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1.  Changes in pulmonary clearance of technetium labelled DTPA during haemodialysis. 
Thorax  1986;41(5):381-385.
An index of pulmonary epithelial permeability has been studied in 12 patients with chronic renal failure during haemodialysis. It was assessed by the half time clearance from lung to blood (t 1/2 LB) of a nebulised solution containing technetium labelled diethylene triamine pentacetic acid (99mTc DTPA). Six patients were cigarette smokers and six were non-smokers. The non-smokers had greater predialysis permeability (mean 37.7, range 24-54 min) than non-smokers without renal disease (mean 60.2, range 38-99 min; p less than 0.025). The t 1/2 LB was measured before dialysis and during the first half hour and the last half hour of dialysis in all 12 patients and also during other periods of dialysis in 10 of them. Dialysis lasted for five hours in 11 patients and four hours in one patient. There was no significant change in the t 1/2 LB of 99mTc DTPA during early dialysis; but as dialysis progressed there was a statistically significant increase in t 1/2 LB, suggesting a reduction of pulmonary epithelial permeability. These results show no increase in an index of pulmonary epithelial permeability in association with the pulmonary sequestration of neutrophils that occurs in early haemodialysis. They also suggest that in chronic renal failure the epithelial permeability is increased and that this can be modified by haemodialysis.
PMCID: PMC1020632  PMID: 3529481
2.  Simplified exercise test for the initial differential diagnosis of Pneumocystis carinii pneumonia in HIV antibody positive patients. 
Thorax  1994;49(2):112-114.
BACKGROUND--This study was designed to evaluate the usefulness of a simplified exercise test in the differential diagnosis of Pneumocystis carinii pneumonia (PCP). METHODS--Forty five subjects with antibodies against the human immunodeficiency virus (HIV) and pneumonia were included and divided into two groups: those with PCP and those with "other pneumonias" (non-PCP). The test involved pedalling for two minutes on a stretcher bed and was considered positive if SaO2 decreased by at least 3%. RESULTS--During the exercise the mean(SE) SaO2 fell in patients with PCP from 88(4)% to 84(3)%, p < 0.01, whilst it improved slightly in subjects with non-PCP from 91(1)% to 93(3)%, p < 0.05. Sensitivity was 77% and specificity 91%. CONCLUSIONS--This simple test seems potentially useful for the initial investigation of HIV antibody positive patients with pneumonia.
PMCID: PMC474319  PMID: 8128398
3.  Carboxyhaemoglobin and pulmonary epithelial permeability in man. 
Thorax  1983;38(2):129-133.
The effect of cigarette smoke exposure on pulmonary epithelial permeability was studied in 45 smokers and 22 non-smokers. An index of cigarette smoke exposure was obtained from the carboxyhaemoglobin concentration (HbCO%). Pulmonary epithelial permeability was proportional to the half-time clearance rate of technetium-99m-labelled diethylene triamine pentacetate (99mTc DTPA) from lung to blood (T1/2LB). The relationship between T1/2LB and HbCO% was hyperbolic in form and the data could be fitted to the quadratic formula (formula; see text) where the parameters a0, a1, and a2 represent respectively the asymptotic T1/2LB value at large carboxyhaemoglobin values and the slope and shape of the curve. The values of these parameters were a0 4.4 (2.6), a1 = 77.8 (15.5), and a2 -25.5 (9.7) (SE). This is the first demonstration of a dose-response relationship between carboxyhaemoglobin and an increased permeability of the lungs in man and provides a technique for identifying the roles of carbon monoxide and other cigarette smoke constituents in causing increased pulmonary epithelial permeability.
PMCID: PMC459501  PMID: 6344310
4.  Diagnostic value of lung clearance of 99mTc DTPA compared with other non-invasive investigations in Pneumocystis carinii pneumonia in AIDS. 
Thorax  1991;46(10):722-726.
Various non-invasive investigations were carried out in patients infected with HIV who had respiratory symptoms with and without pneumocystis pneumonia (with pneumonia, n = 13 (five smokers); without pneumonia, n = 22 (13 smokers]. These included chest radiography; lung function tests (forced expiratory volume in one second, forced vital capacity; transfer factor and coefficient for carbon monoxide); arterial blood gas tensions; arterial oxygen saturation at rest and on exercise; and lung clearance of diethylenetriaminepenta-acetic acid labelled with technetium-99m (99mTc DTPA). The effect of scan time (seven v 45 minutes from peak counts) and subtraction of background counts were examined. There were no significant differences between the two groups in lung function tests or arterial blood gas tensions at rest. The median clearance half time of inhaled 99mTc DTPA for the first seven minutes from peak counts was 7.2 minutes for patients with pneumocystis pneumonia and 22 minutes for those without. The median arterial oxygen desaturation on exercise was 5% in patients with pneumocystis pneumonia and 2% in those without. 99mTc DTPA lung clearance was better than the other non-invasive tests in discriminating pneumocystis pneumonia from other pulmonary disorders in patients positive for HIV. A short scan time of seven minutes was as sensitive and specific as the longer scan time of 45 minutes, and this allows the clearance of 99mTc DTPA to become a rapid screening test.
PMCID: PMC463391  PMID: 1750019
5.  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
6.  Enzyme-Linked Immunosorbent Assay and Serologic Responses to Pneumocystis jiroveci 
Emerging Infectious Diseases  2004;10(5):848-854.
Seroepidemiologic studies of Pneumocystis pneumonia (PCP) in humans have been limited by inadequate reagents. We have developed an enzyme-linked immunosorbent assay (ELISA) using three overlapping recombinant fragments of the human Pneumocystis major surface glycoprotein (MsgA, MsgB, and MsgC) for analysis of antibody responses in HIV-positive patients and healthy blood donors. HIV-positive patients had significantly higher antibody levels to all Msg fragments. Furthermore, HIV-positive patients who experienced a previous episode of PCP (PCP-positive) had higher level of antibodies to MsgC than patients who never had PCP. A significant association was found between ELISA antibody level and reactivity by Western blot in HIV-positive patients, especially those who were PCP-positive. Thus, this ELISA will be useful in studying serum antibody responses to Pneumocystis in different human populations.
PMCID: PMC3323219  PMID: 15200818
Pneumocystis; Major surface glycoprotein; Infection; ELISA; HIV patients; Serum antibodies
7.  Granulomatous Pneumocystis carinii pneumonia in patients with malignancy 
Thorax  2002;57(5):435-437.
Background: A review was undertaken of the clinical features and results of diagnostic tests in non-HIV infected patients who developed granulomatous Pneumocystis carinii pneumonia (PCP).
Methods: A retrospective review was performed of the charts and radiographs of patients with a granulomatous reaction to P carinii identified from computerised pathology records at Memorial Sloan Kettering Cancer Center, a university affiliated tertiary care hospital.
Results: Three cases were identified; the incidence of granulomatous PCP was 3%. All patients had risk factors for PCP and had received high dose corticosteroids which had been stopped. Two patients had received chemotherapy. Presentation was insidious with only mild symptoms; only one patient had fever. Chest radiographs showed a reticulonodular pattern. Bronchoscopy was negative for PCP in all cases and open lung biopsy was necessary.
Conclusion: A granulomatous pathological reaction to PCP occurs rarely in patients with malignancy. In these cases the clinical presentation may be atypical and bronchoscopy can be non-diagnostic.
PMCID: PMC1746334  PMID: 11978921
8.  Extrapulmonary pneumocystosis. 
Clinical Microbiology Reviews  1997;10(3):401-418.
Extrapulmonary pneumocystosis is an exceedingly rare complication of Pneumocystis carinii pneumonia (PCP). Prior to the advent of the human immunodeficiency virus type 1 (HIV-1) epidemic, only 16 cases of extrapulmonary pneumocystosis in individuals who were immunocompromised by a variety of underlying diseases had been reported. Since the beginning of the HIV-1 and related PCP epidemic, at least 90 cases of extrapulmonary pneumocystosis have been reported. This review briefly presents a history of the discovery of P. carinii and its recognition as a human pathogen, the controversy regarding its taxonomy, and the epidemiology of this organism. A more detailed analysis of the incidence of extrapulmonary pneumocystosis in HIV-1-infected individuals and its occurrence despite widespread prophylaxis for PCP with either aerosolized pentamidine or systemic dapsone-trimethoprim is presented. The clinical features of published cases of extrapulmonary pneumocystosis in non-HIV-1-infected individuals are summarized and contrasted with those in HIV-1 infected individuals. The diagnosis of extrapulmonary pneumocystosis is discussed, and because clinical microbiologists and pathologists are the key individuals in establishing the diagnosis, the characteristic microscopic morphology of P. carinii as its appears when stained with a variety of stains is presented and reviewed. The review concludes with a brief discussion of treatments for extrapulmonary pneumocystosis.
PMCID: PMC172927  PMID: 9227859
9.  Ploidy of Cell-Sorted Trophic and Cystic Forms of Pneumocystis carinii 
PLoS ONE  2011;6(6):e20935.
Once regarded as an AIDS-defining illness, Pneumocystis pneumonia (PcP) is nowadays prevailing in immunocompromised HIV-negative individuals such as patients receiving immunosuppressive therapies or affected by primary immunodeficiency. Moreover, Pneumocystis clinical spectrum is broadening to non-severely-immunocompromised subjects who could be colonized by the fungus while remaining asymptomatic for PcP, thus being able to transmit the infection by airborne route to susceptible hosts. Although the taxonomical position of the Pneumocystis genus has been clarified, several aspects of its life cycle remain elusive such as its mode of proliferation within the alveolus or its ploidy level. As no long-term culture model exists to grow Pneumocystis organisms in vitro, an option was to use a model of immunosuppressed rat infected with Pneumocystis carinii and sort life cycle stage fractions using a high-through-put cytometer. Subsequently, ploidy levels of the P. carinii trophic and cystic form fractions were measured by flow cytometry. In the cystic form, eight contents of DNA were measured thus strengthening the fact that each mature cyst contains eight haploid spores. Following release, each spore evolves into a trophic form. The majority of the trophic form fraction was haploid in our study. Some less abundant trophic forms displayed two contents of DNA indicating that they could undergo (i) mating/fusion leading to a diploid status or (ii) asexual mitotic division or (iii) both. Even less abundant trophic forms with four contents of DNA were suggestive of mitotic divisions occurring following mating in diploid trophic forms. Of interest, was the presence of trophic forms with three contents of DNA, an unusual finding that could be related to asymmetrical mitotic divisions occurring in other fungal species to create genetic diversity at lower energetic expenses than mating. Overall, ploidy data of P. carinii life cycle stages shed new light on the complexity of its modes of proliferation.
PMCID: PMC3114859  PMID: 21695077
10.  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
11.  Integrity of the alveolar-capillary barrier and alveolar surfactant system in smokers. 
Thorax  1992;47(8):603-608.
BACKGROUND: The permeability of the alveolar-capillary barrier to technetium-99m labelled diethylenetriamine pentaacetate (99mTc DTPA) is known to be greatly increased in smokers, but the underlying mechanism is poorly understood. Abnormal permeability of the alveolar epithelium as well as impaired surfactant function has been suggested. The purpose of this study was to examine transudation of urea and albumin into the alveoli and alveolar surfactant function in smokers and non-smokers and to relate these variables to the rate of alveolar-capillary transfer of 99mTc DTPA. METHODS: Standardised bronchoalveolar lavage was performed and the yield of urea and albumin measured in the lavage fluid. The integrity of the alveolar surfactant system was assessed by measurement of the surface activity and of the yield of phospholipids in alveolar lavage fluid. RESULTS: The mean decay constant for the pulmonary clearance of 99mTc DTPA was 0.028/min in the smokers and 0.009/min in the non-smokers. The recovery of albumin and urea in alveolar lavage fluid was very similar in the two groups. The surface activity of alveolar lavage fluid was lower in smokers than in non-smokers (minimum surface tension 37.9 versus 28.6 mN/m) and the yield of phospholipids was reduced (2.08 versus 3.86 mg). The rate constant for the pulmonary clearance of 99mTc DTPA correlated with the yield of phospholipids at bronchoalveolar lavage. CONCLUSIONS: The study shows that increased alveolar-capillary transfer of 99mTc DTPA in smokers is not accompanied by increased transudation of small or large molecules into the alveoli. The findings support the hypothesis that increased clearance of 99mTc DTPA in smokers is related to surfactant dysfunction.
PMCID: PMC463921  PMID: 1412116
12.  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
13.  Pneumocystis Pneumonia in Hospitalized Patients; A Detailed Examination of Symptoms, Management, and Outcomes in HIV-infected and HIV-uninfected Persons 
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.
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.
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.
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.
PMCID: PMC3889465  PMID: 22548840
Pneumocystis Pneumonia; Transplant; Infectious Complications
14.  Asbestosis: assessment by bronchoalveolar lavage and measurement of pulmonary epithelial permeability. 
Thorax  1985;40(7):508-514.
Thirty two patients with asbestosis were assessed by means of bronchoalveolar lavage (27 patients) and the half time clearance from lungs to blood (T1/2LB) of an inhaled aerosol of diethylenetriamine pentacetate (DTPA) labelled with technetium 99m (32 patients). T1/2LB was also measured in 20 non-smoking normal individuals and 17 smokers without a history of exposure to asbestos. Thirteen patients (46%) showed an increase in the percentage of neutrophils with or without an increase in the percentage of eosinophils and eight (29%) showed an increased percentage of lymphocytes. The number of neutrophils plus eosinophils expressed as a percentage of the total count was positively correlated with the length of the history of disease (r = 0.53, p less than 0.025) and greater percentages were associated with more severe impairment of lung function. Smokers had lower percentages of lymphocytes than non-smokers (p less than 0.002) and showed increased proportions of neutrophils and eosinophils more often than non-smokers (p less than 0.05). In 18 non-smokers with asbestosis the mean T1/2LB was 33.8 (range 10.0-62.0) minutes, significantly less than 57.2 (30.5-109) minutes in 20 non-smoking normal subjects (p less than 0.002). In non-smokers shorter T1/2LB correlated with a longer time since first exposure to asbestos (r = -0.65, p less than 0.005), longer duration of exposure (r = -0.70, p less than 0.001), and a shorter time since last exposure (r = 0.59, p less than 0.01). Shorter T1/2LB was also associated with increased inflammatory activity as shown by higher bronchoalveolar lavage cell counts (r = -0.53, p less than 0.025) and higher combined percentages of neutrophils, eosinophils, and lymphocytes (r = -0.47, p less than 0.05). The techniques of bronchoalveolar lavage and measurement of inhaled solute clearance may be useful in assessing inflammatory activity in asbestosis.
PMCID: PMC460122  PMID: 4035617
15.  Resolution of Pneumocystis carinii pneumonia in CD4+ lymphocyte- depleted mice given aerosols of heat-treated Escherichia coli 
Mice were thymectomized and depleted of CD4+ lymphocytes by treatment with monoclonal antibody to induce Pneumocystis carinii (PC) pneumonia (PCP). These mice were then exposed to aerosols of heat-treated Escherichia coli three times a week. Aerosol treatment for 10 d caused a slight reduction in numbers of PC nuclei in the lungs of mice, and treatment for 22 d resulted in nearly complete resolution of PCP. Large numbers of macrophages, polymorphonuclear leukocytes, and lymphocytes accumulated in lungs of aerosol-treated mice. Depletion of either CD8+ lymphocytes or asialo GM1+ cells that remained in the mice after CD4+ cell depletion had no effect on the ability of the mice to resolve PCP after E. coli aerosol treatments. However, depletion of Thy-1+ lymphocytes in these mice abrogated their ability to resolve PCP and reduced the numbers of macrophages that accumulated in the lungs. In addition, it was found that resolution of PCP induced by heat-treated E. coli aerosol treatments was also abrogated when mice were treated with polyclonal antibodies against tumor necrosis factor alpha (TNF- alpha). Thus, resolution of PCP in CD4+ lymphocyte-depleted mice by heat-treated E. coli aerosols was not dependent on either CD8+ or asialo GM1+ cells but was dependent on Thy-1+CD4-CD8- lymphocytes and on the participation of TNF. These results indicate that heat-treated E. coli aerosols can act as an immune response modifier by inducing resolution of PCP in mice by a mechanism not dependent on the presence of CD4+ lymphocytes.
PMCID: PMC2119359  PMID: 1355103
16.  Enhanced Lung Injury and Delayed Clearance of Pneumocystis carinii in Surfactant Protein A-Deficient Mice: Attenuation of Cytokine Responses and Reactive Oxygen-Nitrogen Species  
Infection and Immunity  2004;72(10):6002-6011.
Surfactant protein A (SP-A), a member of the collectin family, selectively binds to Pneumocystis carinii and mediates interactions between pathogen and host alveolar macrophages in vitro. To test the hypothesis that mice lacking SP-A have delayed clearance of Pneumocystis organisms and enhanced lung injury, wild-type C57BL/6 (WT) and SP-A-deficient mice (SP-A−/−) with or without selective CD4+-T-cell depletion were intratracheally inoculated with Pneumocystis organisms. Four weeks later, CD4-depleted SP-A-deficient mice had developed a more severe Pneumocystis infection than CD4-depleted WT (P. carinii pneumonia [PCP] scores of 3 versus 2, respectively). Whereas all non-CD4-depleted WT mice were free of PCP, intact SP-A−/− mice also had evidence of increased organism burden. Pneumocystis infection in SP-A-deficient mice was associated histologically with enhanced peribronchial and/or perivascular cellularity (score of 4 versus 2, SP-A−/− versus C57BL/6 mice, respectively) and a corresponding increase in bronchoalveolar lavage (BAL) cell counts. Increases in SP-D content, gamma interferon, interleukin-4, interleukin-5, and tumor necrosis factor alpha in BAL fluid occurred but were attenuated in PCP-infected SP-A−/− mice compared to WT mice. There were increases in total BAL NO levels in both infected groups, but nitrite levels were higher in SP-A−/− mice, indicating a reduction in production of higher oxides of nitrogen that was also reflected in lower levels of 3-nitrotyrosine staining in the SP-A−/− group. We conclude that despite increases in inflammatory cells, SP-A-deficient mice infected with P. carinii exhibit an enhanced susceptibility to the organism and attenuated production of proinflammatory cytokines and reactive oxygen-nitrogen species. These data support the concept that SP-A is a local effector molecule in the lung host defense against P. carinii in vivo.
PMCID: PMC517574  PMID: 15385504
17.  Molecular Evidence of Interhuman Transmission of Pneumocystis Pneumonia among Renal Transplant Recipients Hospitalized with HIV-Infected Patients 
Emerging Infectious Diseases  2004;10(10):1766-1773.
Molecular evidence indicates that P. jirovecii may be nosocomially transmitted to severely immunosuppressed patients.
Ten Pneumocystis jirovecii pneumonia (PCP) cases were diagnosed in renal transplant recipients (RTRs) during a 3-year period. Nosocomial transmission from HIV-positive patients with PCP was suspected because these patients shared the same hospital building, were not isolated, and were receiving suboptimal anti-PCP prophylaxis or none. P. jirovecii organisms were typed with the multitarget polymerase chain reaction–single-strand conformation polymorphism method. Among the 45 patients with PCP hospitalized during the 3-year period, 8 RTRs and 6 HIV-infected patients may have encountered at least 1 patient with active PCP within the 3 months before the diagnosis of their own PCP episode. In six instances (five RTRs, one HIV-infected patient), the patients harbored the same P. jirovecii molecular type as that found in the encountered PCP patients. The data suggest that part of the PCP cases observed in this building, particularly those observed in RTRs, were related to nosocomial interhuman transmission.
PMCID: PMC3323259  PMID: 15504262
Epidemiology; Pneumocystis carinii; Pneumocystis jirovecii; interhuman transmission; cluster analysis; sulfa drug resistance; dihydropteroate synthase; single-strand conformation polymorphism; PCP; research
18.  Histologically atypical Pneumocystis carinii pneumonia. 
Thorax  1993;48(10):996-1001.
BACKGROUND--Infection with Pneumocystis carinii typically results in a pneumonia which histologically is seen to consist of an eosinophilic foamy alveolar exudate associated with a mild plasma cell interstitial infiltrate. Special stains show that cysts of P carinii lie within the alveolar exudate. Atypical histological appearances may occasionally be seen, including a granulomatous pneumonia and diffuse alveolar damage. In these patients the clinical presentation may be atypical and results of investigations negative unless lung biopsies are performed and tissue obtained for histological examination. METHODS--The incidence and mode of presentation of histologically atypical pneumocystis pneumonia was studied in a cohort of HIV-I antibody positive patients. RESULTS--Over a 30 month period 138 patients had pneumocystis pneumonia, of whom eight (6%) had atypical histological appearances which were diagnosed (after negative bronchoalveolar lavage) by open lung biopsy in five, percutaneous biopsy in one, and at post mortem examination in two. Atypical appearances included granulomatous inflammation in four patients, "pneumocystoma" in two (one also had extrapulmonary pneumocystosis), bronchiolitis obliterans organising pneumonia in one patient, diffuse alveolar damage and subpleural cysts in one (who also had intrapulmonary cytomegalovirus infection), and extrapulmonary pneumocystosis in two patients. CONCLUSIONS--Various atypical histological appearances may be seen in pneumocystis pneumonia. Lung biopsy (either percutaneous or open) should be considered when bronchoalveolar lavage is repeatedly negative and evidence of P carinii should be sought, by use of special stains, in all lung biopsy material from HIV-I antibody positive patients.
PMCID: PMC464808  PMID: 8256247
19.  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.
PMCID: PMC3186978  PMID: 21788460
20.  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.
PMCID: PMC2806953  PMID: 19521925
21.  Comparison of community-acquired pneumonia requiring admission to hospital in HIV-and non-HIV-infected patients 
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.
Retrospective chart review.
A tertiary care centre in Halifax, Nova Scotia.
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.
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).
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
22.  Serologic responses to Pneumocystis Proteins in Human Immunodeficiency Virus Patients With and Without Pneumocystis jirovecii Pneumonia 
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).
Retrospective analysis of a prospective cohort
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.
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.
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.
PMCID: PMC3150634  PMID: 21372726
HIV; Acquired Immunodeficiency Syndrome; Pneumocystis; serology
23.  Additive effects of exposure to silica dust and smoking on pulmonary epithelial permeability: a radioaerosol study with technetium-99m labelled DTPA. 
Thorax  1993;48(3):264-268.
BACKGROUND: Increased pulmonary epithelial permeability evaluated by the rate of clearance from lung to blood of the radioaerosol solute technetium-99m labelled diethylenetriamine pentaacetate (99mTc-DTPA) has been reported in smokers and in workers exposed to silica dust. A study was carried out to determine whether there are additive effects of cigarette smoke and exposure to silica dust on clearance rates of 99mTc-DTPA in ceramic workers. METHODS: Thirty one subjects with silicosis were studied, of whom 18 smoked cigarettes and 13 were non-smokers. They had similar histories of exposure to silica dust, and radiological alterations consistent with silicosis. The results from these patients were compared with those from normal subjects and smokers previously studied by the authors. RESULTS: Pulmonary function values were normal in most patients and not significantly different among groups. The median (range) rate of clearance of 99mTc-DTPA in smokers with silicosis was 4.1 (1.9-12.7) %/minute, which was higher than the rates in non-smoking patients with silicosis of 2.2 (1.1-6.6) %/minute and in smokers without exposure to silica dust of 2.9 (1.6-4.5) %/minute. These differences were more evident and significant when the clearance rates of the lower lobes of the three groups were compared. Clearance rates higher than 3%/minute were much more frequent in smokers with silicosis (85%) than in non-smoking patients with silicosis (15%) and in smokers (40%). CONCLUSION: In ceramic workers with radiographic changes resulting from exposure to silica dust, there is an additive effect of inhalation of silica dust and cigarette smoking on clearance rates of 99mTc-DTPA.
PMCID: PMC464365  PMID: 8388578
24.  Clinic HIV-Focused Features and Prevention of Pneumocystis Carinii Pneumonia 
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.
Nonconcurrent prospective study.
New York State Medicaid Program.
Medicaid enrollees diagnosed with AIDS in 1990–1992.
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.
PCP prevention in our study cohort appears to be more successful in clinics offering an array of HIV-focused features.
PMCID: PMC1496898  PMID: 9462490
Pneumocystis carinii pneumonia (PCP); AIDS; clinical competence; ambulatory care; case management
25.  Pharmacokinetics of dapsone in human immunodeficiency virus-infected children. 
Dapsone, administered at various doses and schedules, has been proven to be a safe and effective alternative to trimethoprim-sulfamethoxazole for prevention of Pneumocystis carinii pneumonia (PCP) in adults with human immunodeficiency virus (HIV) infection. Dapsone is also recommended by the Centers for Disease Control for PCP prophylaxis in HIV-infected children. However, the suggested dosage regimen is based upon clinical experience with children with leprosy and dermatitis herpetiformis rather than pharmacokinetic and pharmacodynamic data obtained from the target patient population. In order to determine a rational dosage regimen that could be tested in clinical studies aimed at the evaluation of dapsone for the prevention of PCP in HIV-infected children, we studied the pharmacokinetics of dapsone following a 2-mg/kg of body weight oral dose in twelve HIV-positive children aged 9 months to 9 years. Plasma was collected at the following times after dapsone administration: 0, 2, 4, 6, 12, 24, 48, 72, and 96 h. The levels of dapsone in plasma were determined by high-performance liquid chromatography. Data were analyzed by noncompartmental methods. Expressed as means +/- standard deviations (ranges), the pharmacokinetic parameters were as follows: peak concentration in plasma, 1.12 +/- 0.48 (0.44 to 1.81) mg/liter; time to peak concentration in plasma, 3.8 +/- 1.3 (2 to 6) h; half-life at elimination phase, 24.2 +/- 7.1 (14.4 to 35.0) h; clearance from plasma divided by bioavailability (CL/F), 1.15 +/- 0.67 (0.37 to 2.63) ml/min/kg; and volume of distribution divided by bioavailability (V/F), 2.25 +/- 1.20 (1.00 to 4.57) liters/kg. Oral CL correlated negatively with age (r = 0.614 and P = 0.034), as did V (r = 0.631 and P = 0.028). As a consequence of the high interindividual variability in growth retardation, pharmacokinetic parameters correlated with measures of body development better than they did with age (e.g., for CL/F to height, r = 0.765 and P = 0.004, and for V/F to height, r = 0.748 and P = 0.005). Since oral CL from plasma and V were positively and highly correlated (r = 0.898 and P = 0.0001), a lower absolute F may be the cause, in part, of higher values for CL/F and V/F in smaller children. The results of this study warrant the testing of a 2-mg/kg dose of dapsone administered twice or thrice weekly to HIV-infected children. The monitoring of drug levels in plasma and dosage adjustment may be necessary for smaller children.
PMCID: PMC162691  PMID: 7625796

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