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Consensus Guidelines for Diagnosis, Prophylaxis and Management of Pneumocystis Jirovecii Pneumonia in Patients with Haematological and Solid Malignancies, 2014 L

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Consensus Guidelines for Diagnosis, Prophylaxis and Management of Pneumocystis Jirovecii Pneumonia in Patients with Haematological and Solid Malignancies, 2014 L bs_bs_banner Internal Medicine Journal 44 (2014) Consensus guidelines for diagnosis, prophylaxis and management of Pneumocystis jirovecii pneumonia in patients with haematological and solid malignancies, 2014 L. Cooley,1 C. Dendle,2,3 J. Wolf,4,5 B. W. Teh,6 S. C. Chen,7,8,9 C. Boutlis10,11 and K. A. Thursky6,12 1Department of Microbiology and Infectious Diseases, Royal Hobart Hospital, Hobart, Tasmania, 2Departments of Infectious Diseases and General Medicine, Monash Medical Centre, Monash Health, Clayton, Victoria, 3Southern Clinical School, Faculty of Medicine, Monash University, Melbourne, Victoria, 4Department of Infectious Diseases, St. Jude Children’s Research Center, Memphis, Tennessee, USA, 5University of Tennessee Health Sciences Center, Memphis, Tennessee, USA, 6Department of Infectious Diseases and Infection Control, Peter MacCallum Cancer Centre, East Melbourne, Victoria, 7Centre for Infectious Diseases and Microbiology Laboratory Services, ICPMR – Pathology West, Westmead, New South Wales, 8Department of Infectious Diseases, Westmead Hospital, Westmead, New South Wales, 9Sydney Medical School, The University of Sydney, Sydney, New South Wales, 10Department of Infectious Diseases, Wollongong Hospital, Wollongong, New South Wales, 11Graduate School of Medicine, University of Wollongong, Wollongong, New South Wales, 12Victorian Infectious Diseases Service, The Doherty Institute for Infection and Immunity, Parkville, Victoria Key words Abstract Pneumocystis carinii, Pneumocystis jirovecii, haematological malignancy, solid-organ Pneumocystis jirovecii infection (PJP) is a common cause of pneumonia in patients with tumour, prophylaxis, treatment. cancer-related immunosuppression. There are well-defined patients who are at risk of PJP due to the status of their underlying malignancy, treatment-related immunosup- Correspondence pression and/or concomitant use of corticosteroids. Prophylaxis is highly effective and Karin Thursky, Department of Infectious should be given to all patients at moderate to high risk of PJP. Trimethoprim- Diseases, Peter MacCallum Cancer Centre, sulfamethoxazole is the drug of choice for prophylaxis and treatment, although several Locked Bag Number 1 A’Beckett Street, East alternative agents are available. Melbourne, Vic. 8006, Australia. Email: [email protected] doi:10.1111/imj.12599 Introduction disease is generally more severe in these patients, with increased length of hospital stay and higher rates of inten- Pneumocystis jirovecii infection causes pneumonia (PJP; sive care unit (ICU) admission and mechanical ventila- also known as PCP) in patients with immunosuppression tion, compared with HIV-infected patients.1–4 Significantly due to underlying malignancy, organ transplantation or higher mortality rates are also observed in non-HIV- other conditions. The infection is best studied in those infected individuals (34–39%) compared to those with with human immunodeficiency virus (HIV)/acquired HIV (6–7%).1,5,7 immune deficiency syndrome, as there are significant With a focus on HIV-negative populations, this guide- differences in the clinical features of PJP between HIV- line outlines diagnostic approaches and provides recom- 1–5 infected and non-infected individuals. mendations for prophylaxis and treatment of PJP in Infection in immunosuppressed HIV-negative individ- adults and children undergoing chemotherapy for uals has a shorter duration of onset and fewer systemic haematological and solid-organ tumours. It does not 1 symptoms than in HIV-infected individuals. Bron- discuss P. jirovecii affecting extra-pulmonary sites or infec- choalveolar lavage fluid from immunosuppressed non- tion in the setting of organ transplantation. HIV-infected patients shows lower concentrations of organisms but higher inflammatory scores.6 Clinical Methodology Conflicts of interest: The following authors are consultants or advisory committee members or receive honoraria, fees for Questions asked service, or travel assistance from, or have research or other associations with the organisations listed: Sharon Chen – Gilead, In preparing this update, we aimed to address the follow- Merck Sharp & Dohme, Pfizer; Karin Thursky – Pfizer. ing questions: © 2014 The Authors 1350 Internal Medicine Journal © 2014 Royal Australasian College of Physicians Guidelines for prevention and treatment of PJP 1 What are the current diagnostic strategies for PJP? cation, including: major surface glycoprotein (MSG) 2 Which patients with haematological and solid malig- gene, mitochondrial large subunit (mtLSU) rRNA gene, nancies are at risk for PJP? dihydropteroate synthase (DHPS) gene, dihydrofolate 3 What is the evidence for prophylaxis? Which agents reductase (DHFR) gene, heat shock protein (HSP)70 are most effective? gene and the beta-tubulin gene. Multicopy genes such 4 What are the first- and second-line agents for treat- as mtLSU and MSG offer the greatest sensitivity for ment of PJP? P. jirovecii detection.10 However, they lack specificity 5 Is there any evidence to keep patients with confirmed and have a low positive predictive value due to the PJP in clinical isolation? increased detection of P. jirovecii in patients who are colonised but otherwise well. With a high negative predictive value, PCR is best utilised for excluding the Search strategy diagnosis of PJP.12 A literature review was performed using PubMed to Quantitative PCR (qPCR), with defined upper- and identify papers published since 2007 that pertained to PJP lower-quantitation thresholds of P. jirovecii copy in patients with haematological and solid tumours. number, can be used to distinguish true infection from Search terms included (in combination) ‘Pneumocystis colonisation.13–18 However, there remains an indetermi- carinii’, ‘Pneumocystis jirovecii’, ‘immunocompromised’, nate zone of unclear clinical significance.14–17 Further, ‘non-HIV’, ‘treatment’, ‘prophylaxis’ and ‘diagnostics’. these quantitation thresholds will vary between differ- ent patient populations; clinicians should be cautious Diagnosis of PJP of relying on them as a measure to guide diagnosis or therapy. To improve accuracy, combined diagnostic algorithms have been proposed. These use qPCR and Microbiological tests β(1,3)-D-glucan on serum testing to classify patients Due to difficulties with isolating and culturing this into infection and colonisation categories,19 but valida- pathogen, microscopic examination of respiratory speci- tion is still required in patients with malignancy. mens using various staining methods is used to visualise Due to heterogeneity of methods and diversity of and identify the morphological structures of P. jirovecii. chosen qPCR targets in published literature, gener- Methenamine silver and toluidine blue preparat- alisability of reported cut-off values is limited. Each ions stain only the cyst wall and do not allow detect- institution must establish and validate its own qPCR ion of trophozoites. However, Giemsa stains detect cut-off values appropriate to the preferred molecular all life stages of P. jirovecii. Direct and indirect method. While molecular tests may aid clinical diagno- immunofluorescent assays (DFA, IFA) are specific for sis, there is a lack of correlation between qPCR and different life stages, depending on the antibody used. the clinical features or outcomes of PJP.20 Therefore, Comparative studies have shown DFA and IFA to be the clinicians should take an individual’s clinical risk of most sensitive stains for P. jirovecii in sputum and PJP into consideration when interpreting the cycle bronchoalveolar lavage, with sensitivities of 97% and thresholds. 90% respectively.8 These assays are also commercially Studies on the use of molecular diagnosis have largely available. been based on bronchoalveolar lavage sampling.15,16 Overall, the accuracy of staining methods is highly Although induced sputum samples have also been evalu- dependent on the quality of respiratory specimen, sample ated, they can be demanding to perform on wards and in processing, reaction of the specimen to the stain chosen children.17 Others have reported the use of oral washes and experience of the laboratory observer. The lower and expectorated sputum, but the clinical validity of burden of P. jirovecii in non-HIV-immunocompromised these approaches requires further evaluation.20,21 These patients, and the likelihood that they may already be on approaches certainly produce a lower yield – that may be anti-pneumocystis prophylaxis, remains a challenge for useful – but, overall, their value in this particular setting diagnosis.9 remains unclear. Staining methods have now largely been supplanted by highly sensitive molecular techniques, using semi- or Radiological findings fully quantitative polymerase chain reaction (PCR) tar- geting P. jirovecii-specific genes.10 A meta-analysis of PCR Imaging studies are an essential companion to microbio- studies has shown a pooled sensitivity of 99% and speci- logical testing for diagnosing PJP. High-resolution com- ficity of 92% in the non-HIV patient population.11 puted tomography (CT) is the most commonly used and A variety of gene targets can be used for PCR amplifi- reliable radiological modality for detecting pneumonic © 2014 The Authors Internal Medicine Journal © 2014 Royal Australasian College of Physicians 1351 Cooley et al. changes in immunocompromised patients.22 The most Table 1 Patients with malignancy at high risk for Pneumocystis jirovecii frequent CT findings are bilateral, ground-glass changes pneumonia 22 with apical predominance
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