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Nosocomial Pneumocystis jirovecii Pneumonia: Lessons From a Cluster in Kidney Transplant Recipients

Phipps, Lisa M.1; Chen, Sharon C.-A.2,3,4; Kable, Kathy1; Halliday, Catriona L.2; Firacative, Carolina2,3,4; Meyer, Wieland2,3,4; Wong, Germaine1; Nankivell, Brian J.1,5

doi: 10.1097/TP.0b013e3182384b57
Clinical and Translational Research

Background. Pneumocystis jirovecii pneumonia (PJP) is an important infection-related complication, whose mode of transmission remains uncertain.

Methods. We investigated a nosocomial cluster of 14 PJP cases (11 confirmed and 3 probable) in kidney transplant recipients using epidemiological and genotyping methods.

Results. Poisson regression calculated an incidence density ratio of 42.8 (95% confidence interval [CI], 14.1–129.3) versus background 0.64 cases of 1000 patient-years (P<0.001). All patients presented with respiratory failure, 10 required ventilation, two died, and six transplants failed, costing $31,854 (±SD $26,048) per patient. Four-locus multilocus sequence typing analysis using DNA extracts from 11 confirmed cases identified two closely related genotypes, with 9 of 11 sharing an identical composite multilocus sequence typing genotype. Contact tracing found colocalization of cases within clinic waiting areas, suggesting person-to-person transmission. Minimal and maximal PJP incubation periods were 124±83 to 172±71 days, respectively. Oropharyngeal washes from outpatient staff and ambient air samples were negative for P. jirovecii DNA. Cohort analysis (14 cases vs. 324 unaffected clinic control patients) identified independent risk factors including previous cytomegalovirus infection (odds ratio [OR], 65.9; 95% CI, 7.9–550; P<0.001), underlying pulmonary disease (OR, 10.1; 95% CI, 2.3–45.0; P=0.002), and transplant dysfunction (OR=1.61 per 10 mL/min/1.73 m2, 95% CI, 1.15–2.25, P=0.006). The outbreak was controlled by reintroduction of trimethoprim/sulfamethoxazole prophylaxis to all potentially exposed clinic patients and its extension to 12 months in recent recipients.

Conclusions. Nosocomial PJP clusters are likely due to interhuman transmission by airborne droplets to susceptible hosts. Prompt recognition and a strategy of early preemptive blanket PJP prophylaxis to all exposed transplant clinic recipients from the third confirmed case are recommended to limit outbreak escalation.

SUPPLEMENTAL DIGITAL CONTENT IS AVAILABLE IN THE TEXT.

1 Department of Renal Medicine, Westmead Hospital, Westmead, NSW, Sydney, Australia.

2 Centre for Infectious Diseases and Microbiology, Westmead Hospital, Westmead, NSW, Sydney, Australia.

3 The Molecular Mycology Research Laboratory, Westmead Millennium Institute, Westmead Hospital, Westmead, NSW, Sydney, Australia.

4 Sydney Medical School-Westmead, Westmead Hospital, The University of Sydney, Sydney, Australia.

The authors declare no funding or conflicts of interest.

5 Address correspondence to: Dr. Brian J. Nankivell, M.D., B.S., M.Sc., Ph.D., F.R.A.C.P., Department of Renal Medicine, Westmead Hospital, Westmead, 2145, NSW, Sydney, Australia.

E-mail: Brian_Nankivell@wsahs.nsw.gov.au

L.P. participated in clinical data collection, contact tracing, manuscript preparation, and editing. S.C. participated in case verification, data collection, manuscript preparation, and editing. K.K. participated in clinical data collection, contact tracing, manuscript preparation, and editing. C.H. participated in laboratory diagnosis and manuscript preparation. C.F. participated in genotyping and manuscript preparation. W.M. participated genotyping and analysis, manuscript preparation, and editing. G.W. participated economic evaluation, manuscript preparation, and editing. B.J.N. participated in data collection and analysis, manuscript preparation, and editing.

Supplemental digital content (SDC) is available for this article. Direct URL, citations appear in the printed text, and links to the digital files are, provided in the HTML text of this article on the journal's Web site, (www.transplantjournal.com). A combined file of all SDC is available as SDC 1 (http://links.lww.com/TP/A551).

Received 19 July 2011. Revision requested 10 August 2011.

Accepted 16 September 2011.

Pneumocystis jirovecii (formerly carinii) pneumonia (PJP) is an important infection-related complication in patients with impaired immunity, commonly manifesting as a severe lower respiratory tract infection. Organ transplant recipients typically present with acute breathlessness, dry cough, and progressive respiratory failure with normal lung auscultation. The mortality rate in non-HIV patients ranges from 10% to 60%; however, routine prophylaxis has largely eliminated PJP within the first year of transplantation in solid organ transplantation, with 176 cases per 100,000 person-years by United States Renal Data System data (1–3). Late infection clusters are unusual, with most cases occurring within the first 6 months of transplantation (1, 4).

Postulated mechanisms of transmission of P. jirovecii infection include reactivation of latent infection, environmental exposure, or interhuman transmission. Recent nosocomial PJP clusters in renal transplant recipients sharing a common healthcare facility where a single P. jirovecii genotype has been reported indicate that person-to-person transmission is the most plausible (5–12), yet the exact mode of transmission in immunocompromised individuals remains uncertain. Although there is no standardized method to genotype P. jirovecii, evidence indicates that methods using multilocus sequence typing (MLST) are the most discriminatory (6, 7, 13). Data describing risk factors for PJP in the nosocomial cluster setting are limited (11, 14).

We investigated a cluster of PJP of 14 kidney (including two combined kidney-pancreas) transplant recipients from a single center after introduction by an index case from another transplant unit. We present evidence supporting human-to-human transmission with a long incubation period, identify new risk factors for Pneumocystis by cohort analysis of exposed clinic patients, define adverse outcomes, and report successful epidemic control measures through the implementation of blanket trimethoprim/sulfamethoxazole (TMP-SMZ) prophylaxis in exposed transplant recipients.

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RESULTS

Outbreak Description

During March to October 2010, a suspected cluster of PJP was identified by real-time polymerase chain reaction (PCR) testing of induced sputum (n=6 patients) and bronchoalveolar lavage (BAL) fluid (n=7) from 9 kidney recipients initially. A further three patients were considered probable cases whose illness responded to intravenous high-dose TMP-SMZ (specimens were not sent for PCR testing because the diagnosis of PJP was assumed by the treating clinician) and other causes of respiratory illness were excluded (see Materials and Methods). Grocott methanamine silver staining of BAL fluid tested in six confirmed cases revealed typical P. jirovecii cysts in four (Table 1) by direct microscopy of stored specimens. Another two patients developed PJP in January 2011, yielding a total of 14 patients with PJP (11 confirmed and 3 highly probable) over the 10-month period.

TABLE 1

TABLE 1

Patients presenting with PJP were 46.6±13.2 years old with functioning transplants (Table 2). Causes of end-stage renal failure were glomerulonephritis (n=5), renal vasculitis (n=3), diabetic nephropathy (n=2), and mixed etiologies (n=4). Comorbidities included ischemic heart disease (n=3) and hypertension (n=12). Two patients were combined kidney-pancreas recipients. Two patients previously received antithymocyte globulin, 3 received induction IL-2 blockade, and all except one were treated with tacrolimus, mycophenolate, and prednisolone as maintenance immunosuppression. The cytomegalovirus (CMV) risk was high (serostatus CMV positive to negative) in 6, and intermediate (recipient CMV positive) in 8 of PJP cases. All 14 patients had clinical and radiological features consistent with PJP. The outbreak PJP incidence rate was 28.9 cases per 1000 patient-years (compared with 0.64 background incidence or 4 cases over the previous 20 years). Poisson regression calculated an incidence density ratio of 42.8 (95% confidence interval [CI] 14.1–129.3, P<0.001) for the cluster.

TABLE 2

TABLE 2

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Contact Tracing and Transmission Map

All outpatients were followed in a dedicated clinic of six consultation rooms sharing a common waiting room, without direct contact with inpatients in the physically separate renal ward. The intensive care unit was distant, and patients were nursed in isolated rooms and on returned to the renal ward. No cases occurred in the adjacent dialysis facility. Meticulous contact tracing identified one or more potential contact points in all infected prodromal patients with individuals who later presented with PJP (Fig. 1). The most common interhuman contact was within a newly constructed hospital outpatient clinic (in 12 patients, location 1). Clinic visits were primarily for routine follow-up with patients typically spending 1 to 3 hr in an area shared with up to 20 others. One (case 7 from case 2) contact point may have been one private outpatient clinic (visiting at different times on same day, location 2) and another in a second private clinic (patients 12 and 8, location 3). From patient overlap dates, minimal and maximal incubation periods were calculated as 124±83 days to 172±71 days, respectively.

FIGURE 1.

FIGURE 1.

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Genotyping

Known variable regions within four genetic loci in the P. jirovecii genome were amplified and sequenced using DNA extracts from 11 patients; these sequences have been deposited in GenBank (Table 3). The obtained sequences, assigned allele types and sequence types can be accessed at the P. jirovecii MLST webpage at http://mlst.mycologylab.org—MLST databases—PneumocystisPneumocystis jirovecii. Phylogenetic analysis of the concatenated sequences revealed clear clustering of outbreak-related cases (Table 3, Figs. 1 and 2). The genotypes of nine of 11 confirmed cases were identical, with genotypes of the remaining two (patients 2 and 7 from one private clinic; location 2, Figs. 1 and 2) differing by a single nucleotide at the 85 bp position in the mitochondrial large subunit of the rRNA gene region (mtLSU), β-tubulin (β-TUB), dihydropteroate synthetase [DHPS], and internal transcribed region (of the rRNA gene) [ITS1/2] sequences were identical to each other and the other 9 patients), suggesting early mutation from the common cluster strain. The late presenting patients (13 and 14) displayed identical genotypes to the common outbreak strain (Table 3, Fig. 1).

TABLE 3

TABLE 3

FIGURE 2.

FIGURE 2.

The combined DNA sequence set for P. jirovecii recovered from other contemporaneous PJP patients residing in the Sydney region demonstrated substantial genetic diversity and harbored dissimilar genotypes from the outbreak cluster. From the 20 P. jirovecii isolates analyzed, a single DHPS genotype, 2 β-TUB genotypes, 2 mtLSU, and 4 ITS1/2 genotypes, resulted in seven identified MLST sequence types (Table 3).

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Risk Analysis

Within the case cluster, a case cohort study comprising the 14 patients and 324 unaffected control patients was undertaken to determine risk factors for PJP. Univariate analysis identified several risk factors (Table 2), including impaired graft function (P<0.001). CMV disease within the preceding 12 months occurred in five patients (35.7%, P<0.001 vs. control, with gastrointestinal cytopathic effect confirmed by immunoperoxidase in 4, clinical viremia and response to specific treatment in one). None of the five patients had received antiviral medication at PJP presentation and the interval between CMV and PJP was 20.3±16.0 months [range, 2–40 months]. Underlying pulmonary disease was present in four PJP patients (28.6% from previous H1N1 and later respiratory syncytial virus infections, nonspecific pneumonitis, Wegeners's granulomatosis, and bronchiectasis) compared with 2.6% of controls (P<0.001).

By multivariate analysis, significant risk factors for PJP infection were underlying pulmonary disease (odds ratio [OR], 10.1; 95% CI, 2.3–45.0; P=0.002), previous CMV infection (OR, 65.9; 95% CI, 7.9–550; P<0.001), and impaired estimated glomerular filtration rate (OR, 1.61 per 10 mL/min/1.73 m2; 95% CI, 1.15–2.25; P=0.006) compared with unaffected clinic patients.

Other transplant factors such as human leukocyte antigen (HLA) mismatching, biopsy-proven rejection, previous rejection, and recent (<12 months) pulse corticosteroids and current dose, calcineurin inhibitor type, dose or levels, antimetabolite dose or type, previous OKT3 or antithymocyte globulin therapy, and smoking status were not significantly different between groups. Initial TMP-SMZ prophylaxis rates of 93% of PJP patients for 6.3±9.5 months were comparable with controls. Patients without prophylaxis were transplanted before 1989 by other units. The number of clinic visits (a surrogate for exposure) was comparable between groups, but dominated by recent recipients seen frequently but still protected by routine prophylaxis.

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Outcomes and Infection Control Measures

All cases presented with severe pneumonia and respiratory failure. Ten required ventilation in intensive care for 22.0±7.2 days, and two were managed with noninvasive respiratory support by high-dependency units. Empirical high-dose intravenous TMP-SMZ was commenced on admission in 13 cases (and delayed in two patients), accompanied by increased corticosteroids and supportive measures. Patients were isolated in single rooms until complete clinical response. Two patients (including the index case) died from high pulmonary compliance and failed mechanical ventilation. Six patients displayed severe preexisting transplant dysfunction (serum creatinine, 337±112 μmol/L) and renal failure followed in seven during illness from acute kidney injury. Six patients returned to dialysis and one recovered to baseline creatinine.

PCR testing on oropharyngeal rinses from 18 healthcare workers from the outpatient facility (and 16 nonclinical controls) yielded negative results for P. jirovecii DNA, as did sampling of ambient air from the consulting rooms, corridor, and waiting rooms of outpatient clinic using standard solid supports for trapping of potential organisms tested after outbreak control had commenced.

A policy of extended duration of PJP prophylaxis from 6 to 12 months after transplantation for all recent recipients and preemptive prophylaxis (TMP-SMZ, 800/160 mg daily or alternatives for allergy) was restarted in all potentially exposed asymptomatic prevalent clinic patients. Two late cases of PJP missed TMP-SMZ as their clinic exposure was not recognized, but presented with milder disease.

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DISCUSSION

Although the exact mode of transmission of P. jirovecii infection is unclear, data from molecular genotyping studies of nosocomial clusters have recently suggested interhuman transmission among immunocompromised renal transplant patients (5–9, 12, 13, 15). Earlier studies using single-locus genotyping were inconclusive (16, 17); however, four-locus-based MLST analysis in the present study, incorporating discriminatory loci identified a predominant MLST genotype from our cluster, similar to previously observed results (7, 13, 15). In one study, human-to-human transmission was traceable in 22 of 33 PJP cases using ITS1/2 sequencing (12). Molecular and contact tracing data support the notion of patient-to-patient transmission.

Interhuman PJP transmission is likely mediated by airborne droplets (1, 2). P. jirovecii colonizes the respiratory tract in 0% to 20% healthy adults (1, 18), 65% in postmortem lungs (19), and 31% to 68% of HIV-infected people (1). Colonization frequencies of kidney transplant recipients are poorly documented. Surveillance of this patient group to estimate prevalence of colonization would be of interest yet the clinical significance of such colonization is not known. Although negative P. jirovecii PCR results from oropharyngeal rinses of outpatient health care workers mitigate against asymptomatic a staff reservoir of infection, this possibility is not excluded because the sensitivity of this method in healthy individuals is poorly defined (18); collection of induced sputum samples for PCR analysis was not feasible. Sensitivity of various PCR assays in the detection of P. jirovecii in oropharyngeal washes and other upper airway specimens (nasopharyngeal aspirates) have been reported to range from 78% to 90% in HIV/AIDS and other immunocompromised patients (20, 21). We were unable to detect P. jirovecii in ambient air using standard solid supports for trapping of potential organisms tested after outbreak control was underway, yet others have reported (albeit uncommonly) the presence of P. jirovecii DNA in air filters placed in hospital rooms of patients with PJP (22, 23). More recently, using new liquid impactor air sampling devices P. jirovecii was recovered from exhaled air in 79.8% at 1 m from infected patient's heads and in one third in the adjacent corridor at 8 m, (24) comparable most transplant outpatient clinic dimensions, including ours. Genotyping studies examining the link between patient P. jirovecii isolates with putative source isolates are required to more definitely determine mode of transmission.

Only 4.2% of exposed patients developed PJP, and risk factors derived from sporadic cases collected by registries may not extrapolate to nosocomial outbreaks. Our cohort analysis identified pulmonary disease, previous CMV infection, and transplant dysfunction as independent predictors of PJP; consistent with host vulnerability, but not previous rejection or corticosteroids seen in older studies—where early routine PJP prophylaxis was usually absent and rejection rates higher (11, 14). CMV is an immunosuppressive infection and has been associated with sporadic PJP from old registry series (11, 14) and retrospective United States Renal Data System data (25), and was a strong risk in this nosocomial cluster (OR=65.9).

The new finding of impaired graft function independently associated with PJP, may be also explained by reduced host resistance, as uremia impairs monocyte and T-cell function (needed for PJP clearance) and downregulates costimulatory B7–2 (CD86) molecules (1, 26).

Preexisting lung disease was another novel risk factor identified this our study (OR=10.1). Previous tuberculosis was associated with sporadic PJP in a case-control series from Argentina (11). Asymptomatic Pneumocystis colonization occurs in cystic fibrosis (1.3%–21.6% prevalence) (27), chronic obstructive pulmonary disease (28), or interstitial lung disease (33.8% by BAL sampling) (29). Hence, abnormal lung architecture may be predisposed to P. jirovecii colonization, which along with impaired respiratory clearance may explain the association between underlying lung disease and development of overt disease.

This nosocomial PJP cluster was extremely costly: with a 14% death rate, one-half returning to dialysis with transplant failure (albeit with initial poor function), and substantial healthcare costs from prolonged ICU ventilation as $31,854 (mean±SD $26,048) per patient. Early epidemic control is desirable. Our outbreak was belatedly controlled by extension of the duration of TMP-SMZ prophylaxis from 6 months to 1 year in recent recipients (costing AUD $0.86 per day), and reintroduction of TMP-SMZ to all asymptomatic exposed prevalent clinic patients.

We would propose a preemptive strategy of (1) early recognition of a Pneumocystis cluster (defined by two PJP patients within 1 month) and (2) prompt intervention after the third confirmed case with blanket prophylaxis for all asymptomatic exposed patients—to limit outbreak escalation. Just two cases statistically exceeded our low baseline prevalence rates, which interestingly, is the same number epidemiologists use to define a cluster. Blanket anti-PJP prophylaxis was successful in limiting the number of cases. An alternative strategy would be to extend or reintroduce prophylaxis for only those patients with significant risk factors for PJP, that is, CMV infection, previous lung disease, transplant dysfunction. This approach however is contingent on timely physician and laboratory assessment and adequate resources, and would require consensus for when to institute prophylaxis.

The average incubation period of Pneumocystis ranged from 124 to 172 days (similar to Yazaki's absolute range of 1–24 weeks) (12), means that once outbreaks become established, new cases present regularly (months to years in one outbreak), and can form larger clusters if uncontrolled (6, 12). The strategy of universal blanket prophylaxis and extension from 6 to 12 months TMP-SMZ treatment duration in recent patients to eliminate active Pneumocystis from the unit's transplant population is supported by our economic modeling where prophylaxis with inexpensive generic TMP-SMZ generated 17 days of life and $2634 saved over the lifetime of a transplant recipient, and was cost-saving (data not presented).

In summary, nosocomial PJP clusters in solid organ transplantation are likely due to interhuman transmission by airborne droplets to hosts rendered susceptible from previous CMV infection, pulmonary disease, and uremia. Early recognition of an outbreak and a strategy of prompt preemptive intervention with blanket TMP-SMZ prophylaxis to all exposed transplant clinic patients is recommended to limit its potential escalation.

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MATERIALS AND METHODS

Patients and Case Definitions

During March 2010 to January 2011, 14 cases of PJP occurred in the Renal Transplant Unit of Westmead Hospital, Sydney, beginning with an index case (patient 1) transferred from interstate had not received anti-Pneumocystis prophylaxis. Our unit routinely uses universal TMP-SMZ (800/160 mg) prophylaxis for 6 months after transplantation (or dapsone, pyrimethamine, or trimethoprim combinations for sulfa allergy) (30).

Case definitions used for this cluster included all kidney transplant recipients at Westmead Hospital from March 1, 2010, onward (date chosen from expected incubation period before presentation of index case until the last case in January 2011), who presented with typical symptoms of PJP (including cough and dyspnea), characteristic radiographic findings (pulmonary interstitial abnormalities on imaging), and response to TMP-SMZ treatment. Two patient groups were defined as follows:

  1. Confirmed cases: clinically typical PJP cases where P. jirovecii was detected by a P. jirovecii-specific PCR-based assay. P. jirovecii DNA was detected in induced sputum and/or BAL specimens using an “in-house” real-time PCR assay adapted from Brancart et al. (31) (see Materials and Methods, SDC 2, http://links.lww.com/TP/A552).
  2. Probable cases: clinically typical cases who responded to specific cotrimoxazole therapy occurring within the outbreak time period—but where induced sputum or BAL specimens were unavailable for PCR testing, and alternate causes of lung infection were excluded. All patients had induced sputum/BAL fluid examined for the presence of bacteria (including Nocardia and Legionella culture), mycobacteria, fungi, and respiratory viruses and CMV. In addition, urine was collected for testing for the presence of pneumococcal and Legionella antigen using standard laboratory methods.
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Epidemiological Investigations

Contact tracing was undertaken by review of outpatient clinic visits, hospitalizations, and other potential contact points in all PJP cases. Oropharyngeal rinses from health care workers from the outpatient facility were tested for the presence of P. jirovecii DNA by real-time PCR. Sampling of ambient air from consulting rooms, corridor, and waiting rooms of outpatient clinic used an air sampler placed 1 m above the floor (Model MAS-100, Merck, Whitehorse, NJ) with testing for P. jirovecii DNA within 48 hr (31).

Genotyping of P. jirovecii was performed by MLST based on sequence analysis of four genetic loci: the internal transcribed spacer 1 and 2 (ITS1/2) regions including the 5.8S rRNA gene of the nuclear rRNA gene cluster, and the P. jirovecii-specific β-TUB, mtLSU, and DHPS genes (6, 13). Upper case italics as (β-TUB), Using DNA extracts from 11 confirmed PJP cases, the ITS1/2, β-TUB, β-TUB, mtLSU, and DHPS loci were amplified using primers and amplification conditions as specified (see Table, SDC 3, http://links.lww.com/TP/A553) (32–35). Amplicons were purified and then sequenced commercially (Macrogen Inc., Seoul, Korea). Sequences were aligned (Bioedit Sequence Alignment Editor program, version 7.0.5.3 and Sequencer version 4.7), concatenated, and further aligned with published PJP reference sequences for each of the four MLST loci, archived in the GenBank database (β-TUB; AF170964, DHPS; AJ586567, mtLSU: M58605; and ITS1/2: U07220). Genotypic comparison used DNA extracts from nine outbreak-unrelated patient samples, “the outgroup.” Phylogenetic analyses were performed using the program PAUP* version 4.0b10.

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Statistical Methods

An unpaired Student t test or Wilcoxon test was used for nominal data, conditional binomial tests examined categorical data, and Poisson regression modeled the PJP incidence. Multiple logistic regression identified risk after backward elimination. The incubation period was calculated by the mean of the minimum and maximal clinic cross-over days between prodromal asymptomatic PJP patient before clinical PJP presentation. ORION guidelines for cluster outbreak reporting were used (36). The institutional ethics approval was HREC 2011/4/5.3 (3301). Data are expressed as mean±SD unless stated, and a probability less than 0.05 is considered significant.

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ACKNOWLEDGMENTS

The authors thank Karen Byth-Wilson for statistics; Elaine Chan for costing; Kathy Dempsey and Allison Sutor for collection of samples; Carmen Paterson and Natalie Perkins for contact tracing; the CIDMLS molecular biology staff for DNA extractions; and Sue Sleiman, Vishal Ahujah, and Rady Kim for support in the Mycology Laboratory. The authors acknowledge clinical support from Drs. Jeremy Chapman, Philip O'Connell, Angela Webster, Kamal Sud, Lukas Karaitis, and Grahame Elder.

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Keywords:

Nosocomial; cluster; Pneumocystis jirovecii; Pneumocystis carinii; pneumonia

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