Picard et al.

J Med Case Reports (2021) 15:332

https://doi.org/10.1186/s13256-021-02926-y

CASE REPORT Open Access

Patterns of immunotherapy‑induced
pneumonitis in patients with non‑small‑cell
lung cancer: a case series
Sarah Picard1,2*† , Desiree Goh1,2†, Ashley Tan2,3, Nisha Sikotra3, Eli Gabbay4,5 and Tim Clay2,6,7

Abstract
Background: Immunotherapy has become an efficacious option in the management of solid organ malignancies.
Immune-related adverse events including pneumonitis are well described and may be particularly of concern in
patients receiving immunotherapy for non-small-cell lung cancer.
Case presentations: In this paper, we describe three cases of immunotherapy-induced pneumonitis occurring in
the management of lung malignancy. Our cases include a 54-year-old Caucasian woman with squamous cell lung
cancer who was successfully rechallenged with immunotherapy after prior significant pneumonitis, a 65-year-old
Caucasian man with metastatic squamous cell lung cancer who developed pneumonitis after multiple cycles of
uneventful immunotherapy, and a 73-year-old Caucasian man with squamous cell lung cancer who developed early-
onset pneumonitis with rebound on steroid taper.
Conclusions: This case series has provided further insight into the presentation and risk factors for pneumonitis in
patients with non-small-cell lung cancer. Each of the cases of immunotherapy-induced pneumonitis illustrates the
different potential patterns that may arise when immunotherapy-induced pneumonitis develops. This case series
provides key learning points that may assist physicians managing non-small-cell lung cancer with immunotherapy.
Keywords: Pneumonitis, Immunotherapy, Malignancy, NSCLC, irAE

Background other solid organ malignancies receiving immunotherapy

Immunotherapy is increasingly prescribed for solid organ (2.92% incidence) [2]. In this paper, we describe three
and hematological malignancies, with striking improve- cases of immunotherapy-induced pneumonitis occurring
ments in progression-free and overall survival in some in the management of lung malignancy.
cancers [1]. Immunotherapeutic drugs may cause life- Immune checkpoint inhibitors in routine clinical
threatening immune-related adverse events (irAEs) practice today target programmed death 1 (PD-1), pro-
including pneumonitis, complicating their use in lung grammed death ligand 1 (PD-L1), and cytotoxic T-lym-
cancer. Patients with advanced non-small-cell lung can- phocyte-associated protein 4 (CTLA-4). These pathways
cer (NSCLC) have a higher incidence of pneumonitis are expressed in normal tissue as a mechanism to control
from immunotherapy (4.7% incidence) compared with the immune system, and they can become dysregulated
the overall incidence of pneumonitis in patients with in the tumor microenvironment [3]. Inhibition of these
proteins with monoclonal antibodies causes upregula-
tion of the immune system [3, 4], allowing it to target
*Correspondence: sarah.picard@health.wa.gov.au and destroy cancer cells [2, 5]. However, T cells may
†
Sarah Picard and Desiree Goh contributed equally as co-first authors
1
Sir Charles Gairdner Hospital, Hospital Ave, Nedlands, WA 6009, Australia also attack noncancerous cells, resulting in irAEs [5, 6]
Full list of author information is available at the end of the article including pneumonitis.

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permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the
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Picard et al. J Med Case Reports (2021) 15:332 Page 2 of 9

Pneumonitis is defined as focal or diffuse inflamma- Case 1: key point—rechallenge with immunotherapy
tion of the lung parenchyma [5, 7–9]. Pneumonitis may after prior significant pneumonitis
present asymptomatically and be incidentally found on A 54-year-old Caucasian woman with T3N3M0 stage
computerized tomography (CT) scanning, or present IIIB squamous cell lung cancer was initially treated with
symptomatically with cough, dyspnea, fatigue, or chest induction chemotherapy (carboplatin/paclitaxel) fol-
pain or clinical findings of progressive hypoxemia and lowed by chemoradiotherapy (cisplatin/etoposide) with
respiratory failure [10–12]. Diagnosis is based on appro- curative intent. After 6 months, she relapsed in her pri-
priate history and suggestive radiological findings on CT mary tumor with increased fluorodeoxyglucose (FDG)
scanning. Definitive diagnosis requires a combination of uptake on her positron emission tomography (PET) scan.
bronchoalveolar lavage and/or a biopsy; however, these She was commenced on the PD-1 inhibitor nivolumab.
investigations are often impractical in an acutely unwell She had a prior history of localized cervical cancer, hypo-
individual [10–12]. Suggestive radiological features thyroidism, and a 6 pack-year smoking history. There
include ground glass opacities, interstitial reticulation, or were no other clear risk factors for pneumonitis. Follow-
cryptogenic organizing pneumonia-like changes [8-10, ing her first dose of nivolumab, she immediately expe-
12]. Pneumonitis caused by immunotherapy is graded rienced facial flushing, fever, myalgia, and night sweats.
using the Common Terminology Criteria for Adverse Nine days following commencement of nivolumab, she
Events (CTCAE) severity scale, which ranges from grade was admitted to hospital with dyspnea.
1, asymptomatic, through to grade 5, where death occurs On admission, her observations were oxygen satura-
[2] (Table 1). Initial treatment is often empiric. Treat- tion 80% on room air, heart rate 116 beats per minute,
ment options include supportive therapy alone, oral or and respiratory rate 20 breaths per minute. Her CT scan
intravenous corticosteroids, cessation of immunotherapy, showed extensive patchy ground-glass infiltrates bilater-
and, in refractory cases, the use of steroid-sparing agents ally (Fig. 2). She received supplemental oxygen via nasal
as part of prolonged immunosuppression with mycophe- prongs. She was commenced on intravenous methylpred-
nolate, infliximab, or cyclophosphamide [11, 13]. The nisolone 500 mg daily for 4 days followed by a prolonged
outcome of patients who develop pneumonitis can range taper on oral prednisolone over 3 weeks. She was con-
from complete resolution to death [12, 13]. currently treated with intravenous piperacillin–tazobac-
tam and oral trimethoprim/sulfamethoxazole for 6 days
Case presentations to cover for potential concurrent infection. During her
We present three separate cases of immunotherapy-asso- admission, other causes of pneumonitis were considered
ciated pneumonitis seen at our institution, each of which and excluded, and antibiotics ceased. The pneumonitis
we believe has important teaching points, in accordance was grade 3 as per the Common Terminology Criteria for
with the CARE reporting checklist (Fig. 1). Adverse Events (CTCAE) version 5. Upon discharge, her

Table 1 CTCAE grading of pneumonitis with suggested management as per ESMO guidelines
Grade Clinical features Management

1 Asymptomatic Oral steroids—prednisone 1 mg/kg daily or equivalent with taper over

4–6 weeks after recovery
Clinical and assessment every 2–3 days initially
Delay checkpoint inhibitor until equivalent daily dose of 10 mg oral predniso-
lone or less
2 Symptomatic—limiting instrumental activities of daily living As per grade 2
AND
Radiological assessment every 2–3 days initially
3 Severe symptoms—limiting self-care activities of daily living Hospital admission
High-dose intravenous corticosteroids (methylprednisolone 2–4 mg/kg/day or
equivalent)
Cease immunotherapy permanently
Commence immunosuppression if no clinical or imaging improvement after
2 days (such as infliximab, mycophenolate mofetil, cyclophosphamide)
Wean steroids slowly over 6 or more weeks
4 Life-threatening respiratory compromise As per grade 3
5 Death
CTCAE Common Terminology Criteria for Adverse Events, ESMO European Society for Medical Oncology
Picard et al. J Med Case Reports (2021) 15:332 Page 3 of 9

Immunotherapy Induced Pneumoni s Key Event Timeline

Case 3 Immunotherapy
Commenced

Case 1 Admission #1
Case 3 Admission #2
Case 2 Immunotherapy Case 2 Death
Commenced

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28
Time (Months)
Case 3 Death
Case 2 Admission #1 Case 1 Death

Diagnosis Date Case 3 Admission #1 Case 1 Immunotherapy

Commenced
Fig. 1 Timeline of key events

Fig. 3 Case 1—CT chest 2 months after commencement of

pneumonitis treatment with incomplete resolution of pneumonitis
Fig. 2 Case 1—chest computed tomography (CT) revealing signs of
changes
pneumonitis

cardiorespiratory parameters were within normal range,

was cancer progression on FDG-PET after 5 months
and she had returned to her premorbid function.
off nivolumab. On discussion between the patient and
Two months after treatment, the FDG-PET scan
her treating team, nivolumab was reinstituted and
showed an initial partial metabolic response, with
treatment continued for a period of 18 months with a
incomplete resolution of the changes due to pneumoni-
best response of stable disease. No further episodes of
tis (Fig. 3). Over time, the pneumonitis settled, but there
pneumonitis were observed. The patient subsequently
died from cancer-associated venous thromboembolism
unrelated to her prior immunotherapy.
Picard et al. J Med Case Reports (2021) 15:332 Page 4 of 9

Case 2: key points—pneumonitis occurring after multiple

cycles of immunotherapy
A 65-year-old Caucasian man was diagnosed with meta-
static squamous cell carcinoma of the lung presenting
with a large primary tumor, mediastinal nodal involve-
ment, and a malignant pleural effusion. He was initially
treated with carboplatin and gemcitabine chemotherapy
with partial response. On progression, he was treated
with nivolumab with stable disease as best response. He
had a 47 pack-year smoking history and no other sig-
nificant medical history. The significant smoking history
and the subsequent risk of developing pneumonitis were
considered, and the decision was made to proceed with
immunotherapy and accept the associated risk given the
potential benefit treatment would provide. He was com-
menced on nivolumab and was in his seventh month of
treatment at the time of hospital admission. He presented
3 days following administration of nivolumab with dysp-
nea, productive cough, lethargy, and decreased appetite.
On admission, he was hypoxemic with oxygen satura- Fig. 5 Case 2—CT chest lower lobes revealing signs of pneumonitis,
widespread mixed ground glass and interstitial infiltrate. There is
tion of 82% on room air, respiratory rate of 21 breaths
progression of malignancy
per minute, heart rate of 80 beats per minutes, and tem-
perature of 38.7 °C. His CT chest showed widespread
mixed ground glass and interstitial infiltrate, with pro-
gression of his malignancy (Figs. 4, 5). He was treated azithromycin, and trimethoprim/sulfamethoxazole. He
with intravenous methylprednisolone 1 g for 5 days. continued to deteriorate, with progressively worsening
Mycophenolate was started on the fifth day of admis- hypoxemia, and was subsequently transitioned to end-
sion for a total of 3 days. He received concurrent intra- of-life care with grade 5 pneumonitis (Figs. 6, 7).
venous antibiotic therapy with cefepime, meropenem,

Fig. 4 Case 2—CT chest upper lobes revealing signs of pneumonitis,

widespread mixed ground glass and interstitial infiltrate. There is Fig. 6 Case 2—CT chest upper lobes with deterioration of
progression of malignancy pneumonitis despite treatment
Picard et al. J Med Case Reports (2021) 15:332 Page 5 of 9

Fig. 7 Case 2—CT chest lower lobes with deterioration of Fig. 8 Case 3—CT chest before immunotherapy commenced
pneumonitis despite treatment

Case 3: key points—early‑onset pneumonitis with rebound oncologist in clinic 3 weeks after discharge from hospi-
on steroid taper tal. Immunotherapy was not recommenced. A repeat
A 73-year-old Caucasian man with was diagnosed with CT scan showed marked resolution of the ground-glass
T3N1M0 squamous cell carcinoma of the lung. He changes, and he had returned to his premorbid function
received treatment with chemoradiotherapy (weekly (Fig. 10).
carboplatin/paclitaxel) with curative intent. An early One week after clinic review, the patient was readmit-
FDG-PET scan showed partial response, and consolida- ted to hospital with increasing dyspnea and hemoptysis.
tion immunotherapy durvalumab, a PD-L1 inhibitor, He had been on corticosteroids for a period of 4 weeks
was commenced. He had a background of emphysema, and 4 days at this time. He was hypoxemic at 92% oxygen
cerebellar hematoma, cerebrovascular disease, coronary saturation on 4 L of oxygen per minute via nasal prongs,
artery disease, hyperlipidemia, and hypothyroidism. He
was an ex-smoker with a 75 pack-year history. The signif-
icant smoking history, emphysema, and recent radiother-
apy were considered as risk factors for the development
of pneumonitis. After consideration, treatment pro-
ceeded, given the clear survival benefits demonstrated in
the PACIFIC clinical trial [14]. Six days following the first
dose of durvalumab, he developed dyspnea and a produc-
tive cough.
The patient was admitted to hospital. His initial obser-
vations showed oxygen saturation was 96% on room air
with a respiratory rate of 20 breaths per minute, temper-
ature of 37 °C, and heart rate of 78 breaths per minute.
His CT scan of the chest showed diffuse peribronchial
ground-glass changes and a decrease in size of the lung
cancer (Figs. 8, 9). He was admitted for 6 days and com-
menced on oral prednisolone 100 mg with a weaning
regime and concurrent doxycycline for grade 3 pneumo-
nitis. The patient improved clinically, his observations
were within normal cardiorespiratory parameters, and he
Fig. 9 Case 3—CT chest after immunotherapy given revealing signs
was discharged on a prolonged steroid taper. The patient of pneumonitis, diffuse peribronchial ground-glass changes. There is
was reviewed by his respiratory physician and medical decrease in size of lung cancer
Picard et al. J Med Case Reports (2021) 15:332 Page 6 of 9

to Intensive Care Unit (ICU). Immunosuppression was

increased to pulse methylprednisolone 1 g daily with
subsequent administration of intravenous cyclophos-
phamide. Broad antimicrobial therapy was administered
to cover for concurrent infection (including ceftriaxone,
piperacillin–tazobactam, meropenem, trimethoprim/sul-
famethoxazole, and azithromycin over the period of his
admission). Respiratory support included supplemental
oxygen via high-flow nasal prongs and periodic nonin-
vasive ventilation. Intubation and mechanical ventilation
were deemed inappropriate in view of the guarded prog-
nosis and in discussion with the patient and his family.
Despite maximal therapy, the patient’s condition deterio-
rated, and he died from grade 5 pneumonitis 18 days fol-
lowing admission.

Discussion and conclusion

Checkpoint inhibitor immunotherapy now enjoys wide-
Fig. 10 Case 3—CT chest after treatment of pneumonitis with initial spread use in cancer care. Severe adverse events with sin-
recovery gle-agent PD-1 or PD-L1 inhibition are uncommon but
well described—they can be unpredictable with regard to
timing and severity and can result in significant morbid-
ity and, occasionally, mortality. With any presentation,
irAEs must be considered in the differential diagnosis
and acted on promptly. Pneumonitis remains a toxicity
of particular concern for clinicians treating NSCLC with
greatest incidence of immunotherapy-induced pneumo-
nitis [2]. In the current context, Coronavirus 19 infection
also remains an important differential, and in jurisdic-
tions with community transmission, it is particularly
important to exclude this diagnosis urgently.
The first case highlights that immunotherapy rechal-
lenge is possible but must occur after consideration of
the therapeutic options and a discussion on risks and
benefits. It is important for clinicians to highlight the
uncertainty about the risk of further episodes of irAEs on
immunotherapy rechallenge.
Our case series demonstrates:

1. Patients with underlying lung pathology or smok-

Fig. 11 Case 3—CT chest after relapse of pneumonitis. There is no ing history are susceptible to developing high-grade
change in size of lung cancer pneumonitis.
2. Immunotherapy-induced pneumonitis can present at
any time after commencement of immunotherapy.
3. The severity of immunotherapy-induced pneumoni-
had a respiratory rate of 20 breaths per minute and heart
tis does not appear to be correlated with the time-
rate of 95 beats per minute, and was afebrile. A repeat CT
frame of onset.
scan of the chest showed recurrence of diffuse ground-
4. Immunotherapy-induced pneumonitis can flare or
glass infiltrates, in keeping with acute pneumonitis, and
recur during the period of steroid taper.
no change in the size of the lung cancer (Fig. 11).
5. Following careful consideration, immunotherapy
On readmission, oral corticosteroids were reesca-
rechallenge can occur for some patients with prior
lated to prednisolone 100 mg. The patient rapidly dete-
immunotherapy-induced pneumonitis. A careful dis-
riorated, with worsening hypoxemia requiring admission
cussion of the potential risks and benefits is required
Picard et al. J Med Case Reports (2021) 15:332 Page 7 of 9

with the patient, given the uncertainty about the risk intravenous corticosteroids, cessation of immunotherapy,
of further episodes of irAEs on immunity rechal- and, in refractory cases, the use of immunosuppression
lenge. drugs including mycophenolate, infliximab, and cyclo-
phosphamide [11, 13]. Patients may require admission to
Nishinu et al. identified that pneumonitis more com- hospital and respiratory support in a high-dependency or
monly occurs in patients who have NSCLC 4.1% and intensive care unit. The outcome of patients who develop
renal cell carcinoma 4.1%, compared with patients with pneumonitis can range from complete resolution to
metastatic melanoma 1.6% [1]. Similarly, a meta-analysis relapse, palliation, or death and is dependent on a multi-
of 16 randomized controlled trials found that the low- tude of variables [12, 13]. The mainstay of therapy is cor-
est rates of pneumonitis were seen in patients treated ticosteroids; however, steroid-refractory cases challenge
for advanced melanoma (0.72%) and highest in patients clinicians’ decisions regarding the appropriate dose, tim-
treated for advanced NSCLC 4.7% [2]. Patients with ing, and route of administration [19]. Steroid-sparing
NSCLC are more likely to have underlying lung disease agents are often employed in the case of steroid refrac-
such as chronic obstructive pulmonary disease (COPD), toriness; however, there appears to be limited data on the
potentially increasing their susceptibility to pneumoni- efficacy of these treatments [11]. The length of treatment
tis and/or to developing higher-grade pneumonitis [12]. and weaning regime implemented can also be a chal-
A recent study by Suzuki et al. [15] indicates that lower lenge with rebound toxicity on withdrawal of steroids
lung static volumes such as with large thoracic tumors [19]. As per the European Society for Medical Oncology
are associated with higher pneumonitis risk post-immu- guidelines, prednisolone should be weaned over 6 weeks
notherapy [16]. A past or current smoking history may minimum in grade 2 pneumonitis or minimum 8 weeks
also be a risk factor for the development of severe pneu- in grade 3 or 4 pneumonitis to prevent rebound of pneu-
monitis. Whether this is due to smoking itself or due to monitis symptoms. However, despite a prolonged wean-
smoking-related lung diseases is unclear and perhaps dif- ing regime of immunosuppression following an episode
ficult to discern, with two studies showing smoking on of pneumonitis, pneumonitis may relapse without fur-
its own was not associated with an increased risk or inci- ther exposure to immunotherapy, with cases of chronic
dence of pneumonitis [17, 18]. immune checkpoint pneumonitis as described by Naidoo
Pneumonitis was demonstrated in this case series to et al. [21]. This highlights that the biological effects of
present at variable time frames following administra- immunotherapy can persist for a long time, and relapse
tion of immunotherapy. The onset of pneumonitis from may occur following a prolonged wean.
time of administration of immunotherapy can be vari- The clinical decision to rechallenge with immunother-
able, which can complicate and delay the diagnosis [19]. apy is difficult and needs to be considered on an indi-
In a study by Nishino et al., the median time to onset of vidual basis. Invariably, the use of immunotherapy agents
immunotherapy-induced pneumonitis was 2.6 months, is currently occurring in the setting of advanced disease
ranging from 0.5 to 11.5 months [13]. Pneumonitis where the goal of prolonged cancer control is associated
must be considered among the differential diagnosis for with improved survival. The mortality associated with
patients presenting with early clinical deterioration and the progression of cancer must be weighed up against
respiratory symptoms early in their treatment course. the potentially life-threatening irAEs, and this can be a
However, late onset of irAEs including pneumonitis can challenge for physicians with limited data available. The
occur more than 90 days after cessation of immunother- decision of whether to rechallenge with immunotherapy
apy [20]. Delaunay et al. [9] found that the time to onset following high-grade toxicity is challenging for clinicians
of pneumonitis was shorter in patients with NSCLC com- and patients. In general, it has been suggested that rede-
pared with melanoma, with a median time to onset of velopment of irAE after rechallenge is more common in
2.1 and 5.2 months, respectively. In the same study, they patients with higher-grade irAE (grade 3 or 4). Santini
found that the time to onset and severity of pneumonitis et al. [22] recommend avoiding rechallenging patients
appeared to have no correlation [9]. As pneumonitis has who required hospitalization for their initial irAE, as
a widely variable and unpredictable onset, pneumonitis the recurrence/new rate of irAE’s was up to 87% in these
must be carefully considered in the differential diagnosis patients. Interestingly, in a study of 93 patients who were
of any patient who has received immunotherapy present- rechallenged with immunotherapy for a range of different
ing with dyspnea, hypoxia, and/or cough, regardless of irAEs, the recurrence of new irAE was not more severe
the time of onset. than the original event [23].
Management of pneumonitis is based on the grade We believe that this case series has provided further
attributed by clinicians using the CTCAE definitions insight into the presentation and risk factors for pneu-
[19]. Treatment options include observation, oral or monitis in patients with NSCLC. Each of the cases of
Picard et al. J Med Case Reports (2021) 15:332 Page 8 of 9

immunotherapy-induced pneumonitis illustrates the Author details

1
Sir Charles Gairdner Hospital, Hospital Ave, Nedlands, WA 6009, Australia.
different potential patterns that may arise when immu- 2
St John of God Hospital, 12 Salvado Rd, Subiaco, WA 6008, Australia. 3 Fiona
notherapy-induced pneumonitis develops. Given the var- Stanley Hospital, 11 Robin Warren D, Murdoch, WA 6150, Australia. 4 The Uni-
iable onset and severity of pneumonitis, we recommend versity of Notre Dame, Fremantle, Australia. 5 St John of God, Subiaco, Australia.
6
Adjunct Associate Professor of Medicine, Edith Cowan University, Joondalup,
that immunotherapy-induced pneumonitis must always WA, Australia. 7 Bendat Family Respiratory Research and Development Fund,
be considered as a differential, regardless of the time of Subiaco, Australia.
onset. Special consideration should be given to patients
Received: 24 February 2021 Accepted: 24 May 2021
with underlying lung disease or a significant smoking his-
tory, given the higher risk of mortality. The decision to
rechallenge patients, while difficult, is possible. Early ini-
tiation and perhaps prolonged immunosuppressive ther-
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