University of Manchester



Detection of Pneumocystis jirovecii by quantitative real-time PCR in oral rinses from Pneumocystis pneumonia asymptomatic human immunodeficiency virus patients Marcin G Fraczek,1,* Sameena Ahmad,2 Malcolm Richardson,1,4 Marie Kirwan,3 Paul Bowyer,1 David W Denning,1,3 and Riina Rautemaa1,3,41 The University of Manchester, Faculty of Biology, Medicine and Health, M1 7DN, Manchester, United Kingdom2 Department of Sexual Medicine and HIV, Manchester University NHS Foundation Trust, Manchester, United Kingdom3 The National Aspergillosis Centre, Manchester University NHS Foundation Trust, M23 9LT, United Kingdom4 Mycology Reference Centre Manchester, Manchester University NHS Foundation Trust, M23 9LT, United KingdomRunning title: Pneumocystis jirovecii qRT-PCR in HIV patientsKeywords. Pneumocystis jirovecii; PCP; qRT-PCR; oral rinse; HIVCorrespondence: Marcin G. Fr?czek, PhD, The University of Manchester, Faculty of Biology, Medicine and Health, M1 7DN, Manchester, United KingdomTel.: +44 161 306 8904Email address: marcin.fraczek@manchester.ac.ukAbstractPneumocystis pneumonia (PCP) is a potentially life-threatening fungal infection usually seen in immunocompromised patients. Pneumocystis jirovecii can be easily detected from oral rinse samples in HIV patients with suspected PCP.In this study, a quantitative real-time PCR assay was used to establish the frequency of detection of P. jirovecii in oral rinses from HIV patients without respiratory symptoms or suspicion of PCP. Two saline oral rinses were collected from 100 ambulant HIV patients and from 60 COPD patients (comparator group).Four HIV patients were positive for P. jirovecii. In three patients, the first sample was positive and in one the second one was positive. One of these patients was on PCP prophylaxis and had a CD4+ count of 76 cells/mm3. The mean CD4+ count for all patients was 527 cells/mm3. All qRT-PCR test results for the COPD patients were negative. No patient developed PCP at six months follow-up.The qRT-PCR assay can be used to detect P. jirovecii DNA in oral rinse samples from HIV patients without evident clinical symptoms, however the oral carriage of this fungus is rare in our cohort of patients.In conclusion, although rare, a positive oral rinse P. jirovecii result may reflect colonisation, in particular in patients with HIV. This needs to be kept in mind when using oral rinses and qRT-PCR in the diagnosis of P. jirovecii infection.Main text and table legends word count: 2581Abstract word count: 207INTRODUCTIONPneumocystis jirovecii (formerly Pneumocystis carinii) is the causative agent of Pneumocystis pneumonia (PCP), a potentially life-threatening fungal infection usually seen in immunocompromised or immunosuppressed individuals. If untreated, the mortality rate is as high as 100%, however even with treatment the mortality rate ranges between 10% and 20% ADDIN EN.CITE <EndNote><Cite><Author>Gigliotti</Author><Year>2012</Year><RecNum>1</RecNum><DisplayText>[1]</DisplayText><record><rec-number>1</rec-number><foreign-keys><key app="EN" db-id="9ptdsfvp7dxwe7e9f2nxweznef5drewpa9t2" timestamp="1494339862">1</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Gigliotti, F.</author><author>Wright, T. W.</author></authors></contributors><auth-address>Division of Pediatric Infectious Diseases, Department of Pediatrics, University of Rochester School of Medicine, Rochester, New York, United States of America. francis_gigliotti@urmc.rochester.edu</auth-address><titles><title>Pneumocystis: where does it live?</title><secondary-title>PLoS Pathog</secondary-title><alt-title>PLoS pathogens</alt-title></titles><periodical><full-title>PLoS Pathog</full-title><abbr-1>PLoS pathogens</abbr-1></periodical><alt-periodical><full-title>PLoS Pathog</full-title><abbr-1>PLoS pathogens</abbr-1></alt-periodical><pages>e1003025</pages><volume>8</volume><number>11</number><edition>2012/12/05</edition><keywords><keyword>Animals</keyword><keyword>Humans</keyword><keyword>Pneumocystis/*immunology/*pathogenicity</keyword><keyword>Pneumonia, Pneumocystis/*immunology/pathology/*transmission</keyword><keyword>Rats</keyword></keywords><dates><year>2012</year></dates><isbn>1553-7374 (Electronic)&#xD;1553-7366 (Linking)</isbn><accession-num>23209406</accession-num><work-type>Review</work-type><urls><related-urls><url>;[1]. HIV-positive patients with a CD4+ lymphocyte count lower than 200 cells/mm3 and in particular, lower than 100 cells/mm3, are the main risk group PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LdTwvQXV0aG9yPjxZZWFyPjIwMTI8L1llYXI+PFJlY051

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ADDIN EN.CITE.DATA [2]. In addition, between 10% and 15% of the HIV patients with a CD4+ count higher than 200 cells/mm3 develop PCP PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Lb3ZhY3M8L0F1dGhvcj48WWVhcj4yMDA5PC9ZZWFyPjxS

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ADDIN EN.CITE.DATA [4]. In HIV-negative immunossupressed patients such as those undergoing intensive anticancer chemotherapy or having an underlying lung disease, the risk for PCP may be even higher than in HIV patients who are on ARV therapy and/or PCP prophylaxis, as reported by several studies PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYW5zaGFyYW1hbmk8L0F1dGhvcj48WWVhcj4yMDAwPC9Z

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ADDIN EN.CITE.DATA [9]. Carriage of P. jirovecii has been reported in immunocompetent patients with pulmonary diseases such as with chronic obstructive pulmonary disease (COPD), lung cancer, cystic fibrosis or infected with Mycobacterium tuberculosis and those having bacterial pneumonia. The prevalence of P. jirovecii in those groups of patients ranges from 5% to 55%, depending on the sampling and detection method used, and the stage of the disease PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Qcm9ic3Q8L0F1dGhvcj48WWVhcj4yMDAwPC9ZZWFyPjxS

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ADDIN EN.CITE.DATA [9-12].Data from the Brittany area of France show that P. jirovecii prevalence in patients with cystic fibrosis is lower than those observed in Germany, Spain, Brazil or in other regions of France, illustrating the fact that there are numerous factors that impact on the epidemiology of Pneumocystis disease PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5OZXZlejwvQXV0aG9yPjxZZWFyPjIwMTg8L1llYXI+PFJl

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ADDIN EN.CITE.DATA [14], the gold standard for the diagnosis of PCP is still microscopical examination of respiratory specimens, such as induced sputum or bronchoalveolar lavage (BAL), however lung biopsy has also been used PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IdWFuZzwvQXV0aG9yPjxZZWFyPjIwMTE8L1llYXI+PFJl

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ADDIN EN.CITE.DATA [15-17]. More recently, conventional polymerase chain reaction (PCR) and quantitative real-time PCR (qRT-PCR) are increasingly used as diagnostic tools for PCP, providing important advances compared to microscopy. They target specific loci in P. jirovecii DNA and provide faster and more accurate results, requiring only basic molecular laboratory skills PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Sb2huZXI8L0F1dGhvcj48WWVhcj4yMDA5PC9ZZWFyPjxS

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PgB=

ADDIN EN.CITE.DATA [18]. In developing countries with a high burden of HIV, optimal respiratory specimens are not always readily available and the sensitivity of microscopically examined induced sputum is therefore variable. Thus, there is a need for reliable and sensitive tests where specimens obtained using non-invasive methods could be used. Oral rinses have been suggested for diagnosis of PCP as they can be readily obtained avoiding hazardous invasive procedures, especially in severely sick patients PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SZXNwYWxkaXphPC9BdXRob3I+PFllYXI+MjAwNjwvWWVh

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ADDIN EN.CITE.DATA [19]. In combination with qRT-PCR they could provide fast diagnosis of PCP.Since P. jirovecii can be easily detected from oral rinse samples in HIV patients with suspected PCP PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYXRvczwvQXV0aG9yPjxZZWFyPjIwMDE8L1llYXI+PFJl

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ADDIN EN.CITE.DATA [20-22], we aimed to establish the incidence and level of P. jirovecii carriage in HIV patients without any respiratory symptoms or indication of PCP. Moreover, the aim of this study was to investigate the clinical usefulness of oral samples and a molecular detection method to (qRT-PCR) in this group of patients. COPD patients with no signs and symptoms of PCP were used as a comparator group. A commercially available CE-marked multiplex qRT-PCR assay (MycAssay Pneumocystis; Myconostica, now Novacyt) was used for P. jirovecii detection.MATERIAL AND METHODSPatientsA flow chart (Figure 1) briefly summarises the patient enrolment and sample processing. A total number of 100 HIV positive patients (Table 1) attending the University Hospital of South Manchester (UHSM, Manchester, United Kingdom) Withington Community Hospital Sexual Health Clinic and 60 COPD patients (comparator group) attending the UHSM Wythenshawe Hospital COPD Clinic were enrolled. The study protocol was approved by the North West 9 Research Ethics Committee Greater Manchester West (Reference: 10/H1014/37). Recruitment was performed in accordance with the International Conference on Harmonisation Good Clinical Practice (ICH-GCP) guidance.Patients were enrolled based on the following inclusion criteria: (i) confirmed diagnosis of HIV according to the UK National Guidelines ADDIN EN.CITE <EndNote><Cite><Author>British HIV Association. British Association of Sexual Health and HIV</Author><Year>2008</Year><RecNum>20</RecNum><DisplayText>[23]</DisplayText><record><rec-number>20</rec-number><foreign-keys><key app="EN" db-id="9ptdsfvp7dxwe7e9f2nxweznef5drewpa9t2" timestamp="1494494782">20</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author><style face="normal" font="default" size="100%">British HIV Association</style><style face="normal" font="default" charset="238" size="100%">. British Association of Sexual Health and HIV, British Infection Society.</style></author></authors></contributors><titles><title><style face="normal" font="default" size="100%">UK National Guidelines for HIV Testing </style><style face="normal" font="default" charset="238" size="100%">2008</style></title></titles><pages><style face="normal" font="default" charset="238" size="100%">1-23</style></pages><dates><year><style face="normal" font="default" charset="238" size="100%">2008</style></year></dates><work-type><style face="normal" font="default" charset="238" size="100%">Guidelines</style></work-type><urls><related-urls><url>;[23] and a routine outpatient clinic attendance, (ii) no recent onset or exacerbation of respiratory illness, (iii) no PCP diagnosis for at least the past six months (based on patient records). Patients with an earlier episode of PCP and those on co-trimoxazole or other PCP prophylaxis were also included in the study. Patients less than 18 years old and those in whom the sample collection procedure was unduly risky were excluded from the study. Comparator group patients were enrolled based on the following inclusion criteria: (i) confirmed diagnosis of COPD according to the UK National Guidelines ADDIN EN.CITE <EndNote><Cite><Author>NICE</Author><Year>2010</Year><RecNum>21</RecNum><DisplayText>[24]</DisplayText><record><rec-number>21</rec-number><foreign-keys><key app="EN" db-id="9ptdsfvp7dxwe7e9f2nxweznef5drewpa9t2" timestamp="1494494849">21</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>NICE, National Institute for Health and Care Excellence</author></authors></contributors><titles><title>Chronic obstructive pulmonary disease in over 16s: diagnosis and management</title></titles><dates><year><style face="normal" font="default" charset="238" size="100%">2010</style></year></dates><urls><related-urls><url>;[24] and a routine outpatient clinic attendance, (ii) normal lymphocyte counts and (iii) no PCP diagnosis for at least the past six months (based on patient records).Sample collection and processingTwo oral rinse samples were collected 5 minutes apart from each patient by vigorously washing the oral cavity (but not by gargling the oropharynx to exclude contamination and excretions from the lower respiratory track) with 50 ml of sterile 0.9% saline for 1 minute. Reasoning behind this was that the first sample may contain the higher load of P. jirovecii but also PCR inhibitors. Therefore the second sample was collected to investigate if the dilution factor may play a role in detection sensitivity of this organism. Patients were also asked not to eat or drink for at least 2 h prior to sample collection to minimise possible subsequent qRT-PCR inhibition. No additional examinations (laboratory, radiology) were requested from the patients. Clinical information was collected from medical records and analysed if available.Following collection, samples were immediately placed on ice and transferred to the laboratory, where they were centrifuged at 7000 xg for 10 minutes at 4°C. The supernatant was decanted and the pellet was resuspended in 1 ml of sterile 1x phosphate buffered saline (PBS). This was subsequently transferred to a 1.5 ml Eppendorf tube and centrifuged at 10,000 xg for 2 minutes at 4°C. All but 50 ?l of the supernatant was removed and the pellet was resuspended in the remaining volume. The entire solution was transferred to the bead tube provided in the CE marked MycXtra Fungal DNA Extraction Kit (Myconostica, UK, now Novacyt) and extraction was carried out in accordance with the manufacturer’s instructions. Ten microliters of extracted DNA was tested for the presence of P. jirovecii DNA using the Multiplex qRT-PCR kit, MycAssay Pneumocystis, which targets the Pneumocystis ribosomal large sub-unit as per manufacturer’s instructions. A Cepheid SmartCycler machine with the version 3 diagnostic software was used. A cycle threshold (Ct) of ≤39 was considered positive and Ct>39 was considered negative. RESULTSThe age range of the HIV population was 21 to 80 years, with majority of white British. In the absence of respiratory symptoms, chest radiographs had not been taken for any of the HIV patients within 3 months prior to sampling for this study. None of the HIV or COPD patients developed PCP within 6 months post sampling.A total of 320 oral rinse samples from 100 HIV and 60 COPD patients were collected and analysed for P. jirovecii DNA by a multiplex qRT-PCR assay. Four samples obtained from four HIV patients (4%) were positive for P. jirovecii. Of these, the first collected sample was positive from three patients (qRT-PCR Ct values 32.2, 33.2 and 35.8; patient no. 6, 40 and 41, respectively; Table 2) but the second samples were negative. In one patient (no. 50) only the second sample was positive (Ct 32.8). In the case of three qRT-PCR positive patients for whom the first sample was positive, the time between the first sample collection and last meal/drink was 3 h 25 min, 3 h 05 min and 2 h 25 min, respectively. The time between last meal/drink and the first sample collection for the fourth qRT-PCR positive patient was only 50 min. The times for the remaining patients with two negative qRT-PCR results, varied from 23 min to 17 h. Each qRT-PCR sample was monitored for the PCR inhibition against the internal amplification control (IAC) and 7/320 samples failed as the IAC Ct value was not in the acceptable range designed for the kit. These samples were not analysed further. All samples from COPD patients were qRT-PCR negative.The CD4+ counts for the qRT-PCR positive patients were 76, 391, 448 and 551 cells/mm3 (Table 2). The cell counts for all patients ranged from 76 to 1200 cells/mm3 (mean 527 cells/mm3). The lymphocyte counts for 48 HIV patients were performed on the day of the oral rinse sample collection (of which 2 patients were P. jirovecii qRT-PCR positive). Forty two HIV patients had their CD4+ count analysed within 1 month prior to sample collection (of which 1 patient was qRT-PCR positive), 4 patients within 2 months, 1 patient within 3 months and 3 patients within 4 months. One P. jirovecii qRT-PCR positive patient had a CD4+ count analysed 6 months prior to the oral wash sample collection and at that time the lymphocyte count was 551 cells/mm3. Two of the positive P. jirovecii qRT-PCR patients used tobacco but none had any additional immunodeficiency. Of the qRT-PCR positive patients, only one was on ARV therapy at the time of sample collection (tenofovir disoproxil fumarate/emtricitabine (Truvada); patient 41; Table 2).Six HIV patients were on PCP prophylaxis on the day of oral sample collection, receiving either trimethoprim/sulfamethoxazole (Septrin), diaminodiphenyl sulfone (Dapsone) or atovaquone (Table 2 and 3). These patients were also on ARV therapy receiving either tenofovir disoproxil fumarate/emtricitabine (Truvada), efavirenz/emtricitabine/tenofovir disoproxil fumarate (Atripla), lopinavir/ritonavir (Kaletra), tenofovir or darunavir. One patient (no. 86) was only on AVR therapy but not on PCP prophylaxis. Their CD4+ count ranged from 76 to 647 cells/mm3 but only one patient (patient no. 41) was P. jirovecii qRT-PCR positive (CD4+ count of 76; atovaquone prophylaxis and Truvada therapy). This patient however did not have or developed any symptoms suggestive of PCP during the 6 month follow-up period. Two HIV positive patients had been previously diagnosed with PCP, in 1988 (patient 51) and in 2008 (patient 86) (Table 3). Both were qRT-PCR negative.DISCUSSIONIn the current study we aimed to establish the incidence of P. jirovecii carriage in HIV patients without any respiratory symptoms or indication of PCP. We also aimed to investigate the clinical usefulness of readily available oral wash samples to detect P. jirovecii DNA as this type of specimen may be more suitable for severely ill patients or where bronchoscopy accessibility is limited. We showed that the commercial qRT-PCR assay, MycAssay Pneumocysis, can be used to detect P. jirovecii DNA from this type of sample in such patients. However, the oral carriage of this organism or its DNA in the group tested was shown to be rare, representing only 4% of the analysed samples in the tested HIV population. Three of the four samples collected from HIV patients had a high qRT-PCR detection signal, indicating a high P. jirovecii load. No P. jirovecii DNA was detected in the comparator COPD group.No link was found between the qRT-PCR positivity for P. jirovecii and the CD4+ status, as the CD4+ cell count of three out of four positive qRT-PCR patients >200 cells/ml (Table 2). However, the CD4+ count for one qRT-PCR positive patient was performed 6 months before the oral rinse specimen collection and the CD4+ status of this patient at the time of sample collection was unknown. Therefore it might have changed at the time of this study, resulting in the positive qRT-PCR. The fact that none of the four P. jirovecii qRT-PCR positive patients had or developed PCP and all provided only one positive sample suggests that the result could reflect well controlled immune responses against the fungus or good response to PCP prophylaxis as in case of patient no. 41, who was taking atovaquone at the time of oral rinse sample collection. It is also possible that those patients could have acquired P. jirovecii in their early life, without developing any symptoms of PCP, while the organism remained latent and was only detected by qRT-PCR in the first of paired samples tested. This could suggest transient colonisation, as the fungal DNA was too low or too diluted to be detected in the second sample examined. However, in patient no. 50 only the second of the paired sample tested was qRT-PCR positive. This may indicate (i) sample variability, (ii) that the first of two mouth rinses was not performed thoroughly, (iii) there was contamination between the samples from the lower respiratory track (e.g. after a cough) or (iv) the first oral rinse sample was contaminated with qRT-PCR inhibitors originating from food/drink. The issue of PCR inhibitors originating from food is well known PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TY2hyYWRlcjwvQXV0aG9yPjxZZWFyPjIwMTI8L1llYXI+

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ADDIN EN.CITE.DATA [25-26] and in case of this patient the time between the sample collection and last meal/drink was only ~50 min (as opposed to other 3 qRT-PCR positive samples for which the time was between 2 h 25 min and 3 h 25 min). This could have resulted in decreased sensitivity or a false-negative result. However, since all samples were monitored for IAC, no inhibition was observed for this sample. In the event of both of the paired samples tested being qRT-PCR positive, fungal load or an ongoing infection should be considered. This also applies to cases with low Ct value reflecting high fungal burden. Such results should be further confirmed by other clinical and laboratory tests. However in this study this was not the case.None of the patients from the comparator COPD group were positive for P. jirovecii DNA by qRT-PCR, suggesting that the P. jirovecii colonisation in our COPD cohort is either uncommon, P. jirovecii DNA in the samples obtained was too low to be detected by the method used or the sample type is not adequate for this group of patients. However, as none of the patients in this group developed PCP, the level of sensitivity of the sample type appears not to over-diagnose PCP. Although several studies have reported colonisation in COPD patients, with a prevalence of 5 and 55% PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Nb3JyaXM8L0F1dGhvcj48WWVhcj4yMDA0PC9ZZWFyPjxS

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ADDIN EN.CITE.DATA [11-12], this was not the case in our group of patients using qRT-PCR. A different patient ethnicity in this study compared to previous ones, a different experimental design or that the patients were not colonised by P. jirovecii in the first instance could also explain our results.Our study has some limitations. Firstly, no accompanying sputum samples were collected as patients without any respiratory symptoms cannot produce it. Secondly, no microscopy analyses were performed to confirm the qRT-PCR results. However, as qRT-PCR is more sensitive than microscopy it is highly unlikely that any positive cases were missed. At the same time the proportion of patients with positive results was very low and likely to reflect colonisation. qRT-PCR inhibition originating from food/drink could also have hindered or decrease sensitivity of our results, thus preventing from accurate assessment of incidence of this organism in the tested groups. Although patients were asked not to eat or drink at least 2 h before sample collection, several had had a drink or meal. This should be taken into account if a similar study is performed or results are being clinically assessed. Others have found that qRT-PCR signals can degrade in saliva and oral wash samples, as this is why we placed all the samples in ice for transportation to the laboratory. In addition, no demographic data was available for the comparator group.In summary, we showed that qRT-PCR assay can be used to detect P. jirovecii DNA in oral rinse samples from HIV patients without evident clinical symptoms. However, very few patients were positive. It is likely that the four Pneumocystis qRT-PCR positive patients were transiently colonised and did not have ongoing disease as none of these patients developed any symptoms of PCP 6 months after the study.Funding informationFunding was provided by the University Hospital of South Manchester, UKAuthor contributionMGF processed samples, performed experiments and analysed the data; MGF, RR, MR and DWD wrote the manuscript; RR, MR and DWD designed the study; SA and MK selected patients, obtained their consent and collected samples; MK, SA, PB, DWD obtained ethical approval. All authors approved the final version.Conflicts of interestAll other authors: no reported conflicts of interest.Ethical statementThe study protocol was approved by the North West 9 Research Ethics Committee Greater Manchester West (Reference: 10/H1014/37).References: ADDIN EN.REFLIST [1]Gigliotti F, Wright TW. Pneumocystis: where does it live? PLoS Pathog 2012;8(11):e1003025.[2]Ku NS, Song YG, Han SH, Kim SB, Kim HW, Jeong SJ, et al. Short communication: factors influencing time to CD4(+) T cell counts >200 cells/mm(3) in HIV-infected individuals with CD4(+) T cell <50 cells/mm(3) at the time of starting combination antiretroviral therapy. AIDS Res Hum Retroviruses 2012;28(12):1594-7.[3]Kovacs JA, Masur H. Evolving health effects of Pneumocystis: one hundred years of progress in diagnosis and treatment. JAMA 2009;301(24):2578-85.[4]Coelho L, Veloso VG, Grinsztejn B, Luz PM. Trends in overall opportunistic illnesses, Pneumocystis carinii pneumonia, cerebral toxoplasmosis and Mycobacterium avium complex incidence rates over the 30 years of the HIV epidemic: a systematic review. Braz J Infect Dis 2014;18(2):196-210.[5]Mansharamani NG, Balachandran D, Vernovsky I, Garland R, Koziel H. Peripheral blood CD4 + T-lymphocyte counts during Pneumocystis carinii pneumonia in immunocompromised patients without HIV infection. Chest 2000;118(3):712-20.[6]Nuesch R, Bellini C, Zimmerli W. Pneumocystis carinii pneumonia in human immunodeficiency virus (HIV)-positive and HIV-negative immunocompromised patients. Clin Infect Dis 1999;29(6):1519-23.[7]Overgaard UM, Helweg-Larsen J. Pneumocystis jiroveci pneumonia (PCP) in HIV-1-negative patients: a retrospective study 2002-2004. Scand J Infect Dis 2007;39(6-7):589-95.[8]Roblot F, Godet C, Le Moal G, Garo B, Faouzi Souala M, Dary M, et al. Analysis of underlying diseases and prognosis factors associated with Pneumocystis carinii pneumonia in immunocompromised HIV-negative patients. Eur J Clin Microbiol Infect Dis 2002;21(7):523-31.[9]Probst M, Ries H, Schmidt-Wieland T, Serr A. Detection of Pneumocystis carinii DNA in patients with chronic lung diseases. Eur J Clin Microbiol Infect Dis 2000;19(8):644-5.[10]Helweg-Larsen J, Jensen JS, Dohn B, Benfield TL, Lundgren B. Detection of Pneumocystis DNA in samples from patients suspected of bacterial pneumonia--a case-control study. BMC Infect Dis 2002;2:28.[11]Morris A, Sciurba FC, Lebedeva IP, Githaiga A, Elliott WM, Hogg JC, et al. Association of chronic obstructive pulmonary disease severity and Pneumocystis colonization. Am J Respir Crit Care Med 2004;170(4):408-13.[12]Calderon EJ, Rivero L, Respaldiza N, Morilla R, Montes-Cano MA, Friaza V, et al. Systemic inflammation in patients with chronic obstructive pulmonary disease who are colonized with Pneumocystis jiroveci. Clin Infect Dis 2007;45(2):e17-9.[13]Nevez G, Robert-Gangneux F, Pougnet L, Virmaux M, Belleguic C, Deneuville E, et al. Pneumocystis jirovecii and Cystic Fibrosis in Brittany, France. Mycopathologia 2018;183(1):81-7.[14]Schildgen V, Mai S, Khalfaoui S, Lusebrink J, Pieper M, Tillmann RL, et al. Pneumocystis jirovecii can be productively cultured in differentiated CuFi-8 airway cells. MBio 2014;5(3):e01186-14.[15]Huang L, Cattamanchi A, Davis JL, den Boon S, Kovacs J, Meshnick S, et al. HIV-associated Pneumocystis pneumonia. Proc Am Thorac Soc 2011;8(3):294-300.[16]Oz HS, Hughes WT. Search for Pneumocystis carinii DNA in upper and lower respiratory tract of humans. Diagn Microbiol Infect Dis 2000;37(3):161-4.[17]Nowaseb V, Gaeb E, Fraczek MG, Richardson MD, Denning DW. Frequency of Pneumocystis jirovecii in sputum from HIV and TB patients in Namibia. J Infect Dev Ctries 2014;8(3):349-57.[18]Rohner P, Jacomo V, Studer R, Schrenzel J, Graf JD. Detection of Pneumocystis jirovecii by two staining methods and two quantitative PCR assays. Infection 2009;37(3):261-5.[19]Respaldiza N, Montes-Cano MA, Friaza V, Munoz-Lobato F, Medrano FJ, Varela JM, et al. Usefulness of oropharyngeal washings for identifying Pneumocystis jirovecii carriers. J Eukaryot Microbiol 2006;53 Suppl 1:S100-1.[20]Matos O, Costa MC, Lundgren B, Caldeira L, Aguiar P, Antunes F. Effect of oral washes on the diagnosis of Pneumocystis carinii pneumonia with a low parasite burden and on detection of organisms in subclinical infections. Eur J Clin Microbiol Infect Dis 2001;20(8):573-5.[21]Larsen HH, Huang L, Kovacs JA, Crothers K, Silcott VA, Morris A, et al. A prospective, blinded study of quantitative touch-down polymerase chain reaction using oral-wash samples for diagnosis of Pneumocystis pneumonia in HIV-infected patients. J Infect Dis 2004;189(9):1679-83.[22]Hviid CJ, Lund M, Sorensen A, Ellermann-Eriksen S, Jespersen B, Dam MY, et al. Detection of Pneumocystis jirovecii in oral wash from immunosuppressed patients as a diagnostic tool. PLoS One 2017;12(3):e0174012.[23]British HIV Association. British Association of Sexual Health and HIV BIS. UK National Guidelines for HIV Testing 2008. 2008:1-23.[24]NICE NIfHaCE. Chronic obstructive pulmonary disease in over 16s: diagnosis and management. 2010.[25]Schrader C, Schielke A, Ellerbroek L, Johne R. PCR inhibitors - occurrence, properties and removal. J Appl Microbiol 2012;113(5):1014-26.[26]Sovova T, Krizova B, Hodek J, Ovesna J. Identifying inhibitors/enhancers of quantitative real-time PCR in food samples using a newly developed synthetic plasmid. J Sci Food Agric 2016;96(3):997-1001.Figure 1. A flow chart showing a brief summary of patient enrolment and sample processing.Patient ageEthnicityGenderCD4+ count (cells/mm3)Time between CD4+ count and sample collection:Range: 21-80Mean: 41White British: 81Black British: 2White Irish: 1White Other: 3Black African: 7Asian not specified: 3Chinese Other: 1Not specified: 293 males7 femalesRange: 76-1200Mean: 527Same month: 48 patients (including 2 PCR positive)1 month before: 42 patients (including 1 PCR positive)2 months before: 43 months before: 14 months before: 35 months before: 06 months before: 2 patients (including 1 PCR positive)Table 1. General HIV patient demographic data and time between CD4+ count and oral sample collection. No demographic data is available for COPD patients.Patient no.GenderAgeSmokerRT-PCR result – 1st rinse (Ct)RT-PCR result – 2nd rinse (Ct)CD4+ count; cells/mm3 (months of latest CD4+ count)PCP prophylaxisARV therapyPrevious PCP6M43NOPositive (33.2)Negative391 (-1)NONONO40M37NOPositive (32.2)Negative448 (0)NONONO41F68YESPositive (35.8)Negative76 (0)AtovaquoneTruvadaNO50M49YESNegativePositive (32.8)551 (-6)NONONOTable 2. Positive P. jirovecii qRT-PCR HIV patients, their CD4+ count, PCP prophylaxis and ARV therapy at the time of the oral rinse sample collection as well as their previous PCP status. Only one patient in this group was on PCP prophylaxis and ARV therapy.Patient no.GenderAgeSmokerRT-PCR result – 1st rinse (Ct)RT-PCR result – 2nd rinse (Ct)CD4+ count; cells/mm3 (months of latest CD4+ count)PCP prophylaxisARV therapyPrevious PCP14M43NONegativeNegative108 (-1)DapsoneTruvadaNO32M38NONegativeNegative224 (0)SeptrinAtriplaNO51M39YESNegativeNegative242 (0)DapsoneTruvada/ kaletraYES (in 2008)7276MM3944NONONegativeNegativeNegativeNegative126 (0)122 (-1)DapsoneSeptrinAtriplaAtriplaNONO86M50YESNegativeNegative647 (-1)NOtenofovir/ darunavirYES (in 1988)Table 3. Negative P. jirovecii qRT-PCR HIV patients but on PCP prophylaxis and/or on ARV therapy at the time of the oral rinse sample collection. Their CD4 count and previous PCP status is also presented here. ................
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