A Case of Pneumocystis Pneumonia Associated with Everolimus
Therapy for Renal Cell Carcinoma
Yoshinobu Saito1,*, Mikie Nagayama1, Yukiko Miura1, Satoko Ogushi2, Yasutomo Suzuki2, Rintaro Noro1,
Yuji Minegishi1, Go Kimura2, Yukihiro Kondo2and Akihiko Gemma1
1Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Tokyo,
Japan and2Department of Urology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan
*For reprints and all correspondence: Yoshinobu Saito, Department of Pulmonary Medicine and Oncology, Graduate
School of Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8603, Japan. E-mail: yo-saito@
Received December 17, 2012; accepted January 28, 2013
A 76-year-old female with advanced renal cell carcinoma had been treated with everolimus
for 3 months. She visited our hospital because of a cough and fever lasting a few days. Chest
X-rays showed bilateral infiltrative shadows, and a chest computed tomography scan showed
homogeneous ground-glass opacities with mosaic patterns, especially in the apical region.
The laboratory results revealed a decreased white blood cell count with lymphocytopenia and
high levels of lactate dehydrogenase, C-reactive protein and KL-6. Pneumonitis was sus-
pected and, therefore, everolimus therapy was interrupted. At that time, the pneumonitis was
thought to be drug-induced interstitial lung disease. However, it was not possible to rule out
pneumocystis pneumonia, because the patient was immunocompromised and the computed
tomography findings suggested the possibility of pneumocystis pneumonia. The pneumonitis
progressed rapidly and the patient developed respiratory failure, so we performed broncho-
alveolar lavage to make a definitive diagnosis, and simultaneously started treatment with
prednisolone and trimethoprim–sulfamethoxazole to cover both interstitial lung disease and
pneumocystis pneumonia. A polymerase chain reaction assay of the bronchoalveolar lavage
fluid was positive for Pneumocystis carinii DNA, and the serum level of b-D-glucan was signifi-
cantly elevated. Thus, the patient was diagnosed with pneumocystis pneumonia, which was
cured by the treatment. Interstitial lung disease is a major adverse drug reaction associated
with everolimus, and interstitial lung disease is the first condition suspected when a patient
presents with pneumonitis during everolimus therapy. Pneumocystis pneumonia associated
with everolimus therapy is rare, but our experience suggests that pneumocystis pneumonia
should be considered as a differential diagnosis when pneumonitis is encountered in patients
receiving everolimus therapy.
Key words: everolimus – pneumocystis pneumonia – interstitial lung disease – renal cell
carcinoma – bronchoscopy
Iatrogenic lung diseases, which include drug-induced inter-
stitial lung disease (ILD), radiation pneumonitis, and
pulmonary infection, are often complicated in patients re-
ceiving cancer therapy. Occasionally, they become serious
respiratory conditions that may be fatal. Thus, the manage-
ment of patient safety is an important issue.
Everolimus, a mammalian target of rapamycin (mTOR)
inhibitor, has been used for renal cell carcinoma (RCC)
since 2010 in Japan. ILD is a well-known class effect asso-
ciated with mTOR inhibitors (1–3), and the incident rate of
ILD in the phase III clinical trial of everolimus for RCC was
13.5% of patients (1). ILD is a major and the most common
respiratory side effect caused by everolimus and, therefore,
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Jpn J Clin Oncol 2013;43(5)559–562
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at Nippon Medical School on February 6, 2016
ILD should be suspected when infiltrative shadows appear in
the lungs during everolimus therapy. On the other hand,
everolimus possesses an immunosuppressive effect in add-
ition to its antitumor effect, and has also been used as
an immunosuppressant for patients post-transplantation.
Therefore, as a matter of course, everolimus has the potential
to allow for the development of infectious diseases.
We herein present a case of pneumocystis pneumonia
(PCP) associated with everolimus therapy for RCC, and
discuss the problems related to the diagnosis and manage-
ment of the case.
A 76-year-old female with advanced RCC visited the hos-
pital because of a fever and cough. She had first experienced
weakness of the lower extremities 6 months prior, and had
been suspected to have a thoracic vertebral metastasis from
left RCC based on an examination by spine MRI and ab-
dominal computed tomography (CT). Distant metastases had
also been found in the lung, liver, adrenal gland and medias-
tinal lymph node. A spinal laminectomy had been performed
to eliminate the spinal cord compression that had caused
paresis of the lower extremities, and a definitive diagnosis of
a metastatic clear cell carcinoma had been made by the
pathological examination of the surgical specimen. After the
surgery, she had received sunitinib for the initial treatment
of advanced RCC, however, the disease progressed. Then
treatment regimen was switched to everolimus, and the
therapy had been continued for 3 months. In the course
of the everolimus therapy, the size of the metastatic lesion of
the liver had been reduced, and everolimus had been thought
to be effective. However, she began coughing, then devel-
oped a fever, which prompted her to visit us on the weekend.
When she visited us, her body temperature was 38.58C and
chest auscultation showed fine crackles in both lung fields.
Chest X-rays showed bilateral infiltrative shadows (Fig. 1). A
further investigation by CT showed mosaic patterns with
ground-glass opacities in the apical regions and homoge-
neous ground-glass opacities in the lower regions of the
lungs (Fig. 2A and B). Complete blood cell counts revealed
a decreased white blood cell (WBC) count (2600/ml) and
lymphocytopenia (515/ml). The results of a blood chemistry
analysis showed significantly elevated levels of lactate de-
hydrogenase, C-reactive protein and KL-6 (818 IU/l,
7.09 mg/dl and 820.4 U/ml, respectively). The results of the
arterial blood gas analyses on room air were a PaO2of 74.6
torr, PaCO2of 27.4 torr and pH of 7.453, thus suggesting
that the alveolar–arterial oxygen difference was increased.
Figure 1. A chest X-ray taken on admission. Diffuse infiltrative shadows
were seen in both lung fields.
Figure 2. (A and B) A chest CT scan on admission showed mosaic patterns
with ground-glass opacities in both upper lungs, and diffuse ground-glass
opacities in both lower lungs. (C) The ground-glass opacifications in the
lung fields had almost completely disappeared after the treatment for PCP.
560Pneumocystis pneumonia caused by everolimus
at Nippon Medical School on February 6, 2016
Pneumonitis was suspected, and she was admitted to the hos-
pital the same day.
The everolimus therapy was interrupted; however, the
pneumonitis continued to get worse, and she complained
dyspnea and required oxygen inhalation on the second hos-
pital day. At that time, the pneumonitis was thought to be
drug-induced interstitial pneumonia, but it was not possible
to rule out the possibility of infectious pneumonitis, such as
PCP, because a blood examination showed leukocytopenia
and she had been receiving everolimus, which had caused
immunosuppression. Without waiting for the examination
results, we started administering prednisolone (60 mg/day)
and trimethoprim–sulfamethoxazole (trimethoprim 720 mg/
day) to cover both ILD and PCP, and bronchoscopy was per-
formed to make a definitive diagnosis at the same time.
Bronchoalveolar lavage (BAL) was successfully carried out,
but the patient’s respiratory condition worsened after the
BAL procedure, and thus, an adequate specimen of lung
tissue could not be obtained. An analysis of the BAL fluid
showed marked lymphocytosis, mild eosinophilia and neu-
trophilia (Table 1). No microorganisms, including acid fast
bacilli and fungi, were cultured from the BAL fluid. The
BAL fluid was also negative for the cytomegalovirus
antigen. On the other hand, a polymerase chain reaction
(PCR) assay for Pneumocystis carinii DNA of the BAL fluid
was positive, and the serum level of b-D-glucan was signifi-
cantly elevated (116 pg/ml, normal range; ,20 pg/ml).
Thus, we diagnosed her to have PCP.
After the administration of trimethoprim–sulfamethoxazole
concomitant with the corticosteroid, the infiltrative shadows on
the chest X-rays began to decrease and the respiratory failure
recovered. The prednisolone was rapidly tapered, and was com-
pletely discontinued in 2 weeks. A follow-up chest CT showed
resolution of the infiltrative shadows (Fig. 2C). The serum
levels of b-D-glucan and KL-6 were gradually decreased and
normalized after the recovery from PCP.
Because the everolimus had appeared to be effective for
the patient’s cancer, everolimus was re-administered with a
dose reduction from 10 to 5 mg/day, and trimethoprim–
sulfamethoxazole (trimethoprim 80 mg/day) was also contin-
ued for prophylaxis of PCP. We observed her carefully, and
follow-up chest X-ray and close monitoring of the serum
KL-6 and b-D-glucan levels were performed. Two months
later, progression of the cancer was recognized, and the ad-
ministration of everolimus was stopped. The PCP did not
relapse during the re-administration of everolimus.
This is the first case report regarding the development of
PCP in a patient receiving everolimus for RCC. PCP is a
rare adverse drug reaction associated with everolimus.
However, it is a critical problem, because PCP can be a fatal
infectious disease without an appropriate diagnosis and
In the present case, the diagnosis of PCP was made based
on the patient’s symptoms, chest CT findings, serological
findings and detection of P. carinii DNA in the BAL fluid.
The chest CT showed sharply demarcated patchy ground-
glass opacities, a so-called mosaic pattern, in both lung
fields, which was consistent with PCP (4). The serum levels
of KL-6 and b-D-glucan are useful biomarkers for diagnos-
ing PCP (5–8), and both were significantly elevated at the
diagnosis and were normalized after the treatment for
PCP in the case. A positive result of the PCR analysis
of P. carinii DNA requires a differential diagnosis to deter-
mine whether it means PCP or pulmonary colonization
with Pneumocystis. However, elevation of serum level of
b-D-glucan is rarely seen in patients with Pneumocystis col-
onization (9–11). Based on these considerations, we thought
it was reasonable to diagnose the pneumonitis as PCP.
On the other hand, there was a question regarding the
differential diagnosis of pneumonitis at the initial stage of the
diagnosis. Everolimus is well known to cause ILD. Therefore,
we had to consider whether the pneumonitis was everolimus-
induced ILD or not. The symptoms and the CT findings of the
case were applicable to both PCP and ILD. The BAL analysis
showed marked lymphocytosis and mild eosinophilia
(Table 1). Everolimus-induced ILD in patients with RCC
often presents as marked lymphocytosis and sometimes eo-
sinophilia in the BAL cellular analyses (12–14). However,
the BAL cell differentiation in patients with PCP also reveals
various degrees of lymphocytosis and eosinophilia (15–16).
It has been reported that the lymphocyte count ranges from
under 10 to over 70%, and that eosinophils may increase
within a range of 10% in the BAL fluid of HIV-negative
patients with PCP (15). Therefore, it is difficult to differenti-
ate between everolimus-induced ILD and PCP solely by an
analysis of the BAL cell differentiation. Moreover, it was dif-
ficult to determine whether everolimus-induced ILD was co-
existent with the PCP in the present case. In such cases,
especially in severe cases, concomitant use of prednisolone
and antibiotics for PCP is thought to be a useful strategy to
treat both ILD and PCP.
Table 1. Results of the BAL cellular analyses
Total cell countDifferential cell counts CD4þ/CD8þ
5.1 ? 105/ml24.4%63.2%3.9%8.5% 1.8
Jpn J Clin Oncol 2013;43(5) 561
at Nippon Medical School on February 6, 2016
ILD is the major adverse drug reaction affecting the respira- Download full-text
tory system in patients receiving everolimus therapy, and this
information is well known to the physicians. Therefore, when
infiltrative shadows develop in both lungs during everolimus
therapy, physicians generally suspect everolimus-induced ILD.
However, everolimus also has an immunosuppressive effect
and can cause opportunistic infections, such as PCP. The radio-
graphic findings of PCP resemble those of ILD, and elevation
of the serum level of KL-6 can be seen in both PCP and ILD.
This means that there is a risk of misdiagnosis of pneumonitis
in patients receiving everolimus therapy when they are
assessed solely by the results of chest images and the serum
KL-6 levels. To avoid the risk of a misdiagnosis, the serum
b-D-glucan level should be measured, and if possible, BAL
fluid sampling should be performed for a definitive diagnosis.
The evaluation of PCP should also be done in patients
with asymptomatic ILD, which is seen in about 30% of
the patients with everolimus-induced ILD (14), by measuring
the serum b-D-glucan level. Because package insert of everoli-
mus (AFINITORw) allows to continue everolimus therapy
for patients with asymptomatic ILD, and the continuation of
everolimus might increase the risk of developing a serious
condition when a patient having PCP is misdiagnosed
In conclusion, everolimus has an immunosuppressive
effect and can cause PCP, which is difficult to distinguish
from ILD. When pneumonitis is encountered in patients re-
ceiving everolimus therapy, the possibility of the patient
having PCP should be considered, and physicians should
perform appropriate diagnostic approaches to distinguish
between PCP and ILD.
Conflict of interest statement
Y.S., G.K. and A.G. received lecture fee from Novartis
Pharma Co., Ltd.
1. White DA, Camus P, Endo M, et al. Noninfectious pneumonitis after
everolimus therapy for advanced renal cell carcinoma. Am J Respir Crit
Care Med 2010;182:396–403.
2. Maroto JP, Hudes G, Dutcher JP, et al. Drug-related pneumonitis in
patients with advanced renal cell carcinoma treated with temsirolimus. J
Clin Oncol 2011;29:1750–6.
3. Weiner SM, Sellin L, Vonend O, et al. Pneumonitis associated with
sirolimus: clinical characteristics, risk factors and outcome—a
single-centre experience and review of the literature. Nephrol Dial
4. Webb WR, Mu ¨ller NL, Naidich DP. High-resolution CT of the Lung.
4th edn. Philadelphia: Lippincott Williams & Wilkins 2009;436–43.
5. Yasuoka A, Tachikawa N, Shimada K, Kimura S, Oka S. (1!3)
Beta-D-glucan as a quantitative serological marker for Pneumocystis
carinii pneumonia. Clin Diagn Lab Immunol 1996;3:197–9.
6. Tasaka S, Hasegawa N, Kobayashi S, et al. Serum indicators for the
diagnosis of pneumocystis pneumonia. Chest 2007;131:1173–80.
7. Hamada H, Kohno N, Yokoyama A, et al. KL-6 as a serologic indicator
of Pneumocystis carinii pneumonia in immunocompromised hosts.
Intern Med 1998;37:307–10.
8. Nakamura H, Tateyama M, Tasato D, et al. Clinical utility of serum
beta-D-glucan and KL-6 levels in Pneumocystis jirovecii pneumonia.
Intern Med 2009;48:195–202.
9. Shimizu Y, Sunaga N, Dobashi K, et al. Serum markers in interstitial
pneumonia with and without Pneumocystis jirovecii colonization: a
prospective study. BMC Infect Dis 2009;9:47.
10. Damiani C, Le Gal S, Lejeune D, et al. Serum (1!3)-beta-D-glucan
levels in primary infection and pulmonary colonization with
Pneumocystis jirovecii. J Clin Microbiol 2011;49:2000–2.
11. Matsumura Y, Ito Y, Iinuma Y, et al. Quantitative real-time PCR and the
(1!3)-b-D-glucan assay for differentiation between Pneumocystis jirovecii
pneumonia and colonization. Clin Microbiol Infect 2012;18:591–7.
12. Mizuno R, Asano K, Mikami S, Nagata H, Kaneko G, Oya M. Patterns
of interstitial lung disease during everolimus treatment in patients with
metastatic renal cell carcinoma. Jpn J Clin Oncol 2012;42:442–6.
13. Akata K, Yatera K, Ishimoto H, et al. Two cases of everolimus-
associated interstitial pneumonia in patients with renal cell carcinoma.
Intern Med 2011;50:3013–7.
14. Novartis Pharma K.K. AFINITOR tablets 5 mg: product information for
healthcare providers. http://product.novartis.co.jp/afi/ts/pms_kanshi
tsusei_20120116.pdf (in Japanese).
15. Fleury-Feith J, Van Nhieu JT, Picard C, Escudier E, Bernaudin JF.
Bronchoalveolar lavage eosinophilia associated with Pneumocystis
carinii pneumonitis in AIDS patients. Comparative study with
non-AIDS patients. Chest 1989;95:1198–201.
16. Nu ¨esch R, Bellini C, Zimmerli W. Pneumocystis carinii pneumonia in
human immunodeficiency virus (HIV)-positive and HIV-negative
immunocompromised patients. Clin Infect Dis 1999;29:1519–23.
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