J Infect Chemother (2012) 18:722728

DOI 10.1007/s10156-012-0408-5

ORIGINAL ARTICLE

Analysis of clinical features of non-HIV Pneumocystis jirovecii

pneumonia
Yusuke Ainoda Yuji Hirai Takahiro Fujita
Noriko Isoda Kyoichi Totsuka

Received: 2 December 2011 / Accepted: 11 March 2012 / Published online: 30 March 2012
Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases 2012

Abstract Pneumocystis jirovecii pneumonia (PCP) is

classied as PCP with human immunodeciency virus
(HIV) and non-HIV PCP, and the two forms differ in
progression and prognosis. Although early treatment is
necessary, the diagnosis of non-HIV PCP is often difcult
because of the underlying diseases. However, the outcome
with treatment delay remains unclear because there are no
concrete data indicating a worsened clinical situation or
increased complications related to delayed therapy initiation. We retrospectively examined patients with non-HIV
PCP admitted to Tokyo Womens Medical University
Hospital from November 2008 to October 2010. The
relationship between intubation with mechanical ventilation (within 1 week after starting treatment) and treatment
delay was investigated. Treatment delay was dened as the
period, in days, from onset to therapy initiation. In total, 24
conrmed non-HIV PCP cases were included. Median
treatment delay was 7 4.83 days (120 days). Twelve of
24 cases (50 %) were intubated, and 11 (45.8 %) died of
their underlying diseases within 90 days. Treatment delay
was more than 7 days in the intubation group, but was
within 7 days in 9 of 12 nonintubation cases. The difference in treatment delay was signicant (p = 0.0071)
Y. Ainoda (&)
Y. Hirai
T. Fujita
K. Totsuka
Department of Infectious Disease, Tokyo Womens Medical
University, 8-1 Kawada-cho, Shinjuku-ku,
Tokyo 162-8666, Japan
e-mail: y_ainoda@clabo.twmu.ac.jp
Y. Hirai
K. Totsuka
Department of Hematology, Tokyo Womens Medical
University, Tokyo, Japan
N. Isoda
Department of Laboratory, Tokyo Womens Medical University
Hospital, Tokyo, Japan

123

between the intubation and nonintubation groups, but there

were no signicant differences in survival rate at 90 days
or other ndings. We conclude that starting treatment
within 7 days after onset is important because intubation
and mechanical ventilation may be avoided in many cases.
Keywords Non-HIV Pneumocystis jirovecii pneumonia
(non-HIV PCP)
Treatment delay
Intubation
Mortality

Introduction
Pneumocystis jirovecii (P. jirovecii) pneumonia (PCP), a
pulmonary infection caused by P. jirovecii, is among the
opportunistic infections associated with cellular immunodeciency [13]. P. jirovecii infections usually occur in
childhood, but PCP does not develop in the absence of
cellular immunodeciency [4, 5]. PCP is classied as PCP
with HIV and non-HIV PCP, and the two forms differ in
progression and prognosis [69]. PCP with HIV shows
relatively slow progression, and mortality is well below
10 %, but non-HIV PCP is rapidly progressive and severe,
and expedited treatment initiation is recognized as being
essential [1]. Despite the necessity of early treatment, the
diagnosis of non-HIV PCP is often difcult because of the
underlying disease [10]. However, the outcome of treatment delay remains unclear because concrete data and
reports indicating a worsened clinical situation or an
increase in complications, based on how long therapy initiation is delayed, are lacking. A reliable means of
assessing the likelihood of intubation and mortality at the
initiation of non-HIV PCP therapy, based on the period
from onset until the therapy initiation, would allow determination of when and if to start intensive care without
delay and could be expected to improve both the

J Infect Chemother (2012) 18:722728

management and the prognosis of PCP patients [1113].

Thus, we analyzed non-HIV PCP retrospectively and
especially investigated the relationship between the time
from onset until therapy initiation (treatment delay) and the
severity of non-HIV PCP.

Patients and methods

Patients
We retrospectively examined patients with non-HIV PCP
admitted to Tokyo Womens Medical University Hospital
(a 1,423-bed facility) from November 2008 to October
2010 using the laboratory results database. The relationship
between intubation with mechanical ventilation and treatment delay was investigated. Data regarding physical and
laboratory ndings at treatment initiation were also studied.
In addition, we examined the relationships of mortality
within 90 days to treatment delay, intubation, and other
parameters [white blood cell count (WBC), C-reactive
protein (CRP), lactate dehydrogenase (LDH), and
(1 ? 3)b-D-glucan levels]. This study was approved by the
Ethics Committee of Tokyo Womens Medical University.
Because informed consent had not been obtained, the
information obtained in this study was published during the
investigative period according to the guidelines of the
Ministry of Health, Labour and Welfare of Japan.
Denition of treatment delay
Treatment delay was dened as the period, in days, from
onset until therapy initiation. The date of non-HIV PCP
onset was dened as the rst day that fever ([37.0 C),
dyspnea, or other ndings associated with PCP were noted
in medical records by an infectious disease specialist [1, 2].
Inclusion criteria
Non-HIV PCP was dened according to the following ve
criteria (with reference to a previous report) [14]: (1)
background of cellular immunodeciency (without HIV),
(2) hypoxemia, (3) abnormality on chest images [X-ray or
computed tomography (CT)], (4) positive by polymerase
chain reaction (PCR) or uorescent antibody staining, (5)
positive for (1 ? 3)b-D-glucan (Table 1). Hypoxemia was
dened as PaO2 of less than 70 torr and/or SpO2 less than
94 % on room air. Abnormalities on chest images were
determined by radiologists using either chest X-rays or
chest plain CT [15, 16]. In our institution, all suspected
PCP cases were tested for P. jirovecii by PCR or uorescent antibody staining of specimens from the respiratory
tract (sputum or bronchoalveolar lavage) and were

723

included if either test was positive [17, 18]. A Fungi-Fluor

Kit Pneumocystis Kit (Polysciences Inc.) was used for
uorescent antibody staining, and results were checked by
a trained laboratory technician. (1 ? 3)b-D-glucan was
examined using FangitecG MK (Seikagaku Corp.), and the
cutoff was 20 pg/ml, a value set by our institutions laboratory department [19, 20]. Cases not meeting even one of
these ve criteria and with a treatment period of less than
1 week were excluded. The need for intubation was judged
by intensive care specialists.
Statistical analysis
For the statistical analysis, continuous data were compared
using Welchs t test or Students t test, and noncontinuous
dichotomous data were compared employing Fishers exact
test, as appropriate. All p values were two sided, and statistical signicance was accepted for p \ 0.05. To assess
mortality, survival curves were devised by the Kaplan
Meier method, using the log-rank test. We also evaluate the
sensitivity and specicity of treatment delay for predicting
intubation.

Results
Patients and backgrounds
In total, 25 conrmed cases of non-HIV PCP met the
inclusion criteria. However, 1 case was excluded because
the treatment duration was less than 1 week. Thus, 24 cases
were ultimately included.
The median age was 66.5 18.62 years old, and male to
female ratio was 10:14. None received chemoprophylaxis.
Nine of the 24 patients (37.5 %) had rheumatoid arthritis
(RA), 5 (20.8 %) had undergone kidney transplantation
(UKT), and the remaining patients were immunocompromised by other diseases [malignant lymphoma (ML), interstitial pneumonia (IP), renal cell carcinoma (RCC), ulcerative
colitis (UC), membranoproliferative glomerulonephritis
(MPGN), and hemodialysis (HD)] (Table 1).
All RA patients were treated with methotrexate
(6 mg 3.01 mg/week, but there was no description of dose
for two patients), and seven were treated with prednisolone
(6 mg 2.52 mg/day). The UKT patients had been treated
with mycophenolate mofetil (750 391.66 mg/day),
methylprednisolone (6 2.33 mg/day), and tacrolimus
hydrate (3.5 0.83 mg/day) or cyclosporine (75 mg). The
duration from renal transplantation to the onset of PCP was
58 23.93 months. One of the ML patients was treated with
rituximab (375 mg/m2, on the rst day of chemotherapy) and
prednisolone (45 mg/day from the rst day of chemotherapy
to day 5), and PCP developed after the rst chemotherapy

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J Infect Chemother (2012) 18:722728

Table 1 Background factors

and the relationships between
intubation and other ndings

All (n = 24)

Intubation (?)
(n = 12)

Intubation (-)
(n = 12)

p value

Age

66.5 18.62

66.5 16.95

66.5 19.85

0.539

Male

10

0.214

Female

14

RA

0.4

UKT

ML

0.478

Hemodialysis ? PSL

0.478

IP (with PSL)

RCC (post chemotherapy)

ULT

UC (with azathioprine)

MPGN (with PSL)

Data are presented as

medians SD unless otherwise
indicated

Hemodialysis

Fever

13

0.414

Dyspnea

Bold value indicates p value

\ 0.05

Anorexia

Cough

0.478

WBC (/ll)

6,900 3,672.18

6,655 3,671.8

7,385 3,672.42

0.977

CRP (mg/dl)

8.44 4.52

11.56 3.32

5.98 5.12

0.154

RA rheumatoid arthritis,
UKT underwent kidney
transplantation, ML malignant
lymphoma, IP interstitial
pneumonia, RCC renal cell
carcinoma, ULT underwent liver
transplantation, UC ulcerative
colitis, MPGN
membranoproliferative
glomerulonephritis,
PSL prednisolone

LDH (reference range 119229)

429 209.48

511 231.55

414.5 149.55

0.078

(1 ? 3)b-D-glucan (pg/ml)

89.3 2,110.77

83.8 1,362.44

92.5 2,626.25

0.538

Treatment delay (days)

7 4.83

9 4.08

5.5 4.08

0.0071

Mortality (within 90 days)

11

Total case number

24

12

12

course. The other was treated with prednisolone (20 mg/day).

The MPGN patient was treated with prednisolone (15 mg/
day). The UC patient was treated with prednisolone (25 mg/
day) and azathioprine (50 mg/day). The IP patient was treated with prednisolone (11 mg/day) and azathioprine (50 mg/
day). The RCC patient was treated with betamethasone
(2 mg/day). In HD patients only, the duration of HD was
26 years and in those receiving HD combined with prednisolone (5 mg/day) 12 years and 3 months.
As for initial symptoms, fever was noted in 13 patients
(54.2 %), followed by dyspnea in 7 (29.2 %). The median
treatment delay was 7 4.83 days (120 days). The median
WBC count was 6,900 3,672.18/ll, CRP 8.44 4.52 mg/dl,
LDH 429 209.48 IU/l (reference range for LDH, 119229),
and median (1 ? 3)b-D-glucan was 89.3 2,110.77 pg/ml
(Table 1).
Treatment and mortality
In treating PCP, 21 of the 24 patients were started on SMX/
TMP at a dose of approximately 15 mg/kg/day of trimethoprim (SMX/TMP was reduced by half if the patients
creatinine clearance was below 50 ml/min). Three patients

123

were started with lower doses of SMX/TMP. Eleven of the

24 patients were started on combinations with prednisolone
at doses of 80 mg/day (or 1 mg/kg/day) and decreased
gradually later. Ten patients were started with a methylprednisolone pulse (2501,000 mg/day), and 3 were started
with low-dose prednisolone or dexamethasone. Treatment
was started when the denition of PCP was met or PCP was
strongly suspected. Ten of 24 patients (41.7 %) started
therapy within 24 h after consultation. The median treatment period was 21 5.14 days. Four of 24 patients
(16.7 %) died of their underlying diseases within 30 days
and 11 (45.8 %) within 90 days (Table 1).
Correlations of intubation with treatment delay
and mortality
The intubation group was composed of 12 patients (50 %).
Three of the 12 had RA, 3 had UKT, 2 had ML, and the
others IP, RCC, ULT, and MPGN. The treatment delays in
the intubation group were 720 days (median, 9 4.08
days). The remaining 12 patients (50 %) constituted the
nonintubation group. Six of the 12 had RA, 2 had UKT,
2 had HD with PSL, and the others UC and HD only.

J Infect Chemother (2012) 18:722728

Fig. 1 Relationship between intubation and time until treatment

initiation (treatment delay) in non-human immunodeciency virus
(non-HIV) Pneumocystis jirovecii pneumonia (non-HIV PCP). The
vertical axis of this graph is the days of treatment delay. The left side
of this graph is the nonintubation group, and the right side is the
intubation group. There was a signicant difference (p = 0.0071) in
treatment delay between intubation and nonintubation groups.
*Because of severe prognosis by the underlying disease, the
intubation was refused

The treatment delays in the nonintubation group were

118 days (median, 5.5 4.08 days). There was a significant difference (p = 0.0071) in treatment delay between
the intubation and nonintubation groups (Fig. 1). However, there were no signicant difference in 90-day
mortality (p = 1) or other ndings (background factors,
initial symptoms, WBC, CRP, LDH, (1 ? 3)b-D-glucan)
(Table 1).
The cumulative survival rate of the intubation group
tended to be slightly low from the 40th to the 80th day, but
there was no signicant difference in 90-day survival rates
between the intubation and nonintubation groups (log-rank
test, p = 0.642) (Fig. 2). When the treatment delay cutoff
was 7 days (the overall median), sensitivity was 100 %,
specicity was 75 %, positive likelihood ratio (LR?) was
4, and negative likelihood ratio (LR-) was 0, for intubation (Table 2).
Correlations of mortality with other ndings
Patients were categorized according to whether they died
within 90 days, allowing analysis of the relationships of
outcome with background factors, symptoms, and laboratory ndings [WBC, CRP, LDH, and (1 ? 3)b-D-glucan].
The alive group was composed of 13 patients (54.2 %):
5 UKT, 4 RA, 2 ML, and 2 patients immunocompromised
by other diseases (IP, UC). Of the other 11 (45.8 %)
patients, all of whom died within 90 days, 5 had RA, 2 had
HD with PSL, and the others were immunocompromised
by other diseases (RCC, ULT, MPGN, HD only). The only

725

Fig. 2 Cumulative survival rate of intubation group and nonintubation group. The intubation group tended to be slightly low from the
40th to the 80th day, but there was no signicant difference in 90-day
survival rates between intubation and nonintubation groups (log-rank
test, p = 0.642)

Table 2 Performance of treatment delay (TD) for classication of

intubation
Predicted

Intubation (?)

TD C 7

12

TD \ 7
Total

Intubation (-)
3

Total
15

12

12

24

TD treatment delay
Sensitivity of intubation after 7-day TD was 12/12 = 1 (100 %)
Specicity of intubation after 7-day TD was 9/12 = 0.75 (75 %)
Likelihood ratio for positive nding (LR?) was 4
Likelihood ratio for negative nding (LR-) was 0

signicant difference was an underlying disease in the

UKT patients (p = 0.041) (Table 3).

Discussion
In general, patients with non-HIV PCP present with different clinical manifestations from those with HIV PCP in
terms of both the severity of their underlying diseases and
the severity of the immunocompromised state. Furthermore, disease progression is rapid in the non-HIP PCP
group; thus, treatment should be initiated as early as possible [6, 10]. However, few studies have demonstrated how
treatment delay might inuence the outcomes of non-HIV
PCP cases. The present study revealed that when treatment
was initiated 7 days or more after the onset of non-HIV
PCP, intubation and mechanical ventilation were required
signicantly more often. As for mortality, no signicant
difference was found between the intubation and nonintubation groups. However, treatment with intubation and
mechanical ventilation was found to have a signicant

123

726
Table 3 Background factors
and the relationships between
intubation and other ndings

J Infect Chemother (2012) 18:722728

Death within 90 days

Alive

p value

Age

71 15.25

65 20.03

0.228

Male

0.24

Female

RA

0.675

UKT

0.041

ML

0.482

Hemodialysis ? PSL

0.199

IP (with PSL)

RCC (post chemotherapy)

0.458

ULT

0.458

UC (with azathioprine)

Data are presented as

medians SD unless otherwise
indicated

MPGN (with PSL)

0.458

Hemodialysis

0.458

Fever

Bold value indicates p value

\ 0.05

Dyspnea
Anorexia

4
1

3
1

0.659
1

Cough

0.482

WBC (/ll)

6,640 2,882.62

7,130 4,124.72

0.387

CRP (mg/dl)

7.59 3.78

9.2 5.06

0.85

LDH (reference range 119229)

418 241.99

440 164.64

0.276

(1 ? 3)b-D-glucan (pg/ml)

56.9 42.11

309.2 2721.86

0.115

RA rheumatoid arthritis,
UKT underwent kidney
transplantation, ML malignant
lymphoma, IP interstitial
pneumonia, RCC renal cell
carcinoma, ULT underwent liver
transplantation, UC ulcerative
colitis, MPGN
membranoproliferative
glomerulonephritis,
PSL prednisolone

Treatment delay (days)

7 5.97

7 3.25

0.302

Intubation (cases)

Total case number

11

13

disadvantage because it was associated with an increased

risk of developing complications such as ventilator-associated pneumonia and increased respiratory management
costs [21]. Although it is generally believed that treatment
for non-HIV PCP should be initiated as early as possible,
this belief has not been sufciently examined. The present
study revealed that treatment for non-HIV PCP should be
started within 7 days post onset. This nding may be
helpful for managing non-HIV PCP cases.
According to the report by Matsumura et al. [11], mortality
is related to intubation. However, our study showed no signicant correlation between treatment delay and mortality.
Possible reasons are that the causes of death were the
underlying diseases rather than pneumonia, and there was a
tendency for patients receiving kidney transplantation or with
ML to survive longer. According to the report by Arend et al.,
the mortality rate of PCP after kidney transplantation was less
than 10 %, whereas that of patients with connective tissue
diseases exceeded 30 % [1, 22]. Thus, outcomes of patients
diagnosed with non-HIV PCP may be affected by how the
underlying disease inuences immunocompromised status.
In the present study, there was a tendency for patients with
RA to not require intubation and mechanical ventilation. It
was suggested that effects of the underlying disease might
have impacted our results in that no signicant relationship

123

was found between treatment delay and mortality. In addition, there were also variations in the doses of SMT/TMP and
prednisolone. We therefore advocate that a prospective study
be conducted, focusing on individual underlying diseases [2].
Although the association between early treatment and
reduced mortality was not signicant in the present study, we
speculate that all patients in the intubation group would not
have been curable without intubation. Furthermore, we
believe that early treatment is essential for reducing the risk of
developing complications such as ventilator-associated
pneumonia and for minimizing medical costs by avoiding
intubation and mechanical ventilation [23].
In the present study, treatment delay was dened as the
period from the onset until therapy initiation. Although
more false-positives may have been obtained, we lowered
the fever criterion to a temperature above 37 C. However,
there is a possibility that symptoms might still have been
masked, depending on the severity of the immunocompromised state. In other words, some patients might have
developed insidious symptoms before the documented
onset dates [24].
Laboratory ndings including serum markers are frequently used in clinical practice; however, neither inammatory response parameters nor (1 ? 3)b-D-glucan
correlated with outcomes in this study. Our patients had a

J Infect Chemother (2012) 18:722728

variety of backgrounds, and these differences might have

inuenced the results. At a minimum, the magnitude of the
inammatory response may not be a useful indicator of
prognosis in PCP patients. Although (1 ? 3)b-D-glucan is
reportedly useful for clinically diagnosing PCP, in contrast to
past studies, we did not identify a signicant relationship
between the (1 ? 3)b-D-glucan value and outcomes [19, 25].
The inclusion criteria applied herein were established
based on previous domestic reports, because internationally
standardized diagnostic criteria for PCP are lacking [8]. We
employed a strict inclusion strategy, i.e., the subjects had to
meet all ve criteria. These strict criteria may have limited
the detection of patients with mild symptoms. Inclusion of
patients with mild PCP might have yielded different
results. Further studies are needed to clarify this issue.
In the present study, not all our patients received
prophylaxis. The efcacy of chemoprophylaxis against
non-HIV PCP is still unclear. However, there are reports
indicating that prophylaxis reduces the incidence of PCP
[26]. With greater immunosuppression, or in the situation
of an outbreak with human-to-human transmission, it may
be necessary to consider more prophylaxis [2731].
Although the present study has the aforementioned
limitation, patients with non-HIV PCP appear to be likely
to develop respiratory failure requiring intubation and
mechanical ventilation if they do not receive treatment
within 7 days after the onset. Therefore, we consider early
diagnosis and treatment to be essential for patients with
non-HIV PCP. Furthermore, it is also important that we
consider PCP in the differential diagnosis, and that we
educate patients with immunocompromised status to consult a hospital promptly if symptoms manifest that suggest
PCP. We especially emphasize the importance of starting
treatment within 7 days after symptom onset. Achieving
this goal may allow many patients to avoid intubation and
mechanical ventilation.
Acknowledgments The authors thank the laboratory department staff
and directors of Tokyo Womens Medical University Hospital. We
express our deep appreciation to Makoto Kawashima (Department of
Laboratory), Toru Kotani (Department of Intensive Care Unit), Hisashi
Yamanaka (Department of Rheumatology), Satoshi Teraoka (Department of Surgical Nephrology), Toshiko Motoji (Department of Hematology), Keiko Tatemoto (Department of Gastroenterology), Kosaku
Nitta (Department of Nephrology), Atsushi Nagai (Department of
Pulmonology), and Nobuhisa Hagiwara (Department of Cardiology) of
Tokyo Womens Medical University Hospital.
Conict of interest

None.

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