Received: 26 June 2022

Accepted: 16 August 2022

DOI: 10.1111/1759-7714.14632

CASE REPORT

A case of cytokine release syndrome accompaniedwith COVID-19 infection during treatment with immune
checkpoint inhibitors for non-small cell lung cancer
Daiki Murata|Tomoaki Hoshino

Koichi Azuma

Division of Respirology, Neurology, andRheumatology, Department of Internal Medicine,
Kurume University School of Medicine, Fukuoka,
Japan
Correspondence
Koichi Azuma, Division of Respirology,
Neurology, and Rheumatology, Department ofInternal Medicine, Kurume University School ofMedicine, 67 Asahi-machi, Kurume, Fukuoka
830-0011, Japan.
Email: azuma@med.kurume-u.ac.jp| Saeko Tokisawa | Takaaki Tokito|

Abstract
Cytokine release syndrome (CRS) is a systemic inflammatory disease caused by a variety of factors, including infections and certain drugs. A 70-year-old man who wasdiagnosed with a postoperative recurrence of lung adenocarcinoma received nivolumab, ipilimumab, pemetrexed and carboplatin every 3 weeks for two cycles followedby nivolumab and ipilimumab, which resulted in a partial response. Four days after
the dose of nivolumab, the patient returned with diarrhea and fever. The patient wasdiagnosed with COVID-19 infection accompanied by severe colitis. Although intensive care was performed, the patient suddenly went into cardiopulmonary arrest.
Examination revealed an abnormally high interleukin-6 level, suggesting CRS. This is
the first report of a patient with CRS accompanied with COVID-19 infection during
treatment with ICIs. Cytokine release syndrome (CRS) is a systemic inflammatory disease caused by a variety of factors, including infections and certain drugs. Here, wereport a case of non-small cell lung cancer with CRS caused by COVID-19 infection
during treatment with nivolumab and ipilimumab. Fever is a common event in cancer
patients, especially in COVID-19-infected patients, but when fever develops duringcancer immunotherapy, CRS should always be kept in mind.
KEYWORDS
cancer immunotherapy, cytokine release syndrome, immune-related adverse events, SARS-CoV-2

INTRODUCTION
Cytokine release syndrome (CRS) is a systemic inflammatory
disease characterized by a massive release of cytokines, andtriggered by a variety of factors such as infections and certain
drugs. The clinical picture of CRS is a systemic inflammatory
disease that begins with fever, and severe cases manifests
hypotension, hypoxia, organ dysfunction requiring urgent
treatment. Interleukin-6 (IL-6) is known to play an importantrole in the pathogenesis of CRS, and although immunosuppressive drugs such as corticosteroids have been used, therapies that suppress IL-6 are now being applied clinically.1–5
COVID-19 is now a global pandemic. COVID-19
patients are known to have elevated IL-6 levels. Up to 20%of COVID-19 patients develop acute respiratory distresssyndrome, suggesting CRS.1,2,6
Immune checkpoint inhibitors (ICIs) are the latest
breakthrough in the treatment of patients with advancedtumors. Immune-related adverse events (irAEs) can develop
with ICIs, and ICI-related CRS has been recognized as an
irAE.7,8 Herein, we report a case of CRS acompanied with
COVID-19 infection during treatment with ICIs.

CASE REPORT
A 70-year-old Japanese man visited our hospital. He had
undergone thoracoscopic surgery 2 years prior to admission

This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium,provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
© 2022 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.
Thorac Cancer. 2022;1–4.

wileyonlinelibrary.com/journal/tca

1

MURATA ET AL.

2prior to admission, immunotherapy was resumed. Afterconfirmation of tumor regression and no evidence of pneumonitis and colitis on the contrast-enhanced CT, the patient
was administered nivolumab (Figure 1). Three days afteradministration, the patient had diarrhea more than 10 times
a day. The next day, the patient presented with diarrhea andfever. Although the patient had no respiratory symptoms, heunderwent polymerase chain reaction (PCR) testing forsevere acute respiratory syndrome coronavirus 2 and wasdiagnosed with COVID-19. CT showed no evidence ofpneumonia, but there was bowel edema (Figure 1). The
COVID-19 infection was considered mild because thepatient had no respiratory symptoms and no pneumonitis
on CT. The patient was diagnosed with COVID-19 infection
accompanied by severe colitis and admitted to the intensive

and had been diagnosed with left upper lobe lung adenocarcinoma pT3N0M0, stage IIB. Five months prior to admission, he had received the second dose of COVID-19 vaccinewith no adverse reactions. Around the same time, the lungadenocarcinoma recurred in the right upper lobe with a PDL1 expression level of 30%. The tumor was negative fordriver genes, and the patient was started on nivolumab plus
ipilimumab combined with two cycles of carboplatin andpemetrexed. After two and four cycles of therapy, chest
contrast-enhanced computed tomography (CT) showed thatthe tumor had decreased in size (Figure 1). Three months
prior to admission, the patient developed grade 2 hypophysitis (isolated adrenocorticotropic hormone deficiency), an
irAE. Immunotherapy was held for 1 month and the patient
was treated with corticosteroids. One and a half months
COVID-19
Vaccination

CBDCA+PEM+NIVO+IPI

NIVO+IPINIVO+IPI- 5 months - 4 months - 3 months - 2 months

COVID-19
NIVO InfectionDeath- 4 days Admission+1 dayHypophysitis Grade2Colitis Grade4FeverMulti-system organ failureabc

CBDCA: carboplatin, IPI: ipilimumab, NIVO: Nivolumab, PEM: pemetrexed
F I G U R E 1 Clinical course of lung adenocarcinoma. Lung adenocarcinoma recurred 5 months prior to admission, and nivolumab plus ipilimumab wasstarted combined with two cycles of carboplatin and pemetrexed. After two and four cycles of therapy, contrast-enhanced computed tomography(CT) showed that the tumor had decreased in size. Three months prior to admission, the patient developed grade 2 hypophysitis (isolated
adrenocorticotropic hormone deficiency) as an immune-related adverse event. Immunotherapy was stopped, then restarted a month and a half later. CT
showed no tumor regrowth just 4 days prior to admission. The final dose of nivolumab was administered on this day. Four days after resuming treatment
with nivolumab, the patient returned with diarrhea and high fever. The patient was diagnosed with COVID-19 infection and suggested cytokine releasesyndrome. Findings of thin-section computed tomography. (a) Transition of CT findings over time. The lung adenocarcinoma shrank after the start oftreatment and did not regrow. (b) Chest CT on admission. There was no evidence of pneumonia or acute respiratory distress syndrome which would indicate
COVID-19 infection in the lung fields. (c) Abdominal CT on admission. Bowel edema suspicious of colitis was present

MURATA ET AL.

3care unit. On admission, his body temperature was 39 C,
blood pressure was 120/40 mmHg, and pulse was 110/min.
He did not require treatment with oxygen or a vasopressor.
Although intensive care was performed, including hydration, high dose corticosteroids, and antibiotics, the patient
suddenly went into cardiopulmonary arrest 3 h after admission. Remdesivir was planned but had not yet been administered. A total of 27 min of cardiopulmonary resuscitationand one electrical defibrillation were performed, and thepatient was returned to spontaneous circulation. His laboratory tests submitted before the sudden change showed
increased C-reactive protein and suggested multisystemorgan failure (Table 1). An additional examination revealed
an abnormally high IL-6 level of 69 586 pg/ml. Accordingly,
we diagnosed CRS due to systemic symptoms with inflammation and elevated IL-6. Despite all efforts, he died the day
after admission. Blood cultures were later confirmed
negative.

Results of laboratory tests

TABLE 1WBC (/μl)

Four days beforeadmission

Uponadmission

6.0  103

9.1  103

Neutrophils (%)

57.0

83.3

Lymphocytes (%)

25.5

9.9

Monocytes (%)

9.6

6.6

Basophils (%)

0.7

0.2

Eosinophils (%)

7.2

0.0RBC (/μl)

4.21  106

4.76  106

Hemoglobin (g/dl)

12.4

13.9

Platelets (/μl)

2.0  105

1.3  105

AST (U/l)

22904

ALT (U/l)

11179

LDH (U/l)

188

1616

γ-GTP(U/l)

3135

Total protein (g/dl)

7.4

7.2

Albumin (g/dl)

4.1

3.8

Total bilirubin (mg/dl)

0.8

0.7

BUN (mg/dl)

24

52

Creatinine (mg/dl)

1.22

4.73

CK (U/l)

7657 864

CK-MB (U/l)-101

Sodium (mmol/l)

141

134

Potassium (mmol/l)

4.8

5.7

Chloride (mmol/l)

105

101

D-dimer (μg/ml)-46.4

Procalcitonin (ng/ml)-29.05Lactate (mmol/l)-4.97

Glucose (mg/dl)

103

87

CRP (mg/dl)

0.25

10.29

DISCUSSION
This is the first report of a patient with CRS acompaniedwith COVID-19 infection during treatment with ICIs. It is
not clear whether COVID-19 infection or ICIs were thecause of CRS, but it was determined that CRS was triggeredby COVID-19 infection because it coincided with the timingof COVID-19 infection. IrAEs have been suggested to reflect
the favorable therapeutic efficacy of ICI treatment, but cansometimes be life-threatening.7,9–11 In addition, irAEs canbe triggered by infections.12,13 In the present case, thepatient developed an irAE and showed a favorable response
to immunotherapy. The CRS in this case may have been anirAE triggered by infection. Especially in cases of favorable
tumor response, it is unfortunate that complications canlead to a poor prognosis.
ICIs are known as a cause of CRS in various types ofcancer, and patients who received ICIs have been reported
to develop CRS at a ratio of 0.06%–0.14%.8 Several ICIs areAbbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN,blood urea nitrogen; CK, creatine kinase; CK-MB, creatine kinase-myocardial band;
CRP, C-reactive protein; γ-GTP, gamma-glutamyl transpeptidase; LDH, lactate
dehydrogenase; RBC, red blood cells; WBC, white blood cells.

Previously reported CRS cases induced by nivolumab plus ipilimumab

TABLE 2Authors

Age/sexPrimary cancer

IL-6 level (pg/ml)

Immunosuppressive therapy

OutcomeUrasaki et al.

46/F

Renal cell carcinoma

No dateTocilizumab
MMFIVIg

RecoveredOhira et al.1470/M

Renal cell carcinoma

467

mPSL/PSL
MMF
IVIg

Recovered

Kunimasa et al.15

64/F

Lung cancer

25 100Tocilizumab
Infliximab
mPSL/PSL
MMF

RecoveredPresent study

70/M

Lung cancer

69 586

Hydrocortisone 100 mg

Death

13

Abbreviations: IL-6, interleukin-6; IVIg, intravenous immunoglobulin; MMF, mycophenolate mofetil; mPSL, methylprednisolone; PSL, prednisolone.

MURATA ET AL.

4linked to CRS, including anti-programmed cell death
protein-1/ligand-1 antibodies, and anticytotoxic T lymphocyte antigen-4 antibodies. Because of the progressively
increasing use of ICIs, CRS induced by ICIs is becoming
more easily recognized and diagnosed.8,14–16
Previously reported CRS cases induced by nivolumab
plus ipilimumab are summarized in Table 2. IL-6 values varied from case to case, but the patient described herein had
the highest value. In all previous cases, immunosuppressive
therapy had been used with favorable outcomes. The addition of immunosuppressive therapy such as an IL-6 blockeror IL-6 receptor antagonist may improve the prognosis ofpatients with CRS.
Fever is a common event in cancer patients, especially in
COVID-19-infected patients, but when fever develops during cancer immunotherapy, CRS should always be keptin mind.
CONF LICT OF IN TEREST
KA reports receiving personal fees from AstraZeneca, MSD,Bristol Myers Squibb, Ono Pharmaceutical, Takeda Pharmaceutical, Pfizer and Chugai Pharmaceutical. TT reports
receiving personal fees from AstraZeneca, Bristol Myers
Squibb, MSD, Novartis and Chugai Pharmaceutical. The
remaining authors have no conflicts of interest to disclose.

7.

8.

9.

10.

11.

12.

13.

14.

ORCID
Daiki Murata https://orcid.org/0000-0002-4295-5046
Koichi Azuma https://orcid.org/0000-0001-5040-5856
Takaaki Tokito https://orcid.org/0000-0002-8429-2287

15.

R EF E R EN C E S
1.

2.
3.

4.

5.

6.

Morris EC, Neelapu SS, Giavridis T, Sadelain M. Cytokine release syndrome and associated neurotoxicity in cancer immunotherapy. Nat
Rev Immunol. 2022;22(2):85–96. https://doi.org/10.1038/s41577-02100547-6
Moore JB, June CH. Cytokine release syndrome in severe COVID-19.
Science. 2020;368(6490):473–4. https://doi.org/10.1126/science.abb8925
Gödel P, Shimabukuro-Vornhagen A, von Bergwelt-Baildon M.
Understanding cytokine release syndrome. Intensive Care Med. 2018;
44(3):371–3. https://doi.org/10.1007/s00134-017-4943-5
Lee DW, Gardner R, Porter DL, Louis CU, Ahmed N, Jensen M, et al.
Current concepts in the diagnosis and management of cytokine release
syndrome. Blood. 2014;124(2):188–95. https://doi.org/10.1182/blood2014-05-552729
Shimabukuro-Vornhagen A, Gödel P, Subklewe M, Stemmler H,Schlößer HA, Schlaak M, et al. Cytokine release syndrome.
J Immunother Cancer. 2018;6(1):56. https://doi.org/10.1186/s40425018-0343-9
Chen G, Wu D, Guo W, Cao Y, Huang D, Wang H, et al. Clinical andimmunological features of severe and moderate coronavirus disease2019. J Clin Invest. 2020;130:2620–9. https://doi.org/10.1172/JCI137244

16.

Martins F, Sofiya L, Sykiotis GP, Lamine F, Maillard M, Fraga M,
et al. Adverse effects of immune-checkpoint inhibitors: epidemiology,management and surveillance. Nat Rev Clin Oncol. 2019;16:563–80.
https://doi.org/10.1038/s41571-019-0218-0
Ceschi A, Noseda R, Palin K, Verhamme K. Immune checkpoint
inhibitor-related cytokine release syndrome: analysis of WHO global
pharmacovigilance database. Front Pharmacol. 2020;11:557. https://doi.org/10.3389/fphar.2020.00557
Park R, Lopes L, Saeed A. Anti-PD-1/L1-associated immune-related
adverse events as harbinger of favorable clinical outcome: systematic
review and meta-analysis. Clin Transl Oncol. 2021;23:100–9. https://doi.org/10.1007/s12094-020-02397-5
Hussaini S, Chehade R, Boldt RG, Raphael J, Blanchette P, Maleki
Vareki S, et al. Association between immune-related side effects andefficacy and benefit of immune checkpoint inhibitors: a systematicreview and meta-analysis. Cancer Treat Rev. 2021;92:102134. https://doi.org/10.1016/j.ctrv.2020.102134
Wang DY, Salem JE, Cohen JV, Chandra S, Menzer C, Ye F, et al.
Fatal toxic effects associated with immune checkpoint inhibitors: asystematic review and meta-analysis. JAMA Oncol. 2018;4:1721–8.
https://doi.org/10.1001/jamaoncol.2018.3923
Makunts T, Burkhart K, Abagyan R, Lee P. Retrospective analysis ofclinical trial safety data for pembrolizumab reveals the effect of cooccurring infections on immune-related adverse events. PLoS One.
2022;17(2):e0263402. https://doi.org/10.1371/journal.pone.0263402
Takemura M, Motegi M, Kuroiwa Y, Itai M, Taguchi K, Umetsu K,
et al. Immune-related adverse events caused by treatment with pembrolizumab in a patient with lung cancer who infected influenza virus.
Respir Med Case Rep. 2021;32:101361. https://doi.org/10.1016/j.rmcr.
2021.101361
Urasaki T, Ono M, Mochizuki T, Takeda K, Nishizawa A,Fukagawa E, et al. Case report: a case of trimethoprim/sulfamethoxazole-triggered hypotensive shock: cytokine release syndrome related toimmune checkpoint inhibitors and drug-induced hypersensitivity syndrome. Front Oncol. 2021;11:681997.
Ohira J, Kawamoto M, Sugino Y, Kohara N. A case report of fulminant cytokine release syndrome complicated by dermatomyositis after
the combination therapy with immune checkpoint inhibitors. Medicine. 2020;99:15. https://doi.org/10.1097/MD.0000000000019741
Kunimasa K, Inoue T, Matsueda T, et al. Cytokine release syndrome
and immune-related pneumonitis associated with tumor progression
in a pulmonary pleomorphic carcinoma treated with Nivolumab plus
Ipilimumab treatment: a case report. JTO Clin Res Rep. 2021;3(2):100272. https://doi.org/10.1016/j.jtocrr.2021.100272

How to cite this article: Murata D, Azuma K,
Tokisawa S, Tokito T, Hoshino T. A case of cytokine
release syndrome accompanied with COVID-19
infection during treatment with immune checkpoint
inhibitors for non-small cell lung cancer. Thorac
Cancer. 2022. https://doi.org/10.1111/1759-7714.
14632