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1.  Blood (1→3)-β-D-Glucan as a Diagnostic Test for HIV-Related Pneumocystis jirovecii Pneumonia 
In a large group of HIV-infected clinical trial participants with diverse opportunistic infections, blood beta-glucan was a more sensitive noninvasive test for PCP than serum LDH; sensitivity was also higher than that frequently reported for induced sputum examinations.
(See the editorial commentary by Morris and Masur, on pages 203–204.)
Background. Improved noninvasive diagnostic tests for Pneumocystis jirovecii pneumonia (PCP) are needed. We evaluated the test characteristics of plasma (1→3)-β-D-glucan (β-glucan) for HIV-related PCP among a large group of patients presenting with diverse opportunistic infections (OIs).
Methods. The study population included all 282 participants in AIDS Clinical Trials Group A5164, a study of early versus deferred antiretroviral therapy in conjunction with initial therapy of acute OIs. Baseline plasma samples were assayed for β-glucan, with standard assay reference values defining ≥80 pg/mL as positive. Before this analysis, diagnosis of PCP was independently adjudicated by 2 study investigators after reviewing reports from study sites.
Results. A total of 252 persons had a β-glucan result that could be analyzed, 173 (69%) of whom had received a diagnosis of PCP. Median β-glucan with PCP was 408 pg/mL (interquartile range [IQR], 209–500 pg/mL), compared with 37 pg/mL (IQR, 31–235 pg/mL) without PCP (P < .001). The sensitivity of β-glucan dichotomized at 80 pg/mL for the diagnosis of PCP was 92% (95% confidence interval [CI], 87%–96%), and the specificity was 65% (95% CI, 53%–75%); positive and negative predictive values were 85% (95% CI, 79%–90%) and 80% (95% CI, 68%–89%) respectively, based on the study prevalence of 69% of patients with PCP. Rates of abnormal lactate dehyrogenase levels did not differ significantly between those with and without PCP.
Conclusions. Blood (1→3)-β-D-glucan is strongly correlated with HIV-related PCP. In some clinical centers, this may be a more sensitive test than the induced sputum examination and could reduce the need for both bronchoscopy and empirical therapy of PCP.
doi:10.1093/cid/cir335
PMCID: PMC3165964  PMID: 21690628
2.  Clinic HIV-Focused Features and Prevention of Pneumocystis Carinii Pneumonia 
OBJECTIVE
To examine the association of clinic HIV-focused features and advanced HIV care experience with Pneumocystis carinii pneumonia (PCP) prophylaxis and development of PCP as the initial AIDS diagnosis.
DESIGN
Nonconcurrent prospective study.
SETTING
New York State Medicaid Program.
PARTICIPANTS
Medicaid enrollees diagnosed with AIDS in 1990–1992.
MEASUREMENTS AND MAIN RESULTS
We collected patient clinical and health care data from Medicaid files, conducted telephone interviews of directors of 125 clinics serving as the usual source of care for study patients, and measured AIDS experience as the cumulative number of AIDS patients treated by the study clinics since 1986. Pneumocystis carinii pneumonia prophylaxis in the 6 months before AIDS diagnosis and PCP at AIDS diagnosis were the main outcome measures. Bivariate and multivariate analyses adjusted for clustering of patients within clinics. Of 1,876 HIV-infected persons, 44% had PCP prophylaxis and 38% had primary PCP. Persons on prophylaxis had 20% lower adjusted odds of developing PCP (95% confidence interval [CI] 0.64, 0.99). The adjusted odds of receiving prophylaxis rose monotonically with the number of HIV-focused features offered by the clinic, with threefold higher odds (95% CI 1.6, 5.7) for six versus two or fewer such features. Patients in clinics with three HIV-focused features had 36% lower adjusted odds of PCP than those in clinics with one or none. Neither clinic experience nor specialty had a significant association with prophylaxis or PCP.
CONCLUSIONS
PCP prevention in our study cohort appears to be more successful in clinics offering an array of HIV-focused features.
doi:10.1046/j.1525-1497.1998.00003.x
PMCID: PMC1496898  PMID: 9462490
Pneumocystis carinii pneumonia (PCP); AIDS; clinical competence; ambulatory care; case management
3.  Pneumocystis pneumonia in South African children diagnosed by molecular methods 
BMC Research Notes  2014;7:26.
Background
Pneumocystis pneumonia (PCP) is an important cause of hospitalization and mortality in HIV-infected children. However, the incidence of PCP has been underestimated due to poor sensitivity of diagnostic tests. The use of polymerase chain reaction (PCR) for pneumocystis has enabled more reliable diagnosis. This study describes the incidence, clinical features and outcome of PCP in South African children diagnosed using PCR.
Methods
A prospective study of children hospitalised in South Africa with suspected PCP was done from November 2006 to August 2008. Clinical, laboratory and radiological information were collected. Lower respiratory tract specimens were obtained for PCP immunofluorescence (IF), real- time PCR for pneumocystis, bacterial and mycobacterial culture. Nasopharyngeal aspirates were taken for immunofluorescence (IF), real-time PCR for pneumocystis and PCR for respiratory viruses. A blood specimen for bacterial culture and for cytomegalovirus PCR was taken. Children were followed for the duration of their hospitalisation and the outcome was recorded.
Results
202 children [median (interquartile range, IQR) age 3.2 (2.1– 4.6) months] were enrolled; 124 (61.4%) were HIV infected. PCP was identified in 109 (54%) children using PCR, compared to 43 (21%) using IF and Grocott staining (p < 0.0001). Most PCP cases (88, 81%) occurred in HIV-infected children. All 21 cases (19%) occurring in HIV- negative children had another risk factor for PCP. On logistic regression, predictive factors for PCP were HIV infection, lack of fever, high respiratory rate and low oxygen saturation whilst cotrimoxazole prophylaxis was protective (OR 0.24; 95% CI 0.1 to 0.5; p < 0.002). The case fatality of children with PCP was higher than those without PCP (32.1% versus 17.2%; relative risk 1.87; 95% confidence interval (CI) 1.11 – 3.15). Amongst HIV-infected children, a CD4 less than 15% was the only independent predictor of mortality.
Conclusions
The diagnostic yield for PCP is more than 2.5 times higher on PCR than other detection methods. PCP is a very common cause of severe hypoxic pneumonia and is associated with high mortality in HIV-infected African infants.
doi:10.1186/1756-0500-7-26
PMCID: PMC3892044  PMID: 24410938
Pneumocystis pneumonia; HIV; Children; Prophylaxis; PCR; Diagnosis; Incidence
4.  Simple detection of the 5S ribosomal RNA of Pneumocystis carinii using in situ hybridisation. 
Journal of Clinical Pathology  1996;49(9):712-716.
AIMS: To investigate the effectiveness of digoxigenin incorporated double stranded DNA probes produced by the polymerase chain reaction (PCR), for the detection of Pneumocystis carinii, using in situ hybridisation (ISH). METHODS: Formalin fixed, paraffin wax embedded sections of 26 human lung samples from 11 patients with P carinii pneumonia (PCP), and 15 with various types of fungal and viral pneumonia, were obtained during necropsy or transbronchial lung biopsy. Three additional PCP induced rat lung samples were also tested. PCR probes were prepared using the digoxigenin labelling mixture, and they were amplified from the DNA of a PCP induced rat lung after administration of dexamethasone, on the basis that 5S ribosomal RNA sequences are identical in human and rat P carinii. ISH was performed using this probe, and visualised using the digoxigenin nucleic acid detection kit. An immunohistochemical study using anti-human Pneumocystis monoclonal antibody was also carried out in parallel. RESULTS: ISH positively stained eight (of eight) lung necropsy specimens from patients with PCP, three (of three) transbronchial lung biopsy specimens from patients with PCP, and none of the three PCP induced rat lung specimens. In contrast, none of the specimens from patients with pneumonia caused by Aspergillus sp (n = 5), Candida sp (n = 4), Cryptococcus sp (n = 2), mucormycosis (n = 2), or cytomegalovirus (n = 2) were positive on ISH or immunohistochemistry. CONCLUSIONS: Using a digoxigenin labelled PCR probe for the entire 5S rRNA sequence in conjunction with conventional staining, ISH is highly reactive and specific for the diagnosis of PCP.
Images
PMCID: PMC500718  PMID: 9038753
5.  Pneumocystis jirovecii Pneumonia in Tropical and Low and Middle Income Countries: A Systematic Review and Meta-Regression 
PLoS ONE  2013;8(8):e69969.
Objective
Pneumocystis jirovecii pneumonia (PCP), the commonest opportunistic infection in HIV-infected patients in the developed world, is less commonly described in tropical and low and middle income countries (LMIC). We sought to investigate predictors of PCP in these settings.
Design
Systematic review and meta-regression.
Methods
Meta-regression of predictors of PCP diagnosis (33 studies). Qualitative and quantitative assessment of recorded CD4 counts, receipt of prophylaxis and antiretrovirals, sensitivity and specificity of clinical signs and symptoms for PCP, co-infection with other pathogens, and case fatality (117 studies).
Results
The most significant predictor of PCP was per capita Gross Domestic Product, which showed strong linear association with odds of PCP diagnosis (p<0.0001). This was not explained by study design or diagnostic quality. Geographical area, population age, study setting and year of study also contributed to risk of PCP. Co-infection was common (444 episodes/1425 PCP cases), frequently with virulent organisms. The predictive value of symptoms, signs or simple tests in LMIC settings for diagnosis of PCP was poor. Case fatality was >30%; treatment was largely appropriate. Prophylaxis appeared to reduce the risk for development of PCP, however 24% of children with PCP were receiving prophylaxis. CD4 counts at presentation with PCP were usually <200×103/ml.
Conclusions
There is a positive relationship between GDP and risk of PCP diagnosis. Although failure to diagnose infection in poorer countries may contribute to this, we also hypothesise that poverty exposes at-risk patients to a wide range of infections and that the relatively non-pathogenic P. jirovecii is therefore under-represented. As LMIC develop economically they eliminate the conditions underlying transmission of virulent infection: P. jirovecii, ubiquitous in all settings, then becomes a greater relative threat.
doi:10.1371/journal.pone.0069969
PMCID: PMC3732248  PMID: 23936365
6.  Reduced carbon monoxide transfer factor (TLCO) in human immunodeficiency virus type I (HIV-I) infection as a predictor for faster progression to AIDS. 
Thorax  1993;48(5):481-485.
BACKGROUND--In addition to the acute fall in carbon monoxide transfer factor (TLCO) associated with Pneumocystis carinii pneumonia (PCP) or other opportunistic lung infections, reduced TLCO occurs in HIV-I seropositive individuals without active pulmonary disease. Abnormal TLCO, in the absence of lung disease, may be a surrogate marker of HIV-I induced immunosuppression and, therefore, a predictor for a more rapid progression to AIDS. METHODS--Eighty four individuals with AIDS, who had regular pulmonary function tests before the diagnosis of AIDS was made, were identified from a cohort of patients with HIV-I infection. None had evidence of active pulmonary disease at the time of initial pulmonary function testing. The relation between the time taken to progress to AIDS and initial pulmonary function tests was examined with life table survival analysis. RESULTS--Patients with a TLCO value of < 80% of predicted normal (n = 46) progressed significantly faster to AIDS, with a median time of 8.0 months compared with 16.5 months for those with a TLCO value of > or = 80% (n = 38). When stratified by AIDS defining diagnosis (PCP or non-PCP), median time to PCP was also significantly related to initial TLCO values (TLCO of < 80% = 9.0 months, TLCO of > or = 80% = 19.0 months). Reductions in other measurements of lung function (FEV1, FVC, KCO) were not temporally associated with the development of AIDS. CONCLUSIONS--HIV-I seropositive individuals with TLCO values of < 80% predicted and no evidence of lung disease progress more rapidly to AIDS than those with TLCO values of > or = 80%.
PMCID: PMC464497  PMID: 8322232
7.  AIDS in Africans living in London. 
Genitourinary Medicine  1995;71(6):358-362.
OBJECTIVES--To investigate the presentation of HIV infection and AIDS amongst Africans diagnosed with AIDS living in London. METHODS--Identification of all AIDS cases of African origin attending four HIV specialist centres in South London--Guy's, King's, St George's and St Thomas' Hospitals--up to March 1994, by retrospective review of case notes of all HIV positive patients. RESULTS--Of 86 patients (53 women, 33 men) studied, 59 (69%) were from Uganda. The most frequent AIDS-defining diagnoses were: Pneumocystis carinii pneumonia (PCP) 21%, tuberculosis (TB) 20% (extrapulmonary TB 14%, pulmonary TB 6%), cerebral toxoplasmosis 14%, oesophageal candida 13%, cryptococcal meningitis 11%, wasting 6%, herpes simplex infection > 1 month 5%, Kaposi's sarcoma 5%, other 6%. Cytomegalovirus retinitis was diagnosed in one case. Late presentation was common; 70% were diagnosed HIV positive when admitted to hospital. The diagnosis of AIDS was coincident with a first positive HIV test result in 61%. The mean CD4 counts at both HIV and AIDS diagnoses were similar in both men and women: 87 x 10(6)/l and 74 x 10(6)/l in men and 99 x 10(6)/l and 93 x 10(6)/l in women respectively. Overall, TB 21 (24%) (extrapulmonary TB 12, pulmonary TB 9) was either the AIDS-defining diagnosis or was detected within three months of this event. Sixty-two per cent of TB cases were diagnosed within twelve months of entry to the UK compared to 34% of all other AIDS cases. The prevalence of STD was very low; genital herpes was the commonest STD: 17% of the women, 9% men; 28% of the men and 11% of the women tested had a positive TPHA test. In cases known to be HIV-positive prior to an AIDS diagnosis, 41% took prophylaxis for PCP and 45% had taken zidovudine (ZDV). Forty two of the study participants had 89 children: 59 of these children had mothers in the study. Overall, 37 (42%) of the children had lost at least one parent at the time of data assessment. CONCLUSIONS--PCP and TB were the most common initial AIDS-defining diagnoses. The majority of TB cases were diagnosed within 12 months of entry to the UK. An AIDS-defining diagnosis was the first manifestation of HIV-related illness in the majority of patients. Because of late presentation to medical services, access to treatments for HIV infection and prophylaxis against opportunistic infections was limited. Extending the role of clinics and staff into the community might facilitate both earlier presentation and access to services. Future provision of local services will need to be sensitive to the requirements of individuals from different cultures and backgrounds.
PMCID: PMC1196104  PMID: 8566973
8.  Survival and treatment of AIDS patients 1984-1993: experience of a smaller east London HIV centre. 
Genitourinary Medicine  1997;73(1):44-48.
OBJECTIVE: To assess changes in survival from diagnosis of AIDS for patients managed in a small East London HIV clinic and the impact of therapeutic interventions on these survival patterns. DESIGN: Prospective observational study. SETTING: Grahame Hayton Unit, Royal London Hospital. SUBJECTS: 156 AIDS patients managed between 1984 and 1993. MAIN OUTCOME MEASURE: Survival from diagnosis of AIDS. RESULTS: Median survival for those diagnosed with AIDS before 1 January 1987 was 9.4 months compared with 27.2 months after 1 January 1987 (logrank chi 2 = 10.3, p = 0.001): CD4 count at time of AIDS and treatment with zidovudine or PCP prophylaxis were significantly associated with survival from time of AIDS. Of the 156 AIDS patients, 93 had been treated with zidovudine sometime during their follow up, 60 had received primary and 50 secondary Pneumocystis carinii pneumonia (PCP) prophylaxis. After controlling for gender, sexual orientation, age at time of AIDS, CD4 count at time of AIDS, diagnosis when first presenting to the clinic (AIDS/non-AIDS) and year of AIDS diagnosis, all patients who received either zidovudine or PCP prophylaxis had significant reductions in the risk of dying compared with those who received neither PCP prophylaxis nor zidovudine: a reduction in risk of dying between 71% (95% CI 40% to 86%) and 83% (95% CI 50% to 94%) was observed depending on the combination of zidovudine and PCP prophylaxis. CONCLUSION: A debate is currently taking place about the format and value of HIV service provision with increasing numbers of HIV infected individuals managed at smaller HIV clinics. Larger clinics concentrate clinical expertise on a single site and facilitate clinical trials. Smaller well run HIV units staffed by competent health professionals not only provide clinical outcomes similar to those obtained in the larger centres, but may also allow a more informal and intimate setting for HIV infected individuals who want to be treated nearer their area of residence.
PMCID: PMC1195759  PMID: 9155555
9.  Decreased Production of Local Immunoglobulin A to Pneumocystis carinii in Bronchoalveolar Lavage Fluid from Human Immunodeficiency Virus-Positive Patients 
Infection and Immunity  2000;68(3):1054-1060.
An enzyme-linked immunosorbent assay and a Western blot analysis were developed to study the antibody response to Pneumocystis carinii in serum and bronchoalveolar lavage fluid from 27 human immunodeficiency virus 27 (HIV)-infected patients with P. carinii pneumonia (Pcp), 32 patients without Pcp, and 51 HIV-negative controls. Urea was used for the correct dilution of epithelial lining fluid, and albumin was used to evaluate transudation from plasma for the assessment of local production of antibodies to P. carinii. By contrast with those of immunoglobulin G (IgG), IgA responses to P. carinii were increased in serum from HIV-positive patients compared to negative controls. Local production of antibodies to P. carinii, especially IgA, was decreased in patients with Pcp. In a study of 10 patients of each group, IgG and IgA responses to gp116 from P. carinii were lower in patients with Pcp than in other groups. These results suggest that, in addition to alveolar macrophages, local antibodies may play a role in host defense against P. carinii.
PMCID: PMC97248  PMID: 10678907
10.  Diagnosis of Pneumocystis carinii pneumonia in HIV antibody positive patients by simple outpatient assessments. 
Thorax  1992;47(12):1005-1009.
BACKGROUND: As increasing numbers of patients with immunosuppression induced by the human immunodeficiency virus (HIV) present with respiratory symptoms it is important to differentiate Pneumocystis carinii pneumonia from other chest diseases rapidly and start treatment early. The management of pneumocystis pneumonia could be improved if clinicians could diagnose this condition confidently on the basis of simple clinical assessments. METHODS: Three hundred and eighteen patients with evidence of immunosuppression due to HIV infection and suspected pneumocystis pneumonia were investigated. A clinical history was taken and arterial blood gas analysis, chest radiography, oximetry during exercise, and sputum induction or bronchoscopy (or both) were performed. RESULTS: Pneumocystis pneumonia was confirmed microscopically from induced sputum or bronchoalveolar lavage fluid in 154 patients; 118 had other chest disease. The remaining 46 patients had no definitive diagnosis. The best single independent predictors of a diagnosis of pneumocystis pneumonia were exercise induced oxygen desaturation and obvious interstitial infiltrates on the chest radiograph (odds ratios of 4.88 and 5.44 respectively). The symptom triad of exertional dyspnoea, cough, and fevers; the absence of pneumocystis pneumonia prophylaxis; and resting arterial hypoxaemia were less predictive (odds ratio 2.07, 3.72, and 0.69). An algorithm was developed that gave a positive predictive value for confirmed pneumocystis pneumonia of 95% and also identified those patients with a very small chance of having pneumocystis pneumonia (negative predictive value 85%). CONCLUSIONS: The diagnosis of an initial episode of pneumocystis pneumonia can be confidently made in a large proportion of immunosuppressed patients with respiratory symptoms on the basis of clinical symptoms, the absence of prophylaxis, chest radiographic appearances, and oxygen desaturation during exercise as shown by oximetry. Using these simple features clinicians can rapidly assign patients to the appropriate type of management at presentation.
PMCID: PMC1021090  PMID: 1494761
11.  The unmasking of Pneumocystis jiroveci pneumonia during reversal of immunosuppression: case reports and literature review 
Background
Pneumocystis jiroveci pneumonia (PCP) is an important opportunistic infection among immunosuppressed patients, especially in those infected with human immunodeficiency virus (HIV). The clinical presentation of PCP in immunosuppressed patients have been well-reported in the literature. However, the clinical importance of PCP manifesting in the setting of an immunorestitution disease (IRD), defined as an acute symptomatic or paradoxical deterioration of a (presumably) preexisting infection, which is temporally related to the recovery of the immune system and is due to immunopathological damage associated with the reversal of immunosuppressive processes, has received relatively little attention until recently.
Case presentation
We aim to better define this unique clinical syndrome by reporting two cases of PCP manifesting acutely with respiratory failure during reversal of immunosuppression in non-HIV infected patients, and reviewed the relevant literature. We searched our databases for PCP cases manifesting in the context of IRD according to our predefined case definition, and reviewed the case notes retrospectively. A comprehensive search was performed using the Medline database of the National Library of Medicine for similar cases reported previously in the English literature in October 2003. A total of 28 non-HIV (excluding our present case) and 13 HIV-positive patients with PCP manifesting as immunorestitution disease (IRD) have been reported previously in the literature. During immunorestitution, a consistent rise in the median CD4 lymphocyte count (28/μL to 125/μL), with a concomitant fall in the median HIV viral load (5.5 log10 copies/ml to 3.1 log10 copies/ml) was observed in HIV-positive patients who developed PCP. A similar upsurge in peripheral lymphocyte count was observed in our patients preceding the development of PCP, as well as in other non-HIV immunosuppressed patients reported in the literature.
Conclusions
PCP manifesting as IRD may be more common than is generally appreciated. Serial monitoring of total lymphocyte or CD4 count could serve as a useful adjunct to facilitate the early diagnosis and pre-emptive treatment of this condition in a wide range of immunosuppressed hosts, especially in the presence of new pulmonary symptoms and/or radiographic abnormalities compatible with the diagnosis.
doi:10.1186/1471-2334-4-57
PMCID: PMC539247  PMID: 15588295
12.  Low Prevalence of Pneumocystis pneumonia (PCP) but High Prevalence of Pneumocystis dihydropteroate synthase (dhps) Gene Mutations in HIV-Infected Persons in Uganda 
PLoS ONE  2012;7(11):e49991.
Pneumocystis jirovecii pneumonia (PCP) is an important opportunistic infection in patients infected with HIV, but its burden is incompletely characterized in those areas of sub-Saharan Africa where HIV is prevalent. We explored the prevalence of both PCP in HIV-infected adults admitted with pneumonia to a tertiary-care hospital in Uganda and of putative P. jirovecii drug resistance by mutations in fungal dihydropteroate synthase (dhps) and dihydrofolate reductase (dhfr). In 129 consecutive patients with sputum smears negative for mycobacteria, 5 (3.9%) were diagnosed with PCP by microscopic examination of Giemsa-stained bronchoalveolar lavage fluid. Concordance was 100% between Giemsa stain and PCR (dhps and dhfr). PCP was more prevalent in patients newly-diagnosed with HIV (11.4%) than in patients with known HIV (1.1%; p = 0.007). Mortality at 2 months after discharge was 29% overall: 28% among PCP-negative patients, and 60% (3 of 5) among PCP-positive patients. In these 5 fungal isolates and an additional 8 from consecutive cases of PCP, all strains harbored mutant dhps haplotypes; all 13 isolates harbored the P57S mutation in dhps, and 3 (23%) also harbored the T55A mutation. No non-synonymous dhfr mutations were detected. PCP is an important cause of pneumonia in patients newly-diagnosed with HIV in Uganda, is associated with high mortality, and putative molecular evidence of drug resistance is prevalent. Given the reliability of field diagnosis in our cohort, future studies in sub-Saharan Africa can investigate the clinical impact of these genotypes.
doi:10.1371/journal.pone.0049991
PMCID: PMC3500344  PMID: 23166805
13.  Pneumocystis Pneumonia in Hospitalized Patients; A Detailed Examination of Symptoms, Management, and Outcomes in HIV-infected and HIV-uninfected Persons 
Background
Pneumocystis jiroveci pneumonia is a life-threatening infection for immunocompromised individuals. There are robust data and clear guidelines for prophylaxis and treatment of HIV-related Pneumocystis jiroveci pneumonia (HIV-PCP), yet few data and no guidelines for non-HIV related Pneumocystis pneumonia (NH-PCP). We postulated that prevention and inpatient management of HIV-PCP differed from NH-PCP.
Methods
We performed a retrospective case review of all pathologically confirmed cases of PCP seen at the University of Alabama Medical Center from 1996 to 2008. Data on clinical presentation, hospital course, and outcome were collected using a standardized data collection instrument. Bivariate analysis compared prophylaxis, adjunctive corticosteroids, and clinical outcomes between patients with HIV-PCP and NH-PCP.
Results
Our analysis of the cohort included 97 cases of PCP; 65 HIV and 32 non-HIV cases. Non-HIV cases rarely received primary prophylaxis (4% vs. 38%, p=0.01) and received appropriate antibiotics later in the course of hospitalization (5.2 vs 1.1 days, P<0.005). Among transplant patients, NH-PCP was diagnosed a mean of 1,066 days after transplantation and most patients were on low-dose corticosteroids (87%) at the time of disease onset. No significant differences in adjunctive corticosteroid use (69% vs. 77%, p=0.39) and 90-day mortality (41% vs. 28%, p=0.20) were detected.
Conclusions
Patients who have undergone organ or stem cell transplant remain at risk for PCP for many years after transplantation. In our cohort, patients who developed NH-PCP were rarely given prophylaxis and initiation of appropriate antibiotics was significantly delayed compared to cases of HIV-PCP. Medical providers should be aware of the ongoing risk for NH-PCP, even late after transplantation, and consider more aggressive approaches to both prophylaxis and earlier empiric therapy for PCP.
doi:10.1111/j.1399-3062.2012.00739.x
PMCID: PMC3889465  PMID: 22548840
Pneumocystis Pneumonia; Transplant; Infectious Complications
14.  Usefulness of PCR for diagnosis of Pneumocystis carinii pneumonia in different patient groups. 
Journal of Clinical Microbiology  1997;35(6):1445-1449.
Pneumocystis carinii pneumonia (PCP) is one of the most predominant opportunistic infectious diseases in patients with AIDS. Nested PCR has been described as a sensitive and specific tool for detecting P. carinii DNA in clinical specimens. Little is known about the correlation of positive PCR results and clinical evidence of PCP in patients with different forms of immunosuppression. One hundred and thirty-six sputum samples, 26 tracheal-bronchial aspirate samples, 35 bronchoalveolar lavage samples, and 11 lung biopsy samples from (i) human immunodeficiency virus (HIV)-infected patients with AIDS, (ii) immunocompromised patients with leukemia or lymphoma, and (iii) immunocompetent control patients were investigated by a nested PCR amplifying DNA from the mitochondrial large subunit of P. carinii. All patients suffered from acute episodes of respiratory disease. The resulting data were correlated with clinical evidence of PCP. A high degree of association of positive P. carinii PCR results and clinical evidence of PCP in HIV-infected patients with AIDS was found. When calculated for bronchoalveolar lavage and lung biopsy samples, the positive and the negative predictive values of P. carinii PCR for PCP diagnosis in HIV-infected patients with AIDS were 1 and the specificity and the sensitivity were 100%. In contrast, in the group of patients with leukemia or lymphoma, the positive predictive value of the nested PCR for these materials was found to be as low as 0.09, the negative predictive value was 0.73, the specificity was 44.4%, and the sensitivity was 25.0%. No P. carinii DNA could be detected in specimens from immunocompetent patients. In summary, in contrast to patients with leukemia and lymphoma, nested PCR seems to be a sensitive and specific tool for PCP diagnosis in HIV-infected patients with AIDS.
PMCID: PMC229764  PMID: 9163459
15.  The role of a nested polymerase chain reaction in the diagnosis of Pneumocystis carinii pneumonia 
Clinical Molecular Pathology  1995;48(6):M347-M350.
Aim—To compare the techniques and results of a nested PCR and an immunofluorescence assay (IFA) for the detection of Pneumocystis carinii infection; to consider the role of the nested PCR in the diagnosis of P carinii pneumonia (PCP).
Methods—Serial dilutions of two known P carinii positive samples were tested by IFA and PCR to determine their relative sensitivities. Seventy eight respiratory samples (15 from 11 patients with HIV infection/acquired immunodeficiency syndrome (AIDS) and 63 from 42 patients with other forms of immunodeficiency) were tested using both assays, and the costs and technical requirements of each assay were assessed.
Results—The PCR had a greater relative sensitivity over the IFA of 2 × 101 to 2 × 103 fold in a postmortem lung sample and 2 × 105 to 2 × 106 fold in a bronchoalveolar lavage sample from a patient with PCP. P carinii was detected in all 15 samples from the patients with HIV/AIDS by both IFA and PCR. Of the 63 samples from the patients with immunodeficiencies other than HIV/AIDS, the PCR was more sensitive than IFA.
Conclusions—The nested PCR is a more sensitive assay than the IFA. It may be useful in the diagnosis of PCP in patients with immunodeficiencies other than HIV/AIDS. Similarly, PCR may be of benefit for this patient group as less invasive specimens are needed. PCR has an increasing role to play in the diagnosis of PCP in the routine laboratory.
PMCID: PMC408003  PMID: 16696036
Pneumocystis carinii; PCR; immunofluorescence assay; acquired immunodeficiency syndrome
16.  Evaluation of Diagnostic Value and Epidemiological Implications of PCR for Pneumocystis carinii in Different Immunosuppressed and Immunocompetent Patient Groups 
Journal of Clinical Microbiology  2000;38(4):1461-1467.
To evaluate the value of single and nested PCRs for diagnosis of Pneumocystis carinii pneumonia (PCP) in a variety of respiratorily distressed patient groups, 574 respiratory samples from 334 patients (89 human immunodeficiency virus [HIV]-positive patients, 61 transplant recipients, 66 malignancy patients, 34 otherwise immunosuppressed patients, and 84 immunocompetent patients) were prospectively examined by microscopy and single and nested PCRs. The resulting data were correlated with clinical evidence of PCP. Microscopy and single PCR of bronchoalveolar lavage (BAL) specimens from HIV patients were 100% sensitive and specific in detecting PCP, whereas nested PCR, although being 100% sensitive, reached a specificity of only 97.5%. In the three non-HIV immunosuppressed patient groups, both single and nested PCR invariably produced lower positive predictive values than microscopy. Among immunocompetent patients, the positive predictive values of both PCRs were 0%. Therefore, the diagnostic values of the PCR methods tested do not seem to offer any additional advantage compared to that of conventional microscopy for these patient groups. However, nested PCR identified a significant percentage of clinically silent P. carinii colonizations in about 17 to 20% of immunocompetent and immunosuppressed non-HIV patients.
PMCID: PMC86465  PMID: 10747126
17.  Quantitative and qualitative comparison of DNA amplification by PCR with immunofluorescence staining for diagnosis of Pneumocystis carinii pneumonia. 
Journal of Clinical Pathology  1993;46(2):140-144.
AIM: To compare the results of DNA amplification by the polymerase chain reaction (PCR) with immunofluorescence staining for detecting Pneumocystis carinii in bronchoalveolar lavage specimens taken from symptomatic HIV seropositive patients with suspected P carinii pneumonia (PCP). METHODS: Bronchoalveolar lavage specimens were obtained from 28 symptomatic HIV seropositive patients. Specimens were examined for P carinii using immunofluorescence, and by DNA amplification with PCR to obtain results on gel electrophoresis (gel) and a more sensitive Southern hybridisation (blot) technique. Specimens positive by immunofluorescence and gel electrophoresis were serially diluted to a 10(-6) concentration and each dilution strength tested for P carinii using PCR to compare quantitatively immunofluorescence with PCR. RESULTS: Of the 28 specimens analysed, 18 were negative for P carinii by both immunofluorescence and PCR, two were positive only by the blot technique of PCR, four were equivocally positive and four unequivocally positive by immunofluorescence. Three of the four equivocally positive patients tested by immunofluorescence were negative for P carinii by PCR, although one was positive by PCR (blot) technique. This patient had clinically confirmed PCP. Of the four unequivocally positive patients tested by immunofluorescence, three were gel and blot positive by PCR and had PCP clinically, but one was negative by both gel and blot techniques, although the patient certainly had PCP on clinical grounds. This patient had received nine days of treatment with high dose co-trimoxazole before bronchoalveolar lavage specimens were obtained. The three specimens positive by gel and blot techniques remained gel positive down to dilutions of between 10(-4) and 10(-6). CONCLUSIONS: PCR results may become negative soon after starting treatment for PCP. Specimens should therefore be taken before, or soon after, starting treatment. PCR seems to be between 10(4) and 10(6) times more sensitive than immunofluorescence.
Images
PMCID: PMC501145  PMID: 8459034
18.  Non-HIV Pneumocystis pneumonia: do conventional community-acquired pneumonia guidelines under estimate its severity? 
Background
Non-HIV Pneumocystis pneumonia (PCP) can occur in immunosuppressed patients having malignancy or on immunosuppressive agents. To classify severity, the A-DROP scale proposed by the Japanese Respiratory Society (JRS), the CURB-65 score of the British Respiratory Society (BTS) and the Pneumonia Severity Index (PSI) of the Infectious Diseases Society of America (IDSA) are widely used in patients with community-acquired pneumonia (CAP) in Japan. To evaluate how correctly these conventional prognostic guidelines for CAP reflect the severity of non-HIV PCP, we retrospectively analyzed 21 patients with non-HIV PCP.
Methods
A total of 21 patients were diagnosed by conventional staining and polymerase chain reaction (PCR) for respiratory samples with chest x-ray and computed tomography (CT) findings. We compared the severity of 21 patients with PCP classified by A-DROP, CURB-65, and PSI. Also, patients’ characteristics, clinical pictures, laboratory results at first visit or admission and intervals from diagnosis to start of specific-PCP therapy were evaluated in both survivor and non-survivor groups.
Results
Based on A-DROP, 18 patients were classified as mild or moderate; respiratory failure developed in 15 of these 18 (83.3%), and 7/15 (46.7%) died. Based on CURB-65, 19 patients were classified as mild or moderate; respiratory failure developed in 16/19 (84.2%), and 8 of the 16 (50%) died. In contrast, PSI classified 14 as severe or extremely severe; all of the 14 (100%) developed respiratory failure and 8/14 (57.1%) died. There were no significant differences in laboratory results in these groups. The time between the initial visit and diagnosis, and the time between the initial visit and starting of specific-PCP therapy were statistically shorter in the survivor group than in the non-survivor group.
Conclusions
Conventional prognostic guidelines for CAP could underestimate the severity of non-HIV PCP, resulting in a therapeutic delay resulting in high mortality. The most important factor to improve the mortality of non-HIV PCP is early diagnosis and starting of specific-PCP therapy as soon as possible.
doi:10.1186/2049-6958-7-2
PMCID: PMC3415119  PMID: 22958656
Community acquired pneumonia; Guidelines; Mortality; Non-HIV Pneumocystis pneumonia
19.  Alveolar permeability in HIV antibody positive patients with Pneumocystis carinii pneumonia. 
Genitourinary Medicine  1987;63(4):268-270.
Pulmonary permeability was assessed using the technique of 99mTc (technetium-99m) diethylene triamene pentacetic acid (DTPA) aerosol transfer in 10 patients who had antibodies to human immunodeficiency virus (HIV) and were non-smokers and in 20 HIV antibody positive smokers. Five patients had Pneumocystis carinii pneumonia (PCP) proved by transbronchial lung biopsy; four were non-smokers and one a smoker. Two findings emerged: patients with PCP had greater epithelial permeability than non-smokers and smokers; and the permeability curves were monophasic in smokers and non-smokers, but biphasic in patients with PCP. The biphasic curve observed is indicative of diffuse alveolar damage and might be useful to predict PCP in patients with antibodies to HIV who have normal chest radiographs. As the study was of only five patients with PCP, however, further studies are necessary to confirm this observation.
PMCID: PMC1194081  PMID: 3308684
20.  Serologic responses to Pneumocystis Proteins in Human Immunodeficiency Virus Patients With and Without Pneumocystis jirovecii Pneumonia 
Background
Immune responses to Pneumocystis jirovecii are not well understood in HIV infection, but antibody responses to proteins may be useful as a marker of Pneumocystis risk or presence of Pneumocystis pneumonia (PcP).
Design
Retrospective analysis of a prospective cohort
Methods
Enzyme-linked immunosorbent assays of antibodies to recombinant Pneumocystis proteins of major surface glycoprotein fragments (MsgC1, C3, C8, and C9) and of antibody titers to recombinant kexin protein (KEX1) were performed on three sequential serum samples up to 18 months prior to and three samples after first AIDS-defining illness from Multicenter AIDS Cohort Study participants and compared between those who had PcP or a non-PcP AIDS-defining illness.
Results
Fifty-four participants had PcP and 47 had a non-PcP AIDS-defining illness. IgG levels to MsgC fragments were similar between groups prior to first AIDS-defining illness, but the PcP group had higher levels of IgG to MsgC9 (median units/ml 50.2 vs. 22.2, p=0.047) post-illness. Participants with PcP were more likely to have an increase in MsgC3 (OR 3.9, p=0.02), MsgC8 (OR 5.5, p=0.001), and MsgC9 (OR 4.0, p=0.007). The PcP group was more likely to have low KEX1 IgG prior to development of PcP (OR 3.6, p=0.048) independent of CD4 cell count and to have an increase in high IgG titers to KEX1 after PcP.
Conclusion
HIV-infected individuals develop immune responses to both Msg and kexin proteins after PcP. Low KEX1 IgG titers may be a novel marker of future PcP risk before CD4 cell count has declined below 200 cells/μl.
doi:10.1097/QAI.0b013e3182167516
PMCID: PMC3150634  PMID: 21372726
HIV; Acquired Immunodeficiency Syndrome; Pneumocystis; serology
21.  Development and Evaluation of a Quantitative, Touch-Down, Real-Time PCR Assay for Diagnosing Pneumocystis carinii Pneumonia 
Journal of Clinical Microbiology  2002;40(2):490-494.
A rapid (time to completion, <4 h, including DNA extraction) and quantitative touch-down (QTD) real-time diagnostic Pneumocystis carinii PCR assay with an associated internal control was developed, using fluorescence resonance energy transfer (FRET) probes for detection. The touch-down procedure significantly increased the sensitivity of the assay compared to a non-touch-down procedure. Tenfold serial dilutions of a cloned target were used as standards for quantification. P. carinii DNA has been detected in respiratory specimens from patients with P. carinii pneumonia (PCP) and from patients without clinical evidence of PCP. The latter probably represents colonization or subclinical infection. It is logical to hypothesize that quantification might prove helpful in distinguishing between infected and colonized patients: the latter group would have lower copy numbers than PCP patients. A blinded retrospective study of 98 respiratory samples (49 lower respiratory tract specimens and 49 oral washes), from 51 patients with 24 episodes of PCP and 34 episodes of other respiratory disease, was conducted. PCR-positive samples from colonized patients contained a lower concentration of P. carinii DNA than samples from PCP patients: lower respiratory tract samples from PCP and non-PCP patients contained a median of 938 (range, 2.4 to 1,040,000) and 2.6 (range, 0.3 to 248) (P < 0.0004) copies per tube, respectively. Oral washes from PCP and non-PCP patients contained a median of 49 (range, 2.1 to 2,595) and 6.5 (range, 2.2 to 10) (P < 0.03) copies per tube, respectively. These data suggest that this QTD PCR assay can be used to determine if P. carinii is present in respiratory samples and to distinguish between colonization and infection.
doi:10.1128/JCM.40.2.490-494.2002
PMCID: PMC153364  PMID: 11825961
22.  Critical care management and outcome of severe Pneumocystis pneumonia in patients with and without HIV infection 
Critical Care  2008;12(1):R28.
Background
Little is known about the most severe forms of Pneumocystis jiroveci pneumonia (PCP) in HIV-negative as compared with HIV-positive patients. Improved knowledge about the differential characteristics and management modalities could guide treatment based on HIV status.
Methods
We retrospectively compared 72 patients (73 cases, 46 HIV-positive) admitted for PCP from 1993 to 2006 in the intensive care unit (ICU) of a university hospital.
Results
The yearly incidence of ICU admissions for PCP in HIV-negative patients increased from 1993 (0%) to 2006 (6.5%). At admission, all but one non-HIV patient were receiving corticosteroids. Twenty-three (85%) HIV-negative patients were receiving an additional immunosuppressive treatment. At admission, HIV-negative patients were significantly older than HIV-positive patients (64 [18 to 82] versus 37 [28 to 56] years old) and had a significantly higher Simplified Acute Physiology Score (SAPS) II (38 [13 to 90] versus 27 [11 to 112]) but had a similar PaO2/FiO2 (arterial partial pressure of oxygen/fraction of inspired oxygen) ratio (160 [61 to 322] versus 183 [38 to 380] mm Hg). Ventilatory support was required in a similar proportion of HIV-negative and HIV-positive cases (78% versus 61%), with a similar proportion of first-line non-invasive ventilation (NIV) (67% versus 54%). NIV failed in 71% of HIV-negative and in 13% of HIV-positive patients (p < 0.01). Mortality was significantly higher in HIV-negative than HIV-positive cases (48% versus 17%). The HIV-negative status (odds ratio 3.73, 95% confidence interval 1.10 to 12.60) and SAPS II (odds ratio 1.07, 95% confidence interval 1.02 to 1.12) were independently associated with mortality at multivariate analysis.
Conclusion
The yearly incidence of ICU admissions for PCP in HIV-negative patients in our unit increased from 1993 to 2006. The course of the disease and the outcome were worse in HIV-negative patients. NIV often failed in HIV-negative cases, suggesting that NIV must be watched closely in this population.
doi:10.1186/cc6806
PMCID: PMC2374632  PMID: 18304356
23.  Serum Antibody Levels to the Pneumocystis jirovecii Major Surface Glycoprotein in the Diagnosis of P. jirovecii Pneumonia in HIV+ Patients 
PLoS ONE  2010;5(12):e14259.
Background
Pneumocystis jirovecii remains an important cause of fatal pneumonia (Pneumocystis pneumonia or PcP) in HIV+ patients and other immunocompromised hosts. Despite many previous attempts, a clinically useful serologic test for P. jirovecii infection has never been developed.
Methods/Principal Findings
We analyzed serum antibody responses to the P. jirovecii major surface glycoprotein recombinant fragment C1 (MsgC1) in 110 HIV+ patients with active PcP (cases) and 63 HIV+ patients with pneumonia due to other causes (controls) by an enzyme-linked immunosorbent assay (ELISA). The cases had significantly higher IgG and IgM antibody levels to MsgC1 than the controls at hospital admission (week 0) and intervals up to at least 1 month thereafter. The sensitivity, specificity and positive predictive value (PPV) of IgG antibody levels increased from 57.2%, 61.7% and 71.5% at week 0 to 63.4%, 100%, and 100%, respectively, at weeks 3–4. The sensitivity, specificity and PPV of IgM antibody levels rose from 59.7%, 61.3%, and 79.3% at week 0 to 74.6%, 73.7%, and 89.8%, respectively, at weeks 3–4. Multivariate analysis revealed that a diagnosis of PcP was the only independent predictor of high IgG and IgM antibody levels to MsgC1. A high LDH level, a nonspecific marker of lung damage, was an independent predictor of low IgG antibody levels to MsgC1.
Conclusions/Significance
The results suggest that the ELISA shows promise as an aid to the diagnosis of PCP in situations where diagnostic procedures cannot be performed. Further studies in other patient populations are needed to better define the usefulness of this serologic test.
doi:10.1371/journal.pone.0014259
PMCID: PMC3000336  PMID: 21151564
24.  Transmission of Pneumocystis carinii from patients to hospital staff 
Thorax  1997;52(5):422-424.
BACKGROUND: An extrahuman reservoir of human pathogenic Pneumocystis carinii remains unknown. Host to host transmission has been described in animal studies and in cluster cases among immunodeficient patients. P carinii DNA has recently been detected in air filters from inpatient and outpatient rooms in departments of infectious diseases managing patients with P carinii pneumonia (PCP), suggesting the airborne route of transmission. Exposure of staff to P carinii may occur in hospital departments treating patients with PCP. METHODS: Exposure to P carinii was detected by serological responses to human P carinii by ELISA, Western blotting, and indirect immunofluorescence in 64 hospital staff with and 79 staff without exposure to patients with PCP from Denmark and Sweden. DNA amplification of oropharyngeal washings was performed on 20 Danish staff with and 20 staff without exposure to patients with PCP. RESULTS: There was no significant difference in the frequency or level of antibodies to P carinii between staff exposed and those unexposed to patients with PCP. None of the hospital staff had detectable P carinii DNA in oropharyngeal washings. CONCLUSIONS: There is no difference in antibodies and no detectable P carinii DNA in oropharyngeal washings, which suggests that immunocompetent staff treating patients with PCP are not a potentially infectious source of P carinii for immunocompromised patients. 



PMCID: PMC1758557  PMID: 9176532
25.  Multicenter, Prospective Clinical Evaluation of Respiratory Samples from Subjects at Risk for Pneumocystis jirovecii Infection by Use of a Commercial Real-Time PCR Assay▿† 
Journal of Clinical Microbiology  2011;49(5):1872-1878.
Pneumocystis jirovecii pneumonia (PCP) is a common opportunistic infection. Microscopic diagnosis, including diagnosis using the Merifluor-Pneumocystis direct fluorescent antigen (MP-DFA) test, has limitations. Real-time PCR may assist in diagnosis, but no commercially validated real-time PCR assay has been available to date. MycAssay Pneumocystis is a commercial assay that targets the P. jirovecii mitochondrial large subunit (analytical detection limit, ≤3.5 copies/μl of sample). A multicenter trial recruited 110 subjects: 54 with transplants (40 with lung transplants), 32 with nonmalignant conditions, 13 with leukemia, and 11 with solid tumors; 9 were HIV positive. A total of 110 respiratory samples (92% of which were bronchoalveolar lavage [BAL] specimens) were analyzed by PCR. Performance was characterized relative to investigator-determined clinical diagnosis of PCP (including local diagnostic tests), and PCR results were compared with MP-DFA test results for 83 subjects. Thirteen of 14 subjects with PCP and 9/96 without PCP (including 5 undergoing BAL surveillance after lung transplantation) had positive PCR results; sensitivity, specificity, and positive and negative predictive values (PPV and NPV, respectively) were 93%, 91%, 59%, and 99%, respectively. Fourteen of 83 subjects for whom PCR and MP-DFA test results were available had PCP; PCR sensitivity, specificity, PPV, and NPV were 93%, 90%, 65%, and 98%, respectively, and MP-DFA test sensitivity, specificity, PPV, and NPV were 93%, 100%, 100%, and 98%. Of the 9 PCR-positive subjects without PCP, 1 later developed PCP. The PCR diagnostic assay compares well with clinical diagnosis using nonmolecular methods. Additional positive results compared with the MP-DFA test may reflect low-level infection or colonization.
doi:10.1128/JCM.02390-10
PMCID: PMC3122670  PMID: 21367988

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