COVID-19 infection in febrile neutropenic pediatric hematology oncology patients.

To the Editor:

More than 20 million cases of coronavirus disease 2019 were confirmed worldwide, with a mortality rate of 3.5%. Cancer patients are at increased risk of infection. We attempted to investigate the impact of COVID‐19 infection in pediatric cancer patients.

Over 3 months duration, 75 pediatric cancer patients were admitted to National Cancer Institute, Cairo University to receive their chemotherapy and supportive care. Episodes of febrile neutropenia were recorded in 24 patients. All had chest computed tomography (CT) images and nasopharyngeal swabs that were tested for SARS‐CoV‐2 RNA with RT‐PCR assay. Demographic and clinical characteristics are shown in Table 1.The median (range) age was 7 (2‐18) years; 15 (62.5%) were males. Their diagnoses were acute lymphoblastic leukemia, acute myeloid leukemia, lymphoma, and solid tumors, including brain, bone, and renal tumors, in 12 (50%), four (17%), three (12%), and five (21%) patients, respectively. Out of the 24 patients, seven (29%) had a positive result for COVID‐19 by PCR. Other than the seven confirmed cases, there were no probable COVID‐19 cases according to WHO criteria. The diagnoses of the seven COVID‐19 confirmed cases were acute lymphoblastic leukemia (n = 3), acute myeloid leukemia (n = 2), lymphoma (n = 1), and Wilms tumor (n = 1).

Table 2 shows the laboratory findings of the patients. All the patients were neutropenic, thrombocytopenic, and had absolute lymphocytopenia. There was no significant difference in the total leucocyte count, absolute neutrophil count, and absolute lymphocyte count of COVID‐19‐positive or ‐negative patients. The median (range) C‐reactive protein (CRP) was 163 (1‐268 mg/L) in COVID‐19‐positive patients and 72 (7‐366 mg/L) in COVID‐19‐negative patients; P = .792. The CRP levels were higher than 100 mg/L in five of seven of the positive versus 11/17 of the negative cases.

In the initial chest CT scan, two (28.5%) cases had bilateral focal ground‐glass opacity as the predominant CT imaging pattern, while five patients (71.5%) had no abnormal findings. Follow‐up CT, carried out 7‐14 days after admission, showed patchy consolidation and interstitial abnormalities including reticular appearance and interlobular septal thickening in three patients (42.8%); normal scan of initially free three patients, and no imaging in one patient due to death.

Management was done as recommended by the local authorities’ guidelines according to WHO 2020. The medications used were hydroxychloroquine sulfate 6.5‐10 mg/kg (max 400 mg) given every 12 h in the first day, then in two divided doses for 9 days, and azithromycin 12 mg/kg/day (max 500 mg) for 5 days. Oseltamivir was used in pediatric dose (twice daily for 5 days) according to the body weight: >40 kg: 75 mg; >23‐40 kg: 60 mg; >15‐23 kg: 45 mg; and empirical broad‐spectrum antibiotics in the form of fourth‐generation cephalosporin and carbapenem. Targeted antibiotic therapy according to blood culture results and voriconazole as prophylactic antifungal were administered. Three patients received methylprednisolone 1 mg/kg every 12 h for 5 days as they developed respiratory distress. Nasopharyngeal swabs were repeated after 7 days and then every 72 h.

Duration to a negative PCR was 2 weeks in one case, and 5 weeks in three cases. Three cases were persistently positive and had unfavorable outcome. Admission to ICU was necessary in three cases, due to respiratory distress and desaturation in two patients; one of them due to cancer progression and septic shock in the third patient. Ventilation support was needed in one case. The mortality rate in COVID‐19 cases was 43% (3/7), and 11% (2/17) in the negative cases. Additional contributing factors to mortality included progression of malignancy (n = 1) and bacterial sepsis (n = 1) among both COVID‐19‐positive and ‐negative cases.

The impact of COVID‐19 in children with cancer is not yet clear. In the present study, a severe infection with ICU admission and unfavorable outcome was recorded in three of seven COVID‐19‐positive cases while receiving their chemotherapy. In another case series, COVID‐19‐positive cancer patients were more susceptible to a more severe infection and worse outcome. In another study on 178 pediatric cases with cancer, mild symptoms were related to COVID‐19 in 19/20 positive patients. The different findings in the current case series could be related to the type of malignancy, as our patients were mostly cases with hematological malignant disorders.

Evidence suggested that a subgroup of COVID‐19‐infected cases develop a severe disease due to cytokine storm syndrome leading to a hyperinflammation state. Serum ferritin levels were significantly increased in nonsurvivors, when compared to survivors in 191 COVID‐19‐positive patients. In the current study, serum ferritin levels were remarkably elevated in COVID‐19‐positive pediatric cancer patients. It was documented that elevated serum ferritin levels were closely related to poor prognosis in patients with hematological malignancies; with levels ≥1000 ng/mL denoting poor survival. Thus, using ferritin to stratify the severity of COVID‐19 infection is limited in patients with a diagnosis of hematological malignancies.

Though a reduced platelet count was encountered in our COVID‐19‐positive cancer patients, still this is mostly a chemotherapy‐induced complication. Lymphopenia, CRP, and other lab parameters might not be helpful to support the diagnosis of COVID‐19 in cancer patients, as they frequently have chemotherapy‐induced cytopenias and their CRP is frequently elevated. In normal children with confirmed COVID‐19 infection, 3.5% had a reduced lymphocyte count below 1.2 × 109/L and CRP was elevated above 10 mg/dL in only 20% of the cases.

We can conclude that patients with hematologic malignancies, especially those who are not in a remission, are at risk of developing COVID‐19. Our findings support that a severe infection defined by the need of ICU admission and an unfavorable outcome is common in confirmed COVID‐19‐positive pediatric cancer cases while receiving their chemotherapy. Due to the well‐known blood cell cytopenias and elevated inflammatory markers in cancer, neither the blood counts nor CRP and ferritin may support the preliminary diagnosis of COVID‐19 in cancer. It is evident that pediatric cancer patients represent a unique group with different criteria when they contract SARS‐CoV‐2 virus.

CONFLICT OF INTEREST

The authors declare that there is no conflict of interest.

TABLE 1

Demographic and clinical characteristics of the 24 febrile neutropenic pediatric oncology cases receiving chemotherapy at NCI, Cairo University

Total patients tested	Total patients N = 24	PCR positive N = 7 (%)	PCR negative N = 17 (%)
Age groups
1‐9.9 years	18	5 (71)	13 (76)
10‐18 years	6	2 (29)	4 (24)
Sex
Female	9	3 (43)	6 (35)
Male	15	4 (57)	11 (65)
Disease type
Hematological malignancies	20	6 (86)	14 (82)
Solid tumors	4	1 (14)	3 (18)
Disease status
CR	20	4 (57)	16 (94)
Not CR	4	3 (43)	1 (6)
Respiratory symptoms
Yes	9	4 (57)	5 (29)
No	15	3 (43)	12 (71)
GIT symptoms
Yes	7	4 (57)	3 (18)
No	17	3 (43)	14 (82)
Laboratory findings
Total leucocyte count*	1075 (330‐2700 × 109/L)	1400 (160‐3900 × 109/L)	750 (500‐1500 × 109/L)
Absolute neutrophil count*	150 (40‐1600 × 109/L)	150 (20‐2800 × 109/L)	150 (60‐400 × 109/L)
Absolute lymphocyte count*	468 (160‐1850 × 109/L)	620 (120‐2400 × 109/L)	315 (200‐1300 × 109/L)
ICU admission
Yes	5	3 (43)	2 (12)
No	19	4 (57)	15 (88)
Outcome
Alive	19	4 (57)	15 (88)
Died	5	3 (43)	2 (12)

Note. Values are in median (range).

The P‐values of total leucocyte count, absolute neutrophil count, and absolute lymphocyte count in COVID‐19‐positive patients when compared to COVID‐19‐negative patients were .364, .962, and .669, respectively.

TABLE 2

Baseline laboratory parameters, imaging findings, and outcome of the seven PCR COVID‐19‐positive pediatric oncology cases receiving chemotherapy at NCI, Cairo University

No	Initial TLC109/L	Initial ANC109/L	Initial Ly109/L	Initial Plt109/L	Initial ALTU/L	Initial ASTU/L	Initial ferritinng/mL	Initial CRPmg/L	CT findings initially	CT progression	Time to negative PCR
1	2500	<100	2400	29	25	20	1443	19	No	Yes	5 weeks
2	160	<100	120	23	16	50	>2000	268	No	Yes	Persistently positive for 5 weeks
3	480	150	270	15	51	60	>2000	156	No	No	2 weeks
4	2600	<100	930	429	61	25	300	1	No	No	5 weeks
5	3900	2800	440	74	6	25	>2000	171	Yes	Not evaluated	Persistently positive for 1 week
6	1400	630	620	118	7	24	1338	220	Yes	Yes	Persistently positive for 2 weeks
7	1000	370	620	189	63	38	NA	NA	No	No	5 weeks

Abbreviations: ALT, alanine aminotransferase; ANC, absolute neutrophil count; AST, aspartate aminotransferase; CT, computed topography; Ly, lymphocytes; NA, not available; Plt, platelet count; TLC, total leucocyte count.