J Med Cases

Journal of Medical Cases, ISSN 1923-4155 print, 1923-4163 online, Open Access

Article copyright, the authors; Journal compilation copyright, J Med Cases and Elmer Press Inc

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Case Report

Volume 16, Number 2, February 2025, pages 69-76

An Adverse Double-Hit by Pembrolizumab: A Case Report of Bullous Pemphigoid and Pneumonitis

Figure 1. Tense bulla with clear fluid on the right upper extremity of the patient. Note the erythematous rash with erosions and blistering.

Figure 3. Chest CTPA reveals the presence of honeycombing, traction bronchiectasis, and ground glass opacities suggestive of nonspecific interstitial pneumonitis. CTPA: computed tomography pulmonary angiogram.

**Table 1.** The Vital Signs and the Laboratory Values of the Initial Diagnostic Workup in the ED
Laboratory parameters	On admission	Reference range
ED: emergency department.
Blood pressure	133/74 mm Hg
Heart rate	107
Respiratory rate	30
Temperature	37.6 °C
Oxygen saturation	75%
Electrocardiogram	Normal
High-sensitivity troponin I	150 pg/mL	0 - 34 pg/ml
D-dimers	> 20 mg/L	0 - 0.5 mg/L
Lactate dehydrogenase	400 U/L	120 - 230 U/L
C-reactive protein	43.6 mg/dL	< 0.5 mg/dL
White blood cells (/µL)	17,960	4,000 - 11,000
Neutrophils	86%	50-70%
Lymphocytes	6%	20-40%
Hemoglobin	8.6 g/dL	13 - 17 g/dL
Platelets (/µL)	449,000	150,000 - 400,000

Table 1. The Vital Signs and the Laboratory Values of the Initial Diagnostic Workup in the ED

Laboratory parameters

On admission

Reference range

ED: emergency department.

Blood pressure

133/74 mm Hg

Heart rate

107

Respiratory rate

Temperature

37.6 °C

Oxygen saturation

75%

Electrocardiogram

Normal

High-sensitivity troponin I

150 pg/mL

0 - 34 pg/ml

D-dimers

> 20 mg/L

0 - 0.5 mg/L

Lactate dehydrogenase

400 U/L

120 - 230 U/L

C-reactive protein

43.6 mg/dL

< 0.5 mg/dL

White blood cells (/µL)

17,960

4,000 - 11,000

Neutrophils

86%

50-70%

Lymphocytes

20-40%

Hemoglobin

8.6 g/dL

13 - 17 g/dL

Platelets (/µL)

449,000

150,000 - 400,000

**Table 2.** Treatment of Bullous Pemphigoid (BP) Secondary to Immunotherapy Depending on the Severity of the Rash
Severity of BP secondary to immunotherapy	Discontinuation of immunotherapy	Treatment
N/A: not available.
Grade 1: < 10% of body surface area (BSA)	No	Consider oral corticosteroids (0.5 - 1 mg/kg/day) and non-steroidal immunosuppressants
Grade 2: 10-30% of BSA	No	Treatment as above
Grade 3: > 30% of BSA	Yes	Add oral or intravenous corticosteroids (1 - 2 mg/kg/day)
		Consider non-steroidal immunosuppressants
Grade 4: > 30% of BSA and life-threatening complications, e.g., fluid/electrolyte disorders, intensive care is necessary	Yes	Add intravenous corticosteroids (1 - 2 mg/kg/day)
		Consider non-steroidal immunosuppressants
All grades	N/A	Topical corticosteroids, topical emollients, oral antihistamines
		Tapering of systemic corticosteroids for at least 1 month
		Non-steroidal immunosuppressants: dapsone, doxycycline, mycophenolate mofetil, cyclophosphamide, azathioprine, omalizumab, dupilumab, rituximab, intravenous immunoglobulin

Table 2. Treatment of Bullous Pemphigoid (BP) Secondary to Immunotherapy Depending on the Severity of the Rash

Severity of BP secondary to immunotherapy

Discontinuation of immunotherapy

Treatment

N/A: not available.

Grade 1: < 10% of body surface area (BSA)

Consider oral corticosteroids (0.5 - 1 mg/kg/day) and non-steroidal immunosuppressants

Grade 2: 10-30% of BSA

Treatment as above

Grade 3: > 30% of BSA

Yes

Add oral or intravenous corticosteroids (1 - 2 mg/kg/day)

Consider non-steroidal immunosuppressants

Grade 4: > 30% of BSA and life-threatening complications, e.g., fluid/electrolyte disorders, intensive care is necessary

Yes

Add intravenous corticosteroids (1 - 2 mg/kg/day)

Consider non-steroidal immunosuppressants

All grades

N/A

Topical corticosteroids, topical emollients, oral antihistamines

Tapering of systemic corticosteroids for at least 1 month

Non-steroidal immunosuppressants: dapsone, doxycycline, mycophenolate mofetil, cyclophosphamide, azathioprine, omalizumab, dupilumab, rituximab, intravenous immunoglobulin

**Table 3.** Management of Pneumonitis Secondary to Immunotherapy Depending on the Severity
Severity of pneumonitis secondary to immunotherapy	Definition	Discontinuation of immunotherapy	Administration of corticosteroids
P. jirovecii: Pneumocystis jirovecii; N/A: not available.
Grade 1	Subclinical; observation without treatment	Temporary	No
Grade 2	Mild presentation; outpatient treatment indicated	Temporary	Prednisone 1 - 2 mg/kg/day with a taper; consider gastrointestinal and P. jirovecii prophylaxis
Grade 3	Severe presentation; inpatient treatment indicated	Permanent	Prednisone 1 - 2 mg/kg/day with a taper; consider gastrointestinal and P. jirovecii prophylaxis
Grade 4	Life-threatening; mechanical ventilation indicated	Permanent	Prednisone 1 - 2 mg/kg/day with a taper; consider gastrointestinal and P. jirovecii prophylaxis
Grade 5	Death	N/A	N/A

Table 3. Management of Pneumonitis Secondary to Immunotherapy Depending on the Severity

Severity of pneumonitis secondary to immunotherapy

Definition

Discontinuation of immunotherapy

Administration of corticosteroids

P. jirovecii: Pneumocystis jirovecii; N/A: not available.

Grade 1

Subclinical; observation without treatment

Temporary

Grade 2

Mild presentation; outpatient treatment indicated

Temporary

Prednisone 1 - 2 mg/kg/day with a taper; consider gastrointestinal and P. jirovecii prophylaxis

Grade 3

Severe presentation; inpatient treatment indicated

Permanent

Prednisone 1 - 2 mg/kg/day with a taper; consider gastrointestinal and P. jirovecii prophylaxis

Grade 4

Life-threatening; mechanical ventilation indicated

Permanent

Prednisone 1 - 2 mg/kg/day with a taper; consider gastrointestinal and P. jirovecii prophylaxis

Grade 5

Death

N/A

**Table 4.** Reported Cases of Bullous Pemphigoid and Pneumonitis in Patients Treated With Pembrolizumab
No.	Author	Sex/age (years)/malignancy	Diagnosis; interval between treatment with pembrolizumab and irAE	Treatment	Outcome
NSCLC: non-small cell lung carcinoma; irAE: immune-related adverse event.
1	Correia et al, 2022 [1]	Male/81/bladder cancer	Pruritus; 15 weeks	Pneumonitis: discontinuation of pembrolizumab	Bullous pemphigoid: improvement after 10 days
				Pruritus/bullous pemphigoid: topical clobetasol, oral prednisolone, doxycycline, antihistamine
			Pneumonitis; 33 weeks
			Bullous pemphigoid; 36 weeks
2	Cardona et al, 2021 [2]	Male/73/lung adenocarcinoma (NSCLC)	Pneumonitis (grade 2)	Adrenal insufficiency: corticosteroids	Pneumonitis, adrenal insufficiency: resolution
			Adrenal insufficiency; 75 weeks (25 cycles)		Bullous pemphigoid: lack of response to corticosteroids and infliximab, resolution with cyclophosphamide
			Bullous pemphigoid; 2.5 years (35 cycles)	Bullous pemphigoid: intravenous methylprednisolone, infliximab, oral cyclophosphamide
3	Alsabbagh et al, 2023 [3]	Male/68/bladder cancer	Hypertrophic lichenoid dermatitis; 3 months	Hypertrophic lichenoid dermatitis: topical mometasone	Hypertrophic lichenoid dermatitis: resolution
			Bullous pemphigoid; 12 months	Bullous pemphigoid: transient discontinuation of pembrolizumab, oral prednisolone, and topical corticosteroids	Bullous pemphigoid: resolution within 2 months
			Pneumonitis	Pneumonitis: permanent discontinuation of pembrolizumab
4		Male/66/lung squamous cell carcinoma (non-small cell lung cancer)	Bullous pemphigoid; 16 months (21 cycles)	Bullous pemphigoid: topical clobetasol, oral bilastine	Bullous pemphigoid: improvement with topical corticosteroids, resolution with systemic corticosteroids within 2 weeks
			Pneumonitis (grade 3); 17 months (21 cycles)	Pneumonitis: discontinuation of pembrolizumab, intravenous methylprednisolone with proton pump inhibitor	Pneumonitis: gradual resolution within 2 weeks

Table 4. Reported Cases of Bullous Pemphigoid and Pneumonitis in Patients Treated With Pembrolizumab

No.

Author

Sex/age (years)/malignancy

Diagnosis; interval between treatment with pembrolizumab and irAE

Treatment

Outcome

NSCLC: non-small cell lung carcinoma; irAE: immune-related adverse event.

Correia et al, 2022 [1]

Male/81/bladder cancer

Pruritus; 15 weeks

Pneumonitis: discontinuation of pembrolizumab

Bullous pemphigoid: improvement after 10 days

Pruritus/bullous pemphigoid: topical clobetasol, oral prednisolone, doxycycline, antihistamine

Pneumonitis; 33 weeks

Bullous pemphigoid; 36 weeks

Cardona et al, 2021 [2]

Male/73/lung adenocarcinoma (NSCLC)

Pneumonitis (grade 2)

Adrenal insufficiency: corticosteroids

Pneumonitis, adrenal insufficiency: resolution

Adrenal insufficiency; 75 weeks (25 cycles)

Bullous pemphigoid: lack of response to corticosteroids and infliximab, resolution with cyclophosphamide

Bullous pemphigoid; 2.5 years (35 cycles)

Bullous pemphigoid: intravenous methylprednisolone, infliximab, oral cyclophosphamide

Alsabbagh et al, 2023 [3]

Male/68/bladder cancer

Hypertrophic lichenoid dermatitis; 3 months

Hypertrophic lichenoid dermatitis: topical mometasone

Hypertrophic lichenoid dermatitis: resolution

Bullous pemphigoid; 12 months

Bullous pemphigoid: transient discontinuation of pembrolizumab, oral prednisolone, and topical corticosteroids

Bullous pemphigoid: resolution within 2 months

Pneumonitis

Pneumonitis: permanent discontinuation of pembrolizumab

Male/66/lung squamous cell carcinoma (non-small cell lung cancer)

Bullous pemphigoid; 16 months (21 cycles)

Bullous pemphigoid: topical clobetasol, oral bilastine

Bullous pemphigoid: improvement with topical corticosteroids, resolution with systemic corticosteroids within 2 weeks

Pneumonitis (grade 3); 17 months (21 cycles)

Pneumonitis: discontinuation of pembrolizumab, intravenous methylprednisolone with proton pump inhibitor

Pneumonitis: gradual resolution within 2 weeks