxychloroquine (n = 1) (67), nevertheless, treatment for COVID-19 was not necessary in one Langerhans cell histiocytosis child (n = 1, 14.3%) (170). Children who suffered Langerhans cell histiocytosis and experienced COVID-19 were more likely to have high C-reactive protein (n = 1) (166), elevated ferritin (n = 1) (166), neutropenia (n = 1) (67), low haemoglobin (n = 1) (166) and thrombocytopenia (n = 1) (166). COVID-19 in Langerhans cell histiocytosis children infected with SARS-CoV-2 was asymptomatic (2/7 = 28.6%) (67, 166) or mild (5/7 = 71.4%) (21, 168-170). Most Langerhans cell histiocytosis paediatric cases did not get MIS-C (3/7, 42.8%) (67, 168-170), however, one Langerhans cell histiocytosis child was reported to experience MIS-C (1/7, 14.3%) (166). None of the Langerhans cell histiocytosis children who tested positive for SARS-CoV-2 were admitted to the intensive care units, intubated and placed on mechanical ventilation or suffered acute respiratory distress syndrome (21, 67, 166, 168-170). All paediatric Langerhans cell histiocytosis cases with concurrent COVID-19 recovered (21, 67, 166, 168-170) (see Table 2).
Myeloid neoplasm
Myeloid neoplasm was reported in a white child following SARS-CoV-2 infection, with development of hypereosinophilic syndrome, pleural fibrosis, respiratory failure, sepsis and multiorgan failure (65). Patient needed intensive care unit admission, mechanical ventilation, and suffered acute respiratory distress syndrome. This was a mild case of COVID-19 and patient never experienced MIS-C, however, patient died albeit many therapies were offered and final treatment outcome was not COVID-19-related (see Table 1).