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O R I G I N A L A R T I C L E

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

classified as PCP with human immunodeficiency 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 difficult

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 initia-

tion. We retrospectively examined patients with non-HIV

PCP admitted to Tokyo Women’s Medical University

Hospital from November 2008 to October 2010. The

relationship between intubation with mechanical ventila-

tion (within 1 week after starting treatment) and treatment

delay was investigated. Treatment delay was defined as the

period, in days, from onset to therapy initiation. In total, 24

confirmed non-HIV PCP cases were included. Median

treatment delay was 7 ± 4.83 days (1–20 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 differ-

ence in treatment delay was significant ( p = 0.0071)

between the intubation and nonintubation groups, but there

were no significant differences in survival rate at 90 daysor other findings. 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 immuno-

deficiency [1–3]. P. jirovecii infections usually occur in

childhood, but PCP does not develop in the absence of

cellular immunodeficiency [4, 5]. PCP is classified as PCP

with HIV and non-HIV PCP, and the two forms differ in

progression and prognosis [6–9]. 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 difficult because of the

underlying disease [10]. However, the outcome of treat-

ment delay remains unclear because concrete data and

reports indicating a worsened clinical situation or an

increase in complications, based on how long therapy ini-

tiation 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 deter-

mination of when and if to start intensive care without

delay and could be expected to improve both the

Y. Ainoda (&)

Y. Hirai

T. Fujita

K. TotsukaDepartment of Infectious Disease, Tokyo Women’s Medical

University, 8-1 Kawada-cho, Shinjuku-ku,

Tokyo 162-8666, Japan

e-mail: [email protected]

Y. Hirai K. Totsuka

Department of Hematology, Tokyo Women’s Medical

University, Tokyo, Japan

N. Isoda

Department of Laboratory, Tokyo Women’s Medical University

Hospital, Tokyo, Japan

1 3

J Infect Chemother (2012) 18:722–728

DOI 10.1007/s10156-012-0408-5



management and the prognosis of PCP patients [11–13].

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 Women’s 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 treat-

ment delay was investigated. Data regarding physical and

laboratory findings at treatment initiation were also studied.

In addition, we examined the relationships of mortality

within 90 days to treatment delay, intubation, and otherparameters [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 Women’s 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.

Definition of treatment delay

Treatment delay was defined as the period, in days, from

onset until therapy initiation. The date of non-HIV PCP

onset was defined as the first day that fever ([37.0 C),

dyspnea, or other findings associated with PCP were noted

in medical records by an infectious disease specialist [1, 2].

Inclusion criteria

Non-HIV PCP was defined according to the following five

criteria (with reference to a previous report) [14]: (1)

background of cellular immunodeficiency (without HIV),

(2) hypoxemia, (3) abnormality on chest images [X-ray or

computed tomography (CT)], (4) positive by polymerase

chain reaction (PCR) or fluorescent antibody staining, (5)

positive for (1 ? 3)b-D-glucan (Table 1). Hypoxemia was

defined 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 fluores-

cent antibody staining of specimens from the respiratory

tract (sputum or bronchoalveolar lavage) and were

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

Kit Pneumocystis Kit (Polysciences Inc.) was used for

fluorescent 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 institution’s labo-

ratory department [19, 20]. Cases not meeting even one of

these five criteria and with a treatment period of less than1 week were excluded. The need for intubation was judged

by intensive care specialists.

Statistical analysis

For the statistical analysis, continuous data were compared

using Welch’s t test or Student’s t test, and noncontinuous

dichotomous data were compared employing Fisher’s exact

test, as appropriate. All p values were two sided, and sta-

tistical significance 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 thesensitivity and specificity of treatment delay for predicting

intubation.

Results

Patients and backgrounds

In total, 25 confirmed 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 immunocompro-

mised by other diseases [malignant lymphoma (ML), inter-

stitial pneumonia(IP), renal cellcarcinoma (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 first day of chemotherapy) and

prednisolone (45 mg/day from the first day of chemotherapy

to day 5), and PCP developed after the first chemotherapy

J Infect Chemother (2012) 18:722–728 723

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course. The otherwas 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 trea-

ted 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 prednis-

olone (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 (1–20 days). The median

WBCcountwas 6,900 ± 3,672.18/ ll,CRP8.44 ± 4.52 mg/dl,

LDH 429 ± 209.48 IU/l (reference range for LDH, 119–229),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 tri-

methoprim (SMX/TMP was reduced by half if the patient’s

creatinine clearance was below 50 ml/min). Three patients

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

24 patients were started on combinations with prednisoloneat doses of 80 mg/day (or 1 mg/kg/day) and decreased

gradually later. Ten patients were started with a methyl-

prednisolone pulse (250–1,000 mg/day), and 3 were started

with low-dose prednisolone or dexamethasone. Treatment

was started when the definition of PCP was met or PCP was

strongly suspected. Ten of 24 patients (41.7 %) started

therapy within 24 h after consultation. The median treat-

ment 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 delayand 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 7–20 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.

Table 1 Background factors

and the relationships between

intubation and other findings

Data are presented as

medians ± SD unless otherwise

indicated

Bold value indicates p value

\

0.05 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

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 7 3 0.214

Female 14 5 9

RA 9 3 6 0.4

UKT 5 3 2 1ML 2 2 0 0.478

Hemodialysis ? PSL 2 0 2 0.478

IP (with PSL) 1 1 0 1

RCC (post chemotherapy) 1 1 0 1

ULT 1 1 0 1

UC (with azathioprine) 1 0 1 1

MPGN (with PSL) 1 1 0 1

Hemodialysis 1 0 1 1

Fever 13 8 5 0.414

Dyspnea 7 3 4 1

Anorexia 2 1 1 1

Cough 2 0 2 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

LDH (reference range 119–229) 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 6 5 1

Total case number 24 12 12

724 J Infect Chemother (2012) 18:722–728

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The treatment delays in the nonintubation group were

1–18 days (median, 5.5 ± 4.08 days). There was a signif-

icant difference ( p = 0.0071) in treatment delay between

the intubation and nonintubation groups (Fig. 1). How-

ever, there were no significant difference in 90-day

mortality ( p = 1) or other findings (background factors,

initial symptoms, WBC, CRP, LDH, (1 ? 3)b-D-glucan)

(Table 1).

The cumulative survival rate of the intubation grouptended to be slightly low from the 40th to the 80th day, but

there was no significant 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 %,

specificity was 75 %, positive likelihood ratio (LR?) was

4, and negative likelihood ratio (LR-) was 0, for intuba-

tion (Table 2).

Correlations of mortality with other findings

Patients were categorized according to whether they diedwithin 90 days, allowing analysis of the relationships of

outcome with background factors, symptoms, and labora-

tory findings [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

significant difference was an underlying disease in the

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

Discussion

In general, patients with non-HIV PCP present with dif-

ferent clinical manifestations from those with HIV PCP in

terms of both the severity of their underlying diseases and

the severity of the immunocompromised state. Further-

more, disease progression is rapid in the non-HIP PCP

group; thus, treatment should be initiated as early as pos-

sible [6, 10]. However, few studies have demonstrated how

treatment delay might influence 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

significantly more often. As for mortality, no significant

difference was found between the intubation and nonintu-

bation groups. However, treatment with intubation and

mechanical ventilation was found to have a significant

Fig. 1 Relationship between intubation and time until treatment

initiation (treatment delay) in non-human immunodeficiency 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 significant difference ( p = 0.0071) in

treatment delay between intubation and nonintubation groups.*Because of severe prognosis by the underlying disease, the

intubation was refused

Fig. 2 Cumulative survival rate of intubation group and nonintuba-

tion group. The intubation group tended to be slightly low from the

40th to the 80th day, but there was no significant 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 classification of intubation

Predicted Intubation (?) Intubation (-) Total

TD C 7 12 3 15

TD\7 0 9 9

Total 12 12 24

TD treatment delay

Sensitivity of intubation after 7-day TD was 12/12 = 1 (100 %)

Specificity of intubation after 7-day TD was 9/12 = 0.75 (75 %)

Likelihood ratio for positive finding (LR?) was 4

Likelihood ratio for negative finding (LR-) was 0


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disadvantage because it was associated with an increased

risk of developing complications such as ventilator-asso-

ciated 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 sufficiently examined. The present

study revealed that treatment for non-HIV PCP should be

started within 7 days post onset. This finding may be

helpful for managing non-HIV PCP cases.

Accordingto thereport by Matsumuraet al.[11], mortality

is related to intubation. However, our study showed no sig-

nificant 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.,

themortality rate of PCPafter kidneytransplantation 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 influences 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 significant relationship

was found between treatment delay and mortality. In addi-

tion, 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 significant 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 treatmentis essentialfor reducing therisk 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 defined 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 immunocom-

promised state. In other words, some patients might have

developed insidious symptoms before the documented

onset dates [24].

Laboratory findings including serum markers are fre-

quently used in clinical practice; however, neither inflam-

matory response parameters nor (1? 3)b-D-glucan

correlated with outcomes in this study. Our patients had a

Table 3 Background factors

and the relationships between

intubation and other findings

Data are presented as

medians ± SD unless otherwise

indicated

Bold value indicates p value

\ 0.05

RA rheumatoid arthritis,

UKT underwent kidneytransplantation, ML malignant

lymphoma, IP interstitial

pneumonia, RCC renal cell

carcinoma, ULT underwent liver

transplantation, UC ulcerative

colitis, MPGN

membranoproliferative

glomerulonephritis,

PSL prednisolone

Death within 90 days Alive p value

Age 71 ± 15.25 65 ± 20.03 0.228

Male 3 7 0.24

Female 8 6

RA 5 4 0.675

UKT 0 5 0.041

ML 0 2 0.482

Hemodialysis ? PSL 2 0 0.199

IP (with PSL) 0 1 1

RCC (post chemotherapy) 1 0 0.458

ULT 1 0 0.458

UC (with azathioprine) 0 1 1

MPGN (with PSL) 1 0 0.458

Hemodialysis 1 0 0.458

Fever 6 6 1

Dyspnea 4 3 0.659

Anorexia 1 1 1

Cough 0 2 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 119–229) 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

Treatment delay (days) 7 ± 5.97 7 ± 3.25 0.302

Intubation (cases) 6 6 1

Total case number 11 13


1 3



variety of backgrounds, and these differences might have

influenced the results. At a minimum, the magnitude of the

inflammatory 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 significant relationship

between the(1 ? 3)b-D-glucan value andoutcomes [19, 25].

The inclusion criteria applied herein were establishedbased 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 five 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 efficacy 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 situationof an outbreak with human-to-human transmission, it may

be necessary to consider more prophylaxis [27–31].

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 con-

sult 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 Women’s 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 (Depart-

ment of Surgical Nephrology), Toshiko Motoji (Department of Hema-

tology), Keiko Tatemoto (Department of Gastroenterology), Kosaku

Nitta (Department of Nephrology), Atsushi Nagai (Department of Pulmonology), and Nobuhisa Hagiwara (Department of Cardiology) of

Tokyo Women’s Medical University Hospital.

Conflict of interest None.

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PJP Pneumonia