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1.  Improved survival for HIV infected patients with severe Pneumocystis jirovecii pneumonia is independent of highly active antiretroviral therapy 
Thorax  2006;61(8):716-721.
Background
Despite a decline in incidence of Pneumocystis jirovecii pneumonia (PCP), severe PCP continues to be a common cause of admission to the intensive care unit (ICU) where mortality remains high. A study was undertaken to examine the outcome from intensive care for patients with PCP and to identify prognostic factors.
Methods
A retrospective cohort study was conducted of HIV infected adults admitted to a university affiliated hospital ICU between November 1990 and October 2005. Case note review collected information on demographic variables, use of prophylaxis and highly active antiretroviral therapy (HAART), and hospital course. The main outcome was 1 month mortality, either on the ICU or in hospital.
Results
Fifty nine patients were admitted to the ICU on 60 occasions. Thirty four patients (57%) required mechanical ventilation. Overall mortality was 53%. No patient received HAART before or during ICU admission. Multivariate analysis showed that the factors associated with mortality were the year of diagnosis (before mid 1996 (mortality 71%) compared with later (mortality 34%; p = 0.008)), age (p = 0.016), and the need for mechanical ventilation and/or development of pneumothorax (p = 0.031). Mortality was not associated with sex, ethnicity, prior receipt of sulpha prophylaxis, haemoglobin, serum albumin, CD4 count, Pao2, A‐ao2 gradient, co‐pathology in bronchoscopic lavage fluid, medical co‐morbidity, APACHE II score, or duration of mechanical ventilation.
Conclusions
Observed improved outcomes from severe PCP for patients admitted to the ICU occurred in the absence of intervention with HAART and probably reflect general improvements in ICU management of respiratory failure and ARDS rather than improvements in the management of PCP.
doi:10.1136/thx.2005.055905
PMCID: PMC2104703  PMID: 16601092
AIDS; intensive care; mechanical ventilation;  Pneumocystis jirovecii ; opportunistic infections; respiratory failure
2.  Early Predictors of Mortality from Pneumocystis jirovecii Pneumonia in HIV-Infected Patients: 1985–2006 
Background
Pneumocystis jirovecii pneumonia (PCP) remains the leading cause of opportunistic infection among human immunodeficiency virus (HIV)–infected persons. Previous studies of PCP that identified case-fatality risk factors involved small numbers of patients, were performed over few years, and often focused on patients who were admitted to the intensive care unit.
Objective
The objective of this study was to identify case-fatality risk factors present at or soon after hospitalization among adult HIV-infected patients admitted to University College London Hospitals (London, United Kingdom) from June 1985 through June 2006.
Patients and Methods
We performed a review of case notes for 494 consecutive patients with 547 episodes of laboratory-confirmed PCP.
Results
Overall mortality was 13.5%. Mortality was 10.1% for the period from 1985 through 1989, 16.9% for the period from 1990 through June 1996, and 9.7% for the period from July 1996 through 2006 (P = .142). Multivariate analysis identified factors associated with risk of death, including increasing patient age (adjusted odds ratio [AOR], 1.54; 95% confidence interval [CI], 1.11–2.23; P = .011), subsequent episode of PCP (AOR, 2.27; 95% CI, 1.14–4.52; P = .019), low hemoglobin level at hospital admission (AOR, 0.70; 95% CI, 0.60–0.83; P < .001), low partial pressure of oxygen breathing room air at hospital admission (AOR, 0.70; 95% CI, 0.60–0.81; P < .001), presence of medical comorbidity (AOR, 3.93; 95% CI, 1.77–8.72; P = .001), and pulmonary Kaposi sarcoma (AOR, 6.95; 95% CI, 2.26–21.37; P =.001). Patients with a first episode of PCP were sicker (mean partial pressure of oxygen at admission ± standard deviation, 9.3 ± 2.0 kPa) than those with a second or third episode of PCP (mean partial pressure of oxygen at admission ± standard deviation, 9.9 ± 1.9 kPa; P =.008), but mortality among patients with a first episode of PCP (12.5%) was lower than mortality among patients with subsequent episodes of PCP (22.5%) (P = .019). No patient was receiving highly active antiretroviral therapy before presentation with PCP, and none began highly active antiretroviral therapy during treatment of PCP.
Conclusions
Mortality risk factors for PCP were identifiable at or soon after hospitalization. The trend towards improved outcome after June 1996 occurred in the absence of highly active antiretroviral therapy.
doi:10.1086/526778
PMCID: PMC2735405  PMID: 18190281
3.  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
4.  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
5.  Clinical review: Respiratory failure in HIV-infected patients - a changing picture 
Critical Care  2013;17(3):228.
Respiratory failure in HIV-infected patients is a relatively common presentation to ICU. The debate on ICU treatment of HIV-infected patients goes on despite an overall decline in mortality amongst these patients since the AIDS epidemic. Many intensive care physicians feel that ICU treatment of critically ill HIV patients is likely to be futile. This is mainly due to the unfavourable outcome of HIV patients with Pneumocystis jirovecii pneumonia who need mechanical ventilation. However, the changing spectrum of respiratory illness in HIV-infected patients and improved outcome from critical illness remain under-recognised. Also, the awareness of certain factors that can affect their outcome remains low. As there are important ethical and practical implications for intensive care clinicians while making decisions to provide ICU support to HIV-infected patients, a review of literature was undertaken. It is notable that the respiratory illnesses that are not directly related to underlying HIV disease are now commonly encountered in the highly active antiretroviral therapy (HAART) era. The overall incidence of P. jirovecii as a cause of respiratory failure has declined since the AIDS epidemic and sepsis including bacterial pneumonia has emerged as a frequent cause of hospital and ICU admission amongst HIV patients. The improved overall outcome of HIV patients needing ICU admission is related to advancement in general ICU care, including adoption of improved ventilation strategies. An awareness of respiratory illnesses in HIV-infected patients along with an appropriate diagnostic and treatment strategy may obviate the need for invasive ventilation and improve outcome further. HIV-infected patients presenting with respiratory failure will benefit from early admission to critical care for treatment and support. There is evidence to suggest that continuing or starting HAART in critically ill HIV patients is beneficial and hence should be considered after multidisciplinary discussion. As a very high percentage (up to 40%) of HIV patients are not known to be HIV infected at the time of ICU admission, the clinicians should keep a low threshold for requesting HIV testing for patients with recurrent pneumonia.
doi:10.1186/cc12552
PMCID: PMC3706935  PMID: 23806117
6.  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
7.  Severity and outcomes of Pneumocystis pneumonia in patients newly diagnosed with HIV infection: an observational cohort study 
It is unclear whether patients who are unaware of their HIV infection have different severity or outcomes of Pneumocystis pneumonia (PCP) compared to patients who have been previously diagnosed with HIV. In this retrospective observational cohort study of consecutive HIV-infected patients with microscopically diagnosed PCP at San Francisco General Hospital between 1997 and 2006, 121 of 522 patients (23%) were unaware of their HIV infection prior to their diagnosis of PCP. The proportion of patients with concurrently diagnosed HIV and PCP each year remained unchanged during the study period. Patients with newly diagnosed HIV had a significantly higher alveolar-arterial oxygen gradient at presentation (median 51 versus 45 mm Hg, p=0.03), but there were no differences in mortality, frequency of mechanical ventilation, or admission to intensive care compared to patients with previously diagnosed HIV infection. In multivariate analysis, patients who reported a sexual risk factor for HIV infection were more likely to be newly diagnosed with HIV than patients who reported injection drug use as their only HIV risk factor (odds ratio = 3.14, 95% confidence interval 1.59–6.18, p = 0.001). This study demonstrates a continued need for HIV education and earlier HIV testing, particularly in patients with high-risk sexual behavior.
doi:10.1080/00365540903051633
PMCID: PMC2806953  PMID: 19521925
8.  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
9.  HIV: treating Pneumocystis pneumonia (PCP) 
Clinical Evidence  2008;2008:2501.
Introduction
Pneumocystis pneumonia (PCP) is a common AIDS-defining opportunistic illness in people with HIV infection, but its incidence has fallen with use of prophylactic treatment. Without treatment, PCP is likely to be fatal in people with AIDS, so placebo-controlled studies would be considered unethical.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of first-line antipneumocystis treatments for Pneumocystis pneumonia in people infected with HIV? What are the effects of adjuvant corticosteroids in people receiving first-line antipneumocystis treatments for Pneumocystis pneumonia in people infected with HIV? What are the effects of treatments for Pneumocystis pneumonia in people infected with HIV who have not responded to first-line antipneumocystis treatment? We searched: Medline, Embase, The Cochrane Library, and other important databases up to May 2008 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 22 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic, review we present information relating to the effectiveness and safety of the following interventions: adjuvant corticosteroids; aerosolised or intravenous pentamidine; atovaquone; clindamycin–primaquone; treatment after failure of first-line treatment, trimethoprim–dapsone; and trimethoprim–sulfamethoxazole (TMP–SMX, co-trimoxazole).
Key Points
Pneumocystis pneumonia (PCP) is a common AIDS-defining opportunistic illness in people with HIV infection, but its incidence has fallen with use of prophylactic treatment.
Without treatment, PCP is likely to be fatal in people with AIDS, so placebo-controlled studies would be considered unethical.
Most clinicians consider trimethoprim–sulfamethoxazole (TMP-SMX, co-trimoxazole) to be standard first-line treatment for PCP. TMP-SMX may be more effective than atovaquone, but is more likely to cause adverse effects. Clindamycin–primaquine, trimethoprim–dapsone, and intravenous pentamidine may be as effective as TMP-SMX, with similar adverse-effect rates.Systemic absorption of aerosolised pentamidine is low, so adverse effects are few, but it may be less effective than other treatments in people with severely impaired respiratory function, and is perceived as having a high rate of treatment failure.
Adjuvant corticosteroids reduce mortality when used early in the treatment of moderate to severe PCP, but we don't know whether they are beneficial in mild PCP.
We found no information from RCTs on the effects of treatments in people who have failed to respond to first-line antipneumocystis treatment. We found some evidence that clindamycin–primaquine may be more effective than other treatment options in people who have failed to respond to first-line antipneumocystis treatment, but we found no high-quality studies.
PMCID: PMC2907978  PMID: 19445734
10.  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
11.  Open lung biopsy for investigation of acute respiratory episodes in patients with HIV infection and AIDS. 
Genitourinary Medicine  1995;71(5):280-285.
BACKGROUND--Open lung biopsy (OLB) is rarely necessary for investigation of HIV positive patients with acute respiratory episodes because of the high yield from fibreoptic bronchoscopy with bronchoalveolar lavage (BAL). METHODS--A retrospective review of OLB in HIV positive patients admitted to a specialist inpatient unit with acute respiratory symptoms was carried out in order to define clinical indications, diagnostic yield, impact on management, complications and outcome. RESULTS--OLB was performed in 23 patients; 21 had undergone one or more bronchoscopies with BAL (5 also had negative results from transbronchial biopsy). Indications for OLB were: Group A, 15 patients thought clinically to have pneumocystis pneumonia but not responding to treatment; Group B, 4 patients with focal chest radiographic abnormalities; Group C, 4 patients with diffuse radiographic abnormalities and miscellaneous conditions. Preoperative PaO2 (on air) ranged from 4.4 to 14.5 (mean = 9.5) kPa. The results of OLB were in Group A 5 patients had non specific interstitial pneumonitis (NIP), 1 also had Kaposi's sarcoma, 4 had pneumocystis pneumonia (1 also had bronchiolitis obliterans organising pneumonia [BOOP]), 3 had Kaposi's sarcoma and 1 had BOOP and emphysema, 1 had pulmonary infarction and no infection and 1 had normal lung tissue. In Group B diagnoses were NIP, B cell lymphoma, occult alveolar haemorrhage and Pseudomonas aeruginosa pneumonia with BOOP; In Group C 2 patients had NIP and 2 had pneumocystis pneumonia (1 also had cytomegalovirus pneumonitis). All patients survived surgery and none required mechanical ventilation. OLB results significantly affected management; in Group A inappropriate treatment was discontinued in 11 patients found not to have pneumocystis pneumonia, and alternative therapy was begun in the 4 with pneumocystis and in Groups B and C 6 patients began specific therapy; unnecessary therapy was avoided in one and antimicrobial treatment was modified in one. CONCLUSIONS--Open lung biopsy in HIV positive patients with focal and diffuse radiographic abnormalities has a high diagnostic yield and low morbidity. This investigation should be considered in those with acute respiratory episodes and negative results from bronchoscopic investigations or who have contra-indications to this procedure.
Images
PMCID: PMC1195541  PMID: 7490042
12.  Immune Modulation as Adjunctive Therapy for Pneumocystis pneumonia 
Pneumocystis is an opportunistic fungal respiratory pathogen that causes life-threatening pneumonia (Pcp) in patients suffering from defects in cell-mediated immunity, including those with acquired immunodeficiency syndrome (AIDS) and immunosuppression secondary to chemotherapy or organ transplantation. Despite major advances in health care, the mortality associated with Pcp has changed little over the past 25  years. Pcp remains a leading cause of death among HIV infected patients, with mortality rates of 50% or higher for patients developing severe Pcp. In addition, as more potent immunosuppressive therapies are developed for chronic inflammatory diseases, more cases of Pcp are occurring in non-HIV patients and in previously unreported clinical settings. These features highlight the importance of developing a better understanding of the pathogenesis of this disease, and the need to search for new therapeutic strategies to improve the outcome of Pcp patients. Immune-mediated inflammatory responses play an important role in the pathogenesis of Pcp, and may be even more significant in determining the outcome of Pcp than direct damage due to the organism itself. In this review we will summarize the immunopathogenic mechanisms that contribute to Pcp-associated lung injury, and discuss the potential to target these pathways for adjunctive immune modulation therapy for Pcp.
doi:10.1155/2011/918038
PMCID: PMC3166570  PMID: 21904545
13.  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
14.  Critical Importance of Long-Term Adherence to Care in HIV Infected Patients in the cART Era: New Insights from Pneumocystis jirovecii Pneumonia Cases over 2004–2011 in the FHDH-ANRS CO4 Cohort 
PLoS ONE  2014;9(4):e94183.
Objective
To describe characteristics and outcomes of HIV-infected patients with Pneumocystis jirovecii pneumonia (PCP) over 2004–2011 in France, in particular in those previously enrolled (PE) in the French Hospital Database on HIV (FHDH).
Methods
PE patients with an incident PCP were compared with patients with an inaugural PCP revealing HIV infection (reference). Adequate adherence to care was defined as a CD4 measurement at least every 6 months. Immune reconstitution (CD4≥200/mm3) and risk of death were studied using Kaplan-Meier estimates and multivariable Cox proportional hazards models.
Results
In a context of a decreasing incidence of PCP, 1259 HIV-infected patients had a PCP diagnosis, and 593 (47%) were PE patients of whom 161 (27%) have had a prior history of AIDS-defining clinical illness (prior ADI). Median time since enrolment was 8 years for PE patients; 74% had received cART. Median proportion of time with adequate adherence to care was 85% (IQR, 66–96) for all FHDH enrollees, but only 45% (IQR, 1–81) for PE patients during the 2 years before PCP. Median CD4 cell count (38/mm3) and HIV viral load (5.2 log10 copies/ml) at PCP diagnosis did not differ between PE patients and the reference group. Three year mortality rate of 25% was observed for PE prior ADI group, higher than in PE non-prior ADI group (8%) and the reference group (9%) (p<0.0001). In the PE prior ADI group, poor prognosis remained even after adjustment for virological control and immune reconstitution (HR, 2.4 [95%CI, 1.5–3.7]).
Conclusion
Almost 50% of PCP diagnoses in HIV-infected patients occurred presently in patients already in care, mainly with a previous cART prescription but with waning adherence to care. Having repeated ADI is contributing to the risk of death beyond its impact on immune reconstitution and viral suppression: special efforts must be undertaken to maintain those patients in care.
doi:10.1371/journal.pone.0094183
PMCID: PMC3984113  PMID: 24727746
15.  Acute hypercapnic respiratory failure in patients with chronic obstructive lung disease: risk factors and use of guidelines for management. 
Thorax  1992;47(1):34-40.
BACKGROUND: On the basis of a retrospective survey by this unit it was suggested that patients with acute ventilatory failure should be given sufficient controlled oxygen treatment to raise the arterial oxygen tension (PaO2) to above 6.6 kPa, with the addition of a respiratory stimulant if the hydrogen ion concentration ([H+]) rose above 55 nmol/l and assisted ventilation if the patient remained acidotic despite these measures. This study was designed to verify the prognostic factors that determine survival in acute ventilatory failure and determine the outcome when our guidelines were implemented. METHODS: One hundred and thirty nine episodes of acute hypercapnic (type II) respiratory failure were studied prospectively in 95 patients admitted with acute exacerbations of chronic obstructive lung disease. Patients had to have a PaO2 below 6.6 kPa and an arterial carbon dioxide tension (PaCO2) above 6.6 kPa while breathing air. RESULTS: The mortality associated with episodes of acute ventilatory failure was 12%. Patients who died tended to be older and were significantly more acidotic, hypotensive, and uraemic on admission than those who survived, but they had similar degrees of hypoxaemia and hypercapnia. Death occurred in 10 of the 39 episodes in which arterial [H+] rose to 55 nmol/l or above, compared with seven of the 100 episodes in which it remained below 55 nmol/l. The respiratory stimulant doxapram was used in 37 episodes and was associated with a reduction in [H+] below 55 nmol/l within 24 hours in 23 episodes. Assisted ventilation was used in only four episodes. CONCLUSION: Arterial [H+] is an important prognostic factor for survival. Most patients treated according to the guidelines outlined above can be managed successfully without assisted ventilation.
PMCID: PMC463551  PMID: 1539142
16.  Pneumocystis jirovecii Pneumonia in Patients with or without AIDS, France 
Emerging Infectious Diseases  2014;20(9):1490-1497.
Immunosuppressed patients without AIDS had longer time to treatment and a higher rate of death than did patients with AIDS.
Pneumocystis jirovecii pneumonia (PCP) in patients without AIDS is increasingly common. We conducted a prospective cohort study of consecutive patients with proven PCP; of 544 patients, 223 (41%) had AIDS (AIDS patients) and 321 (59%) had other immunosuppressive disorders (non-AIDS patients). Fewer AIDS than non-AIDS patients required intensive care or ventilation, and the rate of hospital deaths—17.4% overall—was significantly lower for AIDS versus non-AIDS patients (4% vs. 27%; p<0.0001). Multivariable analysis showed the odds of hospital death increased with older age, receipt of allogeneic bone marrow transplant, immediate use of oxygen, need for mechanical ventilation, and longer time to treatment; HIV-positive status or receipt of a solid organ transplant decreased odds for death. PCP is more often fatal in non-AIDS patients, but time to diagnosis affects survival and is longer for non-AIDS patients. Clinicians must maintain a high index of suspicion for PCP in immunocompromised patients who do not have AIDS.
doi:10.3201/eid2009.131668
PMCID: PMC4178412  PMID: 25148074
Immune suppression; HIV/AIDS; cancer; transplantation; mechanical ventilation; viruses; immunosuppressive disorder; France; fungi; Pneumocystis jirovecii; pneumonia; respiratory infections; prophylaxis
17.  Inflammatory Responses in Blood Samples of Human Immunodeficiency Virus-Infected Patients with Pulmonary Infections 
We analyzed the characteristics of the inflammatory response occurring in blood during pulmonary infections in human immunodeficiency virus (HIV)-infected patients. A prospective study of consecutive hospital admissions of HIV-infected patients with new-onset radiologic pulmonary infiltrates was carried out in a tertiary university hospital from April 1998 to May 2001. Plasma cyclic AMP receptor protein (CRP), interleukin 1β (IL-1β), IL-6, IL-8, IL-10, and tumor necrosis factor alpha (TNF-α) levels were determined at the time of admission and 4, 5, and 6 days later. Patients were included in a protocol addressed to study etiology and outcome of disease. A total of 249 episodes of infection were included, with the main diagnoses being bacterial pneumonia (BP) (118 episodes), Pneumocystis carinii pneumonia (PCP) (41 episodes), and mycobacteriosis (36 episodes). For these three patient groups, at the time of admission the median CRP and cytokine levels were as follows: CRP, 10.2, 3.8 and 5 mg/dl, respectively (P = 0.0001); IL-8, 19, 3, and 2.9 pg/ml (P = 0.045); and TNF-α, 46.4, 44, and 75 pg/ml, respectively (P = 0.029). There were no significant differences in levels of IL-1β, IL-6, or IL-10 among the patient groups. A total of 23 patients died. At the time of admission, HIV-infected patients with BP had higher plasma CRP and IL-8 levels than did PCP and mycobacteriosis patients. TNF-α levels were higher in patients with mycobacteriosis. An elevated IL-8 level (>61 pg/ml) at the time of admission was an independent factor associated with higher mortality (odds ratio, 12; 95% confidence interval, 1.2 to 235.5).
doi:10.1128/CDLI.11.3.608-614.2004
PMCID: PMC404570  PMID: 15138189
18.  Comparison of community-acquired pneumonia requiring admission to hospital in HIV-and non-HIV-infected patients 
OBJECTIVE:
To compare community-acquired pneumonia (CAP) in hospitalized human immunodeficiency virus (HIV)-infected patients with that in hospitalized non-HIV-infected patients by assessing presenting characteristics, etiology and outcomes.
DESIGN:
Retrospective chart review.
SETTING:
A tertiary care centre in Halifax, Nova Scotia.
POPULATION STUDIED:
Thirty-two HIV-infected patients requiring hospitalization for treatment of CAP were identified from September 1991 to October 1993 and compared with 33 age-matched non-HIV-infected patients who presented with pneumonia during the same period.
MAIN RESULTS:
The two populations were comparable in age, sex and race. Fifty per cent of the HIV-infected and 20.8% of the non-HIV-infected patients had had a previous episode of pneumonia. Pneumocystis carinii pneumonia (PCP) accounted for 16 of the 32 episodes of CAP in the HIV-infected patients, while none of the non-HIV-infected patients had PCP. Pneumonia secondary to Streptococcus pneumoniae was more common in the non-HIV-infected patients (five versus one, P=0.02). Vital signs and initial PO2 did not differ between the two groups. White blood cell count was lower at admission for the HIV population (5.7×109/L versus 12.7×109/L, P=0.003). The HIV patients were more likely to undergo bronchoscopy (27.7% versus 0%, P<0.001). The length of stay in hospital, transfer to the intensive care unit and necessity for intubation were the same for both groups. The in-hospital mortality for HIV-infected patients was eight of 32 (25%) while for the non-HIV-infected patients it was none of 33 (P=0.002).
CONCLUSIONS:
Patients with HIV infection who present with CAP are more likely to have PCP, to have had a past episode of pneumonia and to die while in hospital than age- and sex-matched non-HIV-infected patients with CAP.
PMCID: PMC3327412  PMID: 22514448
Community-acquired pneumonia; Human immunodeficiency virus infection; Hospitalization
19.  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
20.  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
21.  Immune Modulation with Sulfasalazine Attenuates Immunopathogenesis but Enhances Macrophage-Mediated Fungal Clearance during Pneumocystis Pneumonia 
PLoS Pathogens  2010;6(8):e1001058.
Although T cells are critical for host defense against respiratory fungal infections, they also contribute to the immunopathogenesis of Pneumocystis pneumonia (PcP). However, the precise downstream effector mechanisms by which T cells mediate these diverse processes are undefined. In the current study the effects of immune modulation with sulfasalazine were evaluated in a mouse model of PcP-related Immune Reconstitution Inflammatory Syndrome (PcP-IRIS). Recovery of T cell-mediated immunity in Pneumocystis-infected immunodeficient mice restored host defense, but also initiated the marked pulmonary inflammation and severe pulmonary function deficits characteristic of IRIS. Sulfasalazine produced a profound attenuation of IRIS, with the unexpected consequence of accelerated fungal clearance. To determine whether macrophage phagocytosis is an effector mechanism of T cell-mediated Pneumocystis clearance and whether sulfasalazine enhances clearance by altering alveolar macrophage phagocytic activity, a novel multispectral imaging flow cytometer-based method was developed to quantify the phagocytosis of Pneumocystis in vivo. Following immune reconstitution, alveolar macrophages from PcP-IRIS mice exhibited a dramatic increase in their ability to actively phagocytose Pneumocystis. Increased phagocytosis correlated temporally with fungal clearance, and required the presence of CD4+ T cells. Sulfasalazine accelerated the onset of the CD4+ T cell-dependent alveolar macrophage phagocytic response in PcP-IRIS mice, resulting in enhanced fungal clearance. Furthermore, sulfasalazine promoted a TH2-polarized cytokine environment in the lung, and sulfasalazine-enhanced phagocytosis of Pneumocystis was associated with an alternatively activated alveolar macrophage phenotype. These results provide evidence that macrophage phagocytosis is an important in vivo effector mechanism for T cell-mediated Pneumocystis clearance, and that macrophage phenotype can be altered to enhance phagocytosis without exacerbating inflammation. Immune modulation can diminish pulmonary inflammation while preserving host defense, and has therapeutic potential for the treatment of PcP-related immunopathogenesis.
Author Summary
Pneumocystis is a fungal respiratory pathogen that causes life-threatening pneumonia (PcP) in immunosuppressed patients. PcP remains an infectious complication of AIDS and cancer, and is emerging in previously unrecognized clinical settings. Despite dramatic advances in health care and the availability of antibiotics to treat this infection, mortality rates have improved little over the past 25 years. T cell-mediated immunity is critical for host defense against respiratory fungal infections. However, T cells also cause PcP-related inflammation and lung injury. The results of the current study indicate that the immune response to Pneumocystis can be modulated to reduce tissue damaging inflammation while enhancing anti-fungal host defense. Alveolar macrophages recognize and eliminate pathogens from the lung and also regulate inflammation. We have identified alveolar macrophages as the effector cells for T cell-dependent clearance of Pneumocystis from the lung, and demonstrated that macrophage phenotype can be altered to enhance microbe elimination without promoting inflammatory injury. These results suggest that the effector mechanism of T cell-mediated fungal clearance is distinct from the effector mechanism of T cell-mediated lung inflammation and injury. This conceptual advance can be exploited to develop more effective therapeutic strategies to block inflammation while preserving host defense.
doi:10.1371/journal.ppat.1001058
PMCID: PMC2924364  PMID: 20808846
22.  Inhibition of Pneumocystis carinii dihydropteroate synthetase by para-acetamidobenzoic acid: possible mechanism of action of isoprinosine in human immunodeficiency virus infection. 
Isoprinosine has been reported to decrease progression to AIDS, primarily by preventing Pneumocystis carinii pneumonia (PCP), in human immunodeficiency virus-infected patients, but the mechanism of action is unknown. para-Acetamidobenzoic acid (PAcBA), one component of isoprinosine, is structurally related to para-aminobenzoic acid (PABA), a precursor of de novo folate synthesis. This pathway is known to be important for P. carinii because sulfonamides, which are effective anti-P. carinii agents, inhibit incorporation of PABA into folate precursors by the enzyme dihydropteroate synthetase (DHPS). Inhibition of P. carinii DHPS by PAcBA was investigated by using two assays. In short-term cultures of P. carinii from rats, [3H]PABA incorporation into reduced folates was inhibited by both isoprinosine (mean +/- standard error 50% inhibitory concentration [IC50], 20 +/- 8.4 microM) and PAcBA free acid (IC50, 240 +/- 100 microM); a soluble PAcBA salt was more potent than PAcBA free acid alone (IC50, 29 +/- 48 microM). The activity of PAcBA free acid was confirmed in a cell-free DHPS inhibition assay (IC50, 120 +/- 120 microM). Inosine and dimethylaminopropanol, two other components of isoprinosine, were poor inhibitors of PABA incorporation (IC50, > 1,000 microM). PAcBA free acid also showed activity in inhibiting the DHPS of Toxoplasma gondii, but was a poor inhibitor of the DHPSs of Escherichia coli and Saccharomyces cerevisiae. In a rat model of PCP, the PAcBA salt administered intraperitoneally demonstrated no activity against established PCP either alone or when used in combination with trimethoprim; the lack of efficacy in this model may be due to the rapid metabolism of the drug. Prevention of PCP by PaCBA through inhibition of P. carinii DHPS may explain the activity of isoprinosine in decreasing the progression to AIDS in human immunodeficiency virus-infected patients.
PMCID: PMC187944  PMID: 7687120
23.  Outcome of HIV-associated Pneumocystis pneumonia in hospitalized patients from 2000 through 2003 
Background
Pneumocystis pneumonia (PCP) remains a leading cause of morbidity and mortality in HIV-infected persons. Epidemiology of PCP in the recent era of highly active antiretroviral therapy (HAART) is not well known and the impact of HAART on outcome of PCP has been debated.
Aim
To determine the epidemiology of PCP in HIV-infected patients and examine the impact of HAART on PCP outcome.
Methods
We performed a retrospective cohort study of 262 patients diagnosed with PCP between January 2000 and December 2003 at a county hospital at an academic medical center. Death while in the hospital was the main outcome measure. Multivariate modeling was performed to determine predictors of mortality.
Results
Overall hospital mortality was 11.6%. Mortality in patients requiring intensive care was 29.0%. The need for mechanical ventilation, development of a pneumothorax, and low serum albumin were independent predictors of increased mortality. One hundred and seven patients received HAART before hospitalization and 16 patients were started on HAART while in the hospital. HAART use either before or during hospitalization was not associated with mortality.
Conclusion
Overall hospital mortality and mortality predictors are similar to those reported earlier in the HAART era. PCP diagnoses in HAART users likely represented failing HAART regimens or non-compliance with HAART.
doi:10.1186/1471-2334-8-118
PMCID: PMC2551597  PMID: 18796158
24.  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
25.  Outcomes of Moderate-to-Severe Pneumocystis Pneumonia Treated with Adjunctive Steroid in Non-HIV-Infected Patients▿† 
Antimicrobial Agents and Chemotherapy  2011;55(10):4613-4618.
While it is well-known that adjunctive corticosteroid use improves the outcome of moderate-to-severe Pneumocystis jirovecii pneumonia (PcP) in patients with human immunodeficiency virus (HIV), there are limited data on its efficacy in non-HIV-infected patients with PcP. Patients undergoing fiber-optic bronchoscopy with bronchoalveolar lavage for suspected PcP from January 2007 through December 2010 were reviewed retrospectively. We compared demographics, clinical characteristics, and outcomes in 88 non-HIV-infected patients with moderate-to-severe PcP with (n = 59) and without (n = 29) adjunctive corticosteroid use. Outcomes of PcP were assessed by respiratory failure and 30-day and 90-day all-cause mortality. Survival curves were analyzed by the Kaplan-Meier method and estimated by the log rank test. All-cause mortality of moderate-to-severe PcP at 90 days was lower in the solid-organ transplant recipients than in all other patients (6/26 [23%] versus 34/62 [55%], respectively; P = 0.006), and mortality at 30 days was lower in patients with hematologic malignancies than in all other patients (4/26 [15%] versus 24/62 [39%], respectively; P = 0.03). The outcomes of PcP were not significantly different in moderate-to-severe PcP patients with and without adjunctive corticosteroid use, regardless of recent corticosteroid use. Survival analysis of PcP patients with and without corticosteroid use by the Kaplan-Meier method also did not reveal any difference (log rank test; P = 0.81). There again was no difference within the subgroup of PcP patients with solid-organ transplants. Adjunctive corticosteroid use may not improve the outcome of moderate-to-severe PcP in non-HIV-infected patients.
doi:10.1128/AAC.00669-11
PMCID: PMC3186978  PMID: 21788460

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