We read with interest the article titled “COVID-19 in persons with haematological cancers” by Wenjuan He et al. published recently [1]. The authors conducted a retrospective cohort study of 13 hospitalized patients with hematological malignancies (PHM) from Wuhan, China, who developed coronavirus infectious disease 2019 (COVID-19) and compared their clinical characteristics and outcomes with eleven hospitalized health care providers (HCP). They showed that COVID-19 led to more severe disease and significantly higher case fatality rate (CFR) of 62% in PHM compared to zero in HCP (P = 0.002). We acknowledge these findings since data on COVID-19 infections in PHM have been scarce so far, but we see important limitations that were not explicitly addressed in the article. Furthermore, we present our own retrospective cohort data from Graz, Austria, which differs in terms of demographics and outcome.
First, the cohort of PHM with COVID-19 exhibiting a median age of 35 years and selected by lung CT scan is likely not representative for most PHM whose median age reportedly is around 60 years [2, 3]. In Wuhan, PHM with COVID-19 were a median of 14 years younger compared with PHM without COVID-19 (P = 0.082). Moreover, 62% (8/13) of PHM with COVID-19 had already been in the intensive care unit (ICU) before the COVID-19 pandemic began. Depending on the reason for ICU admission, which is not specified in the article, mortality rates of up to 60% are to be expected [2]. Taken together, younger but obviously already critically ill patients prior to COVID-19 infection were reported by He et al.
Second, predominantly female HCP with COVID-19 having a median age of 32 years are not an ideal comparator group since in these subjects CFR is expected to be below 2.5% [4]. Only 18% (2/11) of HCP were male compared with 54% (7/13) of PHM with COVID-19 and 57% (65/115) of PHM without COVID-19, respectively (Fisher’s exact test, P = 0.0492). It has been previously shown that male gender is strongly associated with worse outcome of COVID-19 [4].
In summary, the expectedly very low CFR in young female HCP and the high mortality in presumably preselected PHM likely overestimated the difference in CFR between these two groups.
We similarly analyzed all consecutive patients infected with SARS-CoV-2 (N = 78; Supplementary Table 1) diagnosed at the University Hospital in Graz, Austria, until May 1, 2020. COVID-19 and acute respiratory distress syndrome (ARDS) were diagnosed as previously described [5]. Importantly, all SARS-CoV-2 infections were confirmed by nucleic acid test (NAT) and were not preselected by lung CT scan.
There were eight PHM with a median age of 57 years showing equal sex distribution (Table 1). Surprisingly, there was no difference in overall survival between PHM and subjects without hematologic cancers given the limitation that the latter were 16 years older (Supplementary Fig. 1; Supplementary Table 1). Despite thorough precautions, four PHM (UPN5–8) got infected most likely by asymptomatic HCP demonstrating the danger of nosocomial transmission as has been noted [1]. Two female patients had undergone allogeneic hematopoietic cell transplantation (HCT) 6 months (UPN7) and 5 weeks (UPN8) prior to SARS-CoV-2 infection and had ongoing immunosuppressive therapy including cyclosporine. Overall, six patients developed bilateral pneumonia diagnosed by chest X-ray and of these, three male PHM (UPN3, UPN5–6) progressed to severe ARDS requiring mechanical ventilation in the ICU. Importantly, these three PHM had recently received cytotoxic therapy, two including anti-CD20 antibodies and granulocyte-colony stimulating factors (G-CSF), confirming antitumor treatment <14 days previously as risk factor for severe COVID-19 course [6].
Several recurrent laboratory findings have been previously described in patients with COVID-19 [5]. In accordance with prior reports, lymphopenia was observed in seven PHM including five prior to infection. Systemic hyperinflammation was documented in all but one PHM (UPN4), but compared to patients without hematologic cancers, PHM showed significantly higher peak levels of IL-6 (median of 1207 vs. 36.4 pg/mL, P = 0.033) and serum ferritin (3756 vs. 558 ng/mL, P < 0.001) but not CRP (Fig. 1a). The latter is in contrast to He et al. reporting significantly higher CRP and procalcitonin levels possibly associated with high bacterial and fungal coinfection rates that resulted in the high CFR [1].
The experimental pharmacological therapy of COVID-19 and treatment outcomes are summarized in Table 1. The two PHM after HCT had a surprisingly unremarkable clinical course. Patients with ARDS also developed cytokine release syndrome and were treated with tocilizumab but no significant improvement of the respiratory situation could be achieved [7]. Therefore, we decided to administer SARS2-CoV-2 convalescent plasma (CP) on a compassionate use basis to patients UPN3 and UPN6, 6 and 11 days after start of mechanical ventilation, respectively [8]. As shown in Fig. 1b, in both cases, IL-6 and serum ferritin decreased dramatically, and patients were off the ventilator 5 and 4 days after CP therapy, respectively. UPN3 and UPN6 achieved a negative NAT whereas another three PHM remained positive after a median time of 55 days. Not surprisingly, compared with subjects without hematologic cancers, PHM needed significantly longer to achieve negative NAT (Table 1; Fig. 1c). Production of anti-SARS-CoV-2 antibodies, which reportedly occur in all COVID-19 patients 19 days after symptom onset, did not always accompany negative NAT in PHM [9]. After a median follow-up of 57 days, one patient (UPN5) died of severe ARDS, two patients (UPN3, UPN6) are in rehabilitation centers without symptoms of COVID-19, and five have been discharged.
Previous studies displayed cancer patients as vulnerable population with high risk of morbidity due to COVID-19 [1, 6, 10]. In our observation, CFR of COVID-19 in PHM is lower than reported by He and co-workers (13% vs. 62%). Nevertheless, we must consider patient heterogeneity and admit that empirical knowledge about the experimental treatment of COVID-19 has evolved since the first outbreak in Wuhan, China. Whether additional administration of anti-CD20 therapy and G-CSF had impact on hyperinflammation and development of ARDS must be assessed in studies with larger patient numbers. As shown in two PHM with severe ARDS due to COVID-19, treatment with CP seems to be promising but requires further evaluation in randomized controlled trials.
References
He W, Chen L, Chen L, Yuan G, Fang Y, Chen W, et al. COVID-19 in persons with haematological cancers. Leukemia. 2020;34:1637–45. https://doi.org/10.1038/s41375-020-0836-7
Azoulay E, Mokart D, Pene F, Lambert J, Kouatchet A, Mayaux J, et al. Outcomes of critically ill patients with hematologic malignancies: prospective multicenter data from France and Belgium-a groupe de recherche respiratoire en reanimation onco-hematologique study. J Clin Oncol. 2013;31:2810–8. https://doi.org/10.1200/jco.2012.47.2365
Howlader N, Noone AM, Krapcho M, Miller D, Brest A, Yu M, et al. (eds.) SEER Cancer Statistics Review, 1975–2017, National Cancer Institute. Bethesda, MD. 2020. https://seer.cancer.gov/csr/1975_2017/, based on November 2019 SEER data submission.
Richardson S, Hirsch JS, Narasimhan M, Crawford JM, McGinn T, Davidson KW, et al. Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City area. JAMA. 2020;323:2052–9. https://doi.org/10.1001/jama.2020.6775
Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med. 2020;382:1708–20. https://doi.org/10.1056/nejmoa2002032
Zhang L, Zhu F, Xie L, Wang C, Wang J, Chen R, et al. Clinical characteristics of COVID-19-infected cancer patients: A retrospective case study in three hospitals within Wuhan, China. Ann Oncol. 2020. https://doi.org/10.1016/j.annonc.2020.03.296.
Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ, et al. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020;395:1033–4. https://doi.org/10.1016/s0140-6736(20)30628-0
Shen C, Wang Z, Zhao F, Yang Y, Li J, Yuan J, et al. Treatment of 5 critically Ill patients with COVID-19 with convalescent plasma. JAMA. 2020;323:1582–9. https://doi.org/10.1001/jama.2020.4783
Long QX, Liu BZ, Deng HJ, Wu GC, Deng K, Chen YK, et al. Antibody responses to SARS-CoV-2 in patients with COVID-19. Nat Med. 2020. https://doi.org/10.1038/s41591-020-0897-1.
Liang W, Guan W, Chen R, Wang W, Li J, Xu K, et al. Cancer patients in SARS-CoV-2 infection: a nationwide analysis in China. Lancet Oncol. 2020;21:335–7. https://doi.org/10.1016/s1470-2045(20)30096-6
Author information
Authors and Affiliations
Contributions
All authors provided care for the patients. SH and ES conceived the study. SH, FE, PK, and ES collected clinical data. SH and ES analyzed data. PS provided convalescent plasma. MHS provided immunologic assays. HG revised the paper. SH, FE, and ES wrote the paper, which was reviewed and approved by all authors.
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Ethical approval
This study was approved by the ethics committee of the Medical University of Graz, Graz, Austria.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
About this article
Cite this article
Hatzl, S., Eisner, F., Schilcher, G. et al. Response to “COVID-19 in persons with haematological cancers”. Leukemia 34, 2265–2270 (2020). https://doi.org/10.1038/s41375-020-0914-x
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41375-020-0914-x
This article is cited by
-
Convalescent plasma therapy and mortality in COVID-19 patients admitted to the ICU: a prospective observational study
Annals of Intensive Care (2021)
-
Hyperimmune plasma in three immuno-deficient patients affected by non-severe, prolonged COVID-19: a single-center experience
BMC Infectious Diseases (2021)
-
Antifungal prophylaxis for prevention of COVID-19-associated pulmonary aspergillosis in critically ill patients: an observational study
Critical Care (2021)