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1.  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
2.  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
3.  Environmental Risk Factors for Pneumocystis Pneumonia Hospitalizations in HIV Patients 
This report identifies both climatological and air pollution constituents as independent risk factors for hospitalization of HIV-positive patients with Pneumocystis pneumonia (PcP). These findings may lead to new insights about the epidemiology and pathogenesis of PcP.
Background. Pneumocystis pneumonia (PcP) is the second leading cause of morbidity and mortality in human immunodeficiency virus (HIV)–infected patients in the United States. Although the host risk factors for the development of PcP are well established, the environmental (climatological, air pollution) risk factors are poorly understood. The major goal of this study was to determine the environmental risk factors for admissions of HIV-positive patients with PcP to a single medical center.
Methods. Between 1997 and 2008, 457 HIV-positive patients with microscopically confirmed PcP were admitted to the San Francisco General Hospital. A case-crossover design was applied to identify environmental risk factors for PcP hospitalizations. Climatological and air pollution data were collected from the Environmental Protection Agency and Weather Warehouse databases. Conditional logistic regression was used to evaluate the association of each environmental factor and PcP hospital admission.
Results. Hospital admissions were significantly more common in the summer than in the other seasons. Increases in temperature and sulfur dioxide levels were independently associated with hospital admissions for PcP, but the effects of sulfur dioxide were modified by increasing carbon monoxide levels.
Conclusions. This study identifies both climatological and air pollution constituents as independent risk factors for hospitalization of HIV-positive patients with PcP in San Francisco. Thus, the environmental effects on PcP are more likely complex than previously thought. Further studies are needed to understand how these factors exert their effects and to determine if these factors are associated with PcP in other geographic locations.
doi:10.1093/cid/cis841
PMCID: PMC3571628  PMID: 23042978
Pneumocystis; PcP; environmental factors; HIV
4.  Prognostic factors influencing the outcome in pneumocystis carinii pneumonia in patients with AIDS. 
Thorax  1995;50(6):668-671.
BACKGROUND--Studies attempting to identify the prognostic factors that influence the outcome of Pneumocystis carinii pneumonia (PCP) in patients with AIDS using a multivariate analysis are few. In order to identify those prognostic factors amenable to medical intervention, univariate and multivariate analyses were performed on 102 patients with AIDS suffering a first episode of PCP. METHODS--One hundred and two consecutive patients with AIDS (51% drug abusers, 45% homosexuals, and 4% with other HIV risk factors) admitted to our institution between 1986 and 1989 whose respiratory infection was diagnosed by bronchoalveolar lavage were studied prospectively. RESULTS--The overall mortality was 28%, rising to 79% in those patients who required mechanical ventilation. According to univariate analysis the following variables were related to a poor prognosis: age > 35 years; risk factor for HIV infection other than drug abuse; and AIDS diagnosis confirmed before 1988; PaO2 < 8 kPa at admission; severe acute respiratory failure on admission (PaO2/FIO2 < 20 kPa); mechanical ventilation; antibiotic therapy for PCP other than trimethoprim-sulphamethoxazole; multiple microbial pulmonary infection; serum lactate dehydrogenase (LDH) > 22.5 mukat/l on admission; serum albumin level < 30 g/l. Multivariate analysis showed that only mechanical ventilation was independently associated with a poor outcome. CONCLUSIONS--The mortality of AIDS patients presenting with a first episode of PCP before 1990 was high (28%). The main prognostic factor associated with poor outcome was the requirement for mechanical ventilation due to severe acute respiratory failure.
PMCID: PMC1021269  PMID: 7638811
5.  Clinical Features and Serum Biomarkers in HIV Immune Reconstitution Inflammatory Syndrome after Cryptococcal Meningitis: A Prospective Cohort Study 
PLoS Medicine  2010;7(12):e1000384.
David Boulware and colleagues investigate clinical features in a prospective cohort with AIDS and recent cryptococcal meningitis after initiation of antiretroviral therapy to identify biomarkers for prediction and diagnosis of CM-IRIS (cryptococcal meninigitis-related immune reconstitution inflammatory syndrome).
Background
Although antiretroviral therapy (ART) improves survival in persons with cryptococcal meningitis (CM) and AIDS, ART frequently elicits HIV immune reconstitution inflammatory syndrome (IRIS), an exaggerated and frequently deadly inflammatory reaction that complicates recovery from immunodeficiency. The pathogenesis of IRIS is poorly understood and prediction of IRIS is not possible.
Methods and Findings
We prospectively followed 101 ART-naïve Ugandans with AIDS and recent CM for one year after initiating ART, and used Luminex multiplex assays to compare serum cytokine levels in participants who did or did not develop IRIS. IRIS occurred in 45% of participants with recent CM on ART, including 30% with central nervous system (CNS) manifestations. The median time to CM-IRIS was 8.8 wk on ART. Overall mortality on ART was 36% with IRIS and 21% without IRIS. CM-IRIS was independently associated with death (HR = 2.3, 95% CI 1.1–5.1, p = 0.04). Patients experiencing subsequent CM-IRIS had 4-fold higher median serum cryptococcal antigen (CRAG) levels pre-ART (p = 0.006). Higher pre-ART levels of interleukin (IL)-4 and IL-17 as well as lower tumor necrosis factor (TNF)-α, granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), and vascular endothelial growth factor (VEGF) predicted future IRIS in multivariate analyses (area under the curve [AUC] = 0.82). An algorithm based on seven pre-ART serum biomarkers was a robust tool for stratifying high (83%), moderate (48%), and low risk (23%) for IRIS in the cohort. After ART was initiated, increasing levels of C-reactive protein (CRP), D-dimer, IL-6, IL-7, IL-13, G-CSF, or IL-1RA were associated with increasing hazard of IRIS by time-to-event analysis (each p≤0.001). At the time of IRIS onset, multiple proinflammatory cytokine responses were present, including CRP and IL-6. Mortality was predicted by pre-ART increasing IL-17, decreasing GM-CSF, and CRP level >32 mg/l (highest quartile). Pre-ART CRP level >32 mg/l alone was associated with future death (OR = 8.3, 95% CI 2.7–25.6, p<0.001).
Conclusions
Pre-ART increases in Th17 and Th2 responses (e.g., IL-17, IL-4) and lack of proinflammatory cytokine responses (e.g., TNF-α, G-CSF, GM-CSF, VEGF) predispose individuals to subsequent IRIS, perhaps as biomarkers of immune dysfunction and poor initial clearance of CRAG. Although requiring validation, these biomarkers might be an objective tool to stratify the risk of CM-IRIS and death, and could be used clinically to guide when to start ART or use prophylactic interventions.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Since 1981, AIDS has killed more than 25 million people and about 33 million people are now infected with HIV, which causes AIDS. HIV, which is most often transmitted through unprotected sex with an HIV-infected partner, infects and kills immune system cells. Eventually, the immune system becomes so weak that unusual infections begin to occur. These “opportunistic” infections are infections that take advantage of the opportunity offered by a weakened immune system. One common and deadly opportunistic infection in people affected by AIDS is cryptococcal meningitis (CM), an infection around the brain that is caused by the fungus Cryptococcus neoformans. About one million cases of CM occur every year. CM can be treated with a drug called amphotericin but usually recurs unless another drug called fluconazole is taken daily thereafter. HIV therapy is lifesaving by suppressing the HIV virus and allowing immune system recovery. This immune recovery also helps to prevent the recurrence of CM.
Why Was This Study Done?
Unfortunately, HIV therapy can also elicit a serious condition called immune reconstitution inflammatory syndrome (IRIS) in people with CM and AIDS. IRIS is an exaggerated inflammatory immune response that kills up to one-third of affected people. Inflammation, which is characterized by swelling and redness, is the body's first defense against infection, but uncontrolled inflammation causes widespread tissue damage. Experts think that CM-IRIS may be the result of an unbalanced recovery of the immune system leading to an inappropriate immune response to persisting C. neoformans fragments and proteins that are slowly cleared from the body over months. Unfortunately, it is impossible to predict which individuals with CM and AIDS will develop IRIS when they are given HIV therapy. In this prospective study, the researchers investigated clinical features and cytokine profiles in a group of Ugandans with AIDS and recent CM for one year after starting HIV therapy to identify biomarkers that could be used to predict and diagnose CM-IRIS. Cytokines are proteins secreted by immune system cells that regulate the immune response; biomarkers are proteins found in the blood that indicate specific diseases.
What Did the Researchers Do and Find?
The researchers enrolled 101 Ugandans with AIDS and recent CM who had not previously received HIV therapy. They compared cytokine patterns in individuals who did and did not subsequently develop IRIS after starting HIV therapy. Overall, 45% of the patients developed IRIS. Deaths occurred in 36% of the patients who developed IRIS and in 21% of those who did not develop IRIS. Patients who developed CM-IRIS after starting HIV therapy had 4-fold higher baseline concentrations of cryptococcal antigen in their blood than patients who did not develop CM-IRIS. Prior to starting HIV therapy, higher levels of the cytokines IL-4 and IL-17 and lower levels of four cytokines—TNF-α, G-CSF, GM-CSF, and VEGF—predicted IRIS development, and an algorithm (formula) based on the baseline levels of seven serum biomarkers was able to group the patients into high, moderate, and low risk of IRIS. After starting HIV therapy, increasing levels of the inflammatory proteins C-reactive protein and D-dimer, and of several cytokines, were associated with an increased risk of IRIS. At the time of IRIS onset, the levels of many proinflammatory cytokine increased. Biomarkers also predicted death after starting HIV therapy with increasing levels of IL-17, decreasing levels of GM-CSF, and a C-reactive protein level of more than 32 mg/l (four times higher than normal) predicted death within one year.
What Do These Findings Mean?
These findings support the hypothesis that some AIDS patients who have a very damaged immune system have a very poor initial immune response and poor clearance of cryptococcus, which predisposes them to IRIS. The findings also identify three distinct phases of IRIS development. Before HIV therapy, a very damaged immune system with a lack of inflammatory responses to infection or inappropriate responses leads to ineffective clearance of the organism and its antigens. After HIV therapy is started, the presence of copious antigens promotes proinflammatory signaling to the immune system. As the immune system recovers proinflammatory immune cells are promoted. Finally, at the time of IRIS, a generalized “cytokine storm” occurs, which is potentially fatal when this inflammation occurs in the brain. The biomarkers identified here as indicators of a predisposition to IRIS need to be validated in more patients in more countries before they can be used as a clinical tool for predicting the risk of IRIS. If they are validated, they could help clinicians decide when to start HIV therapy in patients with AIDS and recent CM, and could guide the use of therapies that could help prevent the abnormal inflammatory responses.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000384.
The US National Institute of Allergy and Infectious Diseases provides information on HIV infection and AIDS
HIV InSite has information on all aspects of HIV/AIDS, including Knowledge Base Chapters on cryptococcosis and HIV and on the clinical implications of IRIS
Information is available from Avert, an international AIDS charity on all aspects of HIV/AIDS, including HIV-related opportunistic infections (in English and Spanish)
The MedlinePlus encyclopedia has a page on cryptococcal meningitis (in English and Spanish)
AIDS InfoNet provides fact sheets on many HIV/AIDS topics, including a fact sheet on cryptococcal meningitis (in several languages) and treatment guidelines for opportunistic infections
doi:10.1371/journal.pmed.1000384
PMCID: PMC3014618  PMID: 21253011
6.  HIV-related Pneumocystis carinii Pneumonia in Older Patients Hospitalized in the Early HAART Era 
OBJECTIVE
To determine whether older age continues to influence patterns of care and in-hospital mortality for hospitalized persons with HIV-related Pneumocustis carinii pneumonia (PCP), as determined in our prior study from the 1980s.
DESIGN
Retrospective chart review.
PATIENTS/SETTING
Patients (1,861) with HIV-related PCP at 78 hospitals in 8 cities from 1995 to 1997.
MEASUREMENTS
Medical record notation of possible HIV infection; alveolar-arterial oxygen gradient; CD4 lymphocyte count; presence or absence of wasting; timely use of anti-PCP medications; in-hospital mortality.
MAIN RESULTS
Compared to younger patients, patients ≥50 years of age were less likely to have HIV mentioned in their progress notes (70% vs 82%, P < .001), have mild or moderately severe PCP cases at admission (89% vs 96%, P < .002), receive anti-PCP medications within the first 2 days of hospitalization (86% vs 93%, P <.002), and survive hospitalization (82% vs 90%, P < .003). However, age was not a significant predicator of mortality after adjustment for severity of PCP and timeliness of therapy.
CONCLUSIONS
While inpatient PCP mortality has improved by 50% in the past decade, 2-fold age-related mortality differences persist. As in the 1980s, these differences are associated with lower rates of recognition of HIV, increased severity of illenss at admission, and delays in initiation of PCP-specific treatments among older individuals—factors suggestive of delayed recognition of HIV infection, pneumonia, and PCP, respectively. Continued vigilance for the possibility of HIV and HIV-related PCP among persons ≥50 years of age who present with new pulmonary symptoms should be encouraged.
doi:10.1046/j.1525-1497.2001.016009583.x
PMCID: PMC1495267  PMID: 11556938
HIV; Pneumocystis carinii pneumonia; age; quality of care; outcomes
7.  Inflammatory and Coagulation Biomarkers and Mortality in Patients with HIV Infection 
PLoS Medicine  2008;5(10):e203.
Background
In the Strategies for Management of Anti-Retroviral Therapy trial, all-cause mortality was higher for participants randomized to intermittent, CD4-guided antiretroviral treatment (ART) (drug conservation [DC]) than continuous ART (viral suppression [VS]).
We hypothesized that increased HIV-RNA levels following ART interruption induced activation of tissue factor pathways, thrombosis, and fibrinolysis.
Methods and Findings
Stored samples were used to measure six biomarkers: high sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), amyloid A, amyloid P, D-dimer, and prothrombin fragment 1+2. Two studies were conducted: (1) a nested case–control study for studying biomarker associations with mortality, and (2) a study to compare DC and VS participants for biomarker changes. For (1), markers were determined at study entry and before death (latest level) for 85 deaths and for two controls (n = 170) matched on country, age, sex, and date of randomization. Odds ratios (ORs) were estimated with logistic regression. For each biomarker, each of the three upper quartiles was compared to the lowest quartile. For (2), the biomarkers were assessed for 249 DC and 250 VS participants at study entry and 1 mo following randomization. Higher levels of hsCRP, IL-6, and D-dimer at study entry were significantly associated with an increased risk of all-cause mortality. Unadjusted ORs (highest versus lowest quartile) were 2.0 (95% confidence interval [CI], 1.0–4.1; p = 0.05), 8.3 (95% CI, 3.3–20.8; p < 0.0001), and 12.4 (95% CI, 4.2–37.0; p < 0.0001), respectively. Associations were significant after adjustment, when the DC and VS groups were analyzed separately, and when latest levels were assessed. IL-6 and D-dimer increased at 1 mo by 30% and 16% in the DC group and by 0% and 5% in the VS group (p < 0.0001 for treatment difference for both biomarkers); increases in the DC group were related to HIV-RNA levels at 1 mo (p < 0.0001). In an expanded case–control analysis (four controls per case), the OR (DC/VS) for mortality was reduced from 1.8 (95% CI, 1.1–3.1; p = 0.02) to 1.5 (95% CI, 0.8–2.8) and 1.4 (95% CI, 0.8–2.5) after adjustment for latest levels of IL-6 and D-dimer, respectively.
Conclusions
IL-6 and D-dimer were strongly related to all-cause mortality. Interrupting ART may further increase the risk of death by raising IL-6 and D-dimer levels. Therapies that reduce the inflammatory response to HIV and decrease IL-6 and D-dimer levels may warrant investigation.
Trial Registration: ClinicalTrials.gov (NCT00027352).
Analyzing biomarker data from participants in a previous randomized controlled trial of continuous versus interrupted HIV treatment (the SMART trial), James Neaton and colleagues find that mortality was related to IL-6 and fibrin D-dimers.
Editors' Summary
Background.
Globally, more than 30 million people are infected with the human immunodeficiency virus (HIV), the virus that causes acquired immunodeficiency syndrome (AIDS). HIV infects and destroys immune system cells (including CD4 cells, a type of lymphocyte). The first stage of HIV infection can involve a short flu-like illness but in the second stage, which can last many years, HIV replicates in the lymph glands (small immune system organs throughout the body) without causing any symptoms. Eventually, however, the immune system becomes so damaged that HIV-infected individuals begin to succumb to “opportunistic” infections (for example, bacterial pneumonia) and cancers (in particular, Karposi sarcoma) that the immune system would normally prevent. AIDS itself is characterized by one or more severe opportunistic infections or cancers (so-called AIDS-related diseases) and by a low blood CD4 cell count. HIV infections cannot be cured but antiretroviral therapy (ART)—combinations of powerful antiretroviral drugs—can keep them in check, so many HIV-positive people now have substantially improved life expectancy.
Why Was This Study Done?
Unfortunately, the effectiveness of ART sometimes wanes over time and prolonged ART can cause unpleasant side effects. Consequently, alternative ART regimens are continually being tested in clinical trials. In the Strategies for Management of Anti-Retroviral Therapy (SMART) trial, for example, HIV-positive patients received either continuous ART (the viral suppression or VS arm), or ART only when their CD4 cell counts were below 250 cells/mm3 (the drug conservation or DC arm; the normal adult CD4 cell count is about 1,000 cells/mm3). Unexpectedly, more people died in the DC arm than in the VS arm from non-AIDS diseases (including heart and circulation problems), a result that led to the trial being stopped early. One possible explanation for these excess deaths is that increased HIV levels following ART interruption might have induced an inflammatory response (a non-specific immune response that occurs with infection or wounding) and/or a hypercoagulable state (a condition in which blood clots form inside undamaged blood vessels) and that these changes increased the risk of death from non-AIDS diseases. In this study, the researchers test this hypothesis.
What Did the Researchers Do and Find?
The researchers measured the levels of proteins that indicate the presence of inflammation or increased coagulation (biomarkers) in stored blood samples from the 85 people who died during the SMART trial (55 and 30 of the participants assigned to receive DC and VS, respectively) and from 170 survivors who served as comparison (control) participants. (Two control participants were “matched” to each participant who had died (cases). In this “case-control” study, an increased risk of death was associated with higher levels at study entry of the inflammation biomarkers high-sensitivity C-reactive protein (hsCRP) and interleukin 6 (IL-6) and of the coagulation biomarker D-dimer. The risk of death among people with hsCRP values in the highest quarter of measured values was twice that among people with hsCRP values in the lowest quarter (this is expressed as an odds ratio of 2). For IL-6 and D-dimer, the equivalent odds ratios were 8.3 and 12.4, respectively. Furthermore, increases in hsCRP, IL-6 and D-dimer after study entry were associated with an increased risk of death. The researchers also measured blood levels of the same biomarkers in 250 randomly chosen patients from each of the two treatment arms. IL-6 levels increased by 30% over the first month of the trial in the DC arm but were unchanged in the VS arm. Over the same period, D-dimer levels increased by 16% and 5% in the DC and VS arms, respectively. Increases in both markers in the DC arm were related to HIV RNA levels after one month.
What Do These Findings Mean?
Taken together, these findings suggest that HIV-induced activation of inflammation and coagulation increases the risk of death among HIV-positive patients and that interrupting ART further increases this risk, possibly by increasing IL-6 and D-dimer levels. Because only a small number of people died in this study, the relationship between these biomarkers and death and illness among treated and untreated HIV-positive individuals needs to be confirmed in further studies. However, these findings suggest that the development of therapies that reduce the effect that HIV replication has on inflammation and blood coagulation, or that reduce IL-6 and D-dimer levels, might extend the life-expectancy of HIV-positive people.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050203.
Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS and about the SMART trial
HIV InSite has comprehensive information on all aspects of HIV/AIDS
Information is also available from Avert, an international AIDS charity, on HIV/AIDS
More information about the SMART trial is available on ClinicalTrials.gov, a database of clinical trials maintained by the US National Institutes of Health
doi:10.1371/journal.pmed.0050203
PMCID: PMC2570418  PMID: 18942885
8.  Humoral Immune Responses to Pneumocystis jirovecii Antigens in HIV-Infected and Uninfected Young Children with Pneumocystis Pneumonia 
PLoS ONE  2013;8(12):e82783.
Background
Humoral immune responses in human immunodeficiency virus (HIV)-infected and uninfected children with Pneumocystis pneumonia (PcP) are poorly understood.
Methods
Consecutive children hospitalized with acute pneumonia, tachypnea, and hypoxia in South Africa were investigated for PcP, which was diagnosed by real-time polymerase chain reaction on lower respiratory tract specimens. Serum antibody responses to recombinant fragments of the carboxyl terminus of Pneumocystis jirovecii major surface glycoprotein (MsgC) were analyzed.
Results
149 children were enrolled of whom 96 (64%) were HIV-infected. PcP occurred in 69 (72%) of HIV-infected and 14 (26%) of HIV-uninfected children. HIV-infected children with PcP had significantly decreased IgG antibodies to MsgC compared to HIV-infected patients without PcP, but had similar IgM antibodies. In contrast, HIV-uninfected children with PcP showed no change in IgG antibodies to MsgC, but had significantly increased IgM antibodies compared to HIV-uninfected children without PCP. Age was an independent predictor of high IgG antibodies, whereas PcP was a predictor of low IgG antibodies and high IgM antibodies. IgG and IgM antibody levels to the most closely related MsgC fragments were predictors of survival from PcP.
Conclusions
Young HIV-infected children with PcP have significantly impaired humoral immune responses to MsgC, whereas HIV-uninfected children with PcP can develop active humoral immune responses. The children also exhibit a complex relationship between specific host factors and antibody levels to MsgC fragments that may be related to survival from PcP.
doi:10.1371/journal.pone.0082783
PMCID: PMC3873266  PMID: 24386119
9.  Pneumocystis jiroveci pneumonia and pneumomediastinum in an anti-TNFα naive patient with ulcerative colitis 
We report the case of a 21-year-old man who was noted to have pneumomediastinum during an admission for an acute flare of ulcerative colitis. At that time, he was on maintenance treatment with azathioprine at a dose of 1.25 mg/kg per day, and had not received supplementary steroids for 9 mo. He had never received anti-tumor necrosis factor (TNF)α therapy. Shortly after apparently effective treatment with intravenous steroids and an increased dose of azathioprine, he developed worsening colitic and new respiratory symptoms, and was diagnosed with Pneumocystis jiroveci (carinii) pneumonia (PCP). Pneumomediastinum is rare in immunocompetent hosts, but is a recognized complication of PCP in human immunodeficiency virus (HIV) patients, although our patient’s HIV test was negative. Treatment of PCP with co-trimoxazole resulted in resolution of both respiratory and gastrointestinal symptoms, without the need to increase the steroid dose. There is increasing vigilance for opportunistic infections in patients with inflammatory bowel disease following the advent of anti-TNFα therapy. This case emphasizes the importance of considering the possibility of such infections in all patients with inflammatory bowel disease, irrespective of the immunosuppressants they receive, and highlights the potential of steroid-responsive opportunistic infections to mimic worsening colitic symptoms in patients with ulcerative colitis.
doi:10.3748/wjg.15.1897
PMCID: PMC2670420  PMID: 19370790
Pneumocystis jiroveci; Ulcerative colitis; Pneumomediastinum; Azathioprine; Corticosteroids
10.  Pneumocystis Pneumonia in HIV-Infected and Immunocompromised Non-HIV Infected Patients: A Retrospective Study of Two Centers in China 
PLoS ONE  2014;9(7):e101943.
Background
Pneumocystis pneumonia (PCP) is an emerging infectious disease in immunocompromised hosts. However, the clinical characteristics of these patients are poorly understood in mainland China.
Methods
We performed a retrospective study of PCP from 2008 to 2012. Information was collected regarding clinical manifestations, hospitalization, and outcome. A prognostic analysis was performed using a Cox regression model.
Results
151 cases of PCP were included; 46 non-HIV and 105 HIV cases. All-cause mortality (15.2% vs. 12.4%, p = 0.64) and the results of time-to-event analysis (log-rank test, p = 0.62) were similar between non-HIV and HIV infected cases, respectively. From 2008 to 2012, time from admission to initial treatment in non-HIV infected PCP patients showed declining trend [median (range) 20 (9–44) vs. 12 (4–24) vs. 9 (2–23) vs. 7 (2–22) vs. 7 (1–14) days]. A similar trend was observed for all-cause mortality (33.3% vs. 20.0% vs.14.3% vs. 14.3% vs. 6.7%). Patients with four or more of the following clinical manifestations (cough, dyspnea, fever, chest pain, and weight loss) [adjusted HR (AHR) 29.06, 95% CI 2.13–396.36, P = 0.01] and admission to intensive care unit (ICU) [AHR 22.55, 95% CI 1.36–375.06, P = 0.03] were independently associated with all-cause mortality in non-HIV infected PCP patients. Variables associated with mortality in HIV infected PCP patients were admission to ICU (AHR 72.26, 95% CI 11.76–443.87, P<0.001) and albumin ≤30 g/L (AHR 9.93 95% CI 1.69–58.30, P = 0.01).
Conclusions
Upon admission comprehensive clinical assessment including assessment of four or more clinical manifestations (cough, dyspnea, fever, chest pain, and weight loss) in non-HIV infected PCP patients and albumin ≤30 g/L in HIV infected patients might improve prognosis.
doi:10.1371/journal.pone.0101943
PMCID: PMC4100803  PMID: 25029342
11.  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
12.  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
13.  Time-dependent changes of plasma inflammatory biomarkers in type A aortic dissection patients without optimal medical management 
Objectives
To investigate the time-dependent changes in plasma levels of interleukin-6, C-reactive protein, and tumor necrosis factor-α in patients with type A aortic dissection (TAAD) who received unoptimal medical management since the onset of dissections.
Design and methods
Plasma levels of interleukin-6, C-reactive protein, and tumor necrosis factor-α were detected by ELISA and immuno-turbidimetric assay in 92 TAAD patients at hospital admission. Blood samples from 78 patients with uncontrolled hypertension and 82 healthy volunteers were also analyzed as controls. The occurrence of TAAD-related complication and its relationship with the plasma levels of these inflammatory biomarkers was also investigated.
Results
The concentrations of inflammatory mediators were significant higher in TAAD than those in the uncontrolled hypertension and the healthy group. The time to peak plasma level of IL-6.and TNF-α was shorter than that of CRP in TAAD group. In the TAAD group, 51 patients suffered TAAD-related complications, and their plasma level of CRP was significantly higher than that in patients without TAAD-related complications (94.5 ± 58.8 mg/L versus 47.4 ± 47.8 mg/L, p < 0.001). Also, CRP levels strongly correlated with the value of PaO2/FiO2 ratio (r = −0.69, p < 0.001) and creatinine (r = 0.60, p < 0.001). The time to the peak level of CRP was shorter and the duration of persistently high CRP level was longer in the complication group than those in the complication-free group.
Conclusions
Elevated and persistently high levels of plasma CRP, IL-6 and TNF-α were associated with progressively development of the TAAD. The changing pattern of CRP might be a marker for diagnosis and prophylactic treatment of complications. Our findings suggested a critical role of the inflammation in the progression of dissection and TAAD-related complications.
doi:10.1186/s13019-014-0199-0
PMCID: PMC4302155  PMID: 25592634
Type A aortic dissection; Inflammatory mediator; Interleukin-6; C-reactive protein; Tumor necrosis factor-α; Complication
14.  Causes of Acute Hospitalization in Adolescence: Burden and Spectrum of HIV-Related Morbidity in a Country with an Early-Onset and Severe HIV Epidemic: A Prospective Survey 
PLoS Medicine  2010;7(2):e1000178.
Rashida Ferrand and colleagues show that HIV infection is the commonest cause of hospitalization among adolescents in a high HIV prevalence setting.
Background
Survival to older childhood with untreated, vertically acquired HIV infection, which was previously considered extremely unusual, is increasingly well described. However, the overall impact on adolescent health in settings with high HIV seroprevalence has not previously been investigated.
Methods and Findings
Adolescents (aged 10–18 y) systematically recruited from acute admissions to the two public hospitals in Harare, Zimbabwe, answered a questionnaire and underwent standard investigations including HIV testing, with consent. Pre-set case-definitions defined cause of admission and underlying chronic conditions. Participation was 94%. 139 (46%) of 301 participants were HIV-positive (median age of diagnosis 12 y: interquartile range [IQR] 11–14 y), median CD4 count = 151; IQR 57–328 cells/µl), but only four (1.3%) were herpes simplex virus-2 (HSV-2) positive. Age (median 13 y: IQR 11–16 y) and sex (57% male) did not differ by HIV status, but HIV-infected participants were significantly more likely to be stunted (z-score<−2: 52% versus 23%, p<0.001), have pubertal delay (15% versus 2%, p<0.001), and be maternal orphans or have an HIV-infected mother (73% versus 17%, p<0.001). 69% of HIV-positive and 19% of HIV-negative admissions were for infections, most commonly tuberculosis and pneumonia. 84 (28%) participants had underlying heart, lung, or other chronic diseases. Case fatality rates were significantly higher for HIV-related admissions (22% versus 7%, p<0.001), and significantly associated with advanced HIV, pubertal immaturity, and chronic conditions.
Conclusion
HIV is the commonest cause of adolescent hospitalisation in Harare, mainly due to adult-spectrum opportunistic infections plus a high burden of chronic complications of paediatric HIV/AIDS. Low HSV-2 prevalence and high maternal orphanhood rates provide further evidence of long-term survival following mother-to-child transmission. Better recognition of this growing phenomenon is needed to promote earlier HIV diagnosis and care.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Acquired immunodeficiency syndrome (AIDS) has killed more than 25 million people since 1981, and more than 30 million people are now infected with the human immunodeficiency virus (HIV) that causes AIDS. HIV destroys the cells in the immune system that normally provide protection against disease-causing organisms. Consequently, people infected with HIV are susceptible to so-called opportunistic infections, including tuberculosis and pneumonia. HIV is most commonly spread through unprotected sex with an infected partner but another major route of transmission is mother-to-child (vertical transmission) during pregnancy or delivery or during breast feeding. Mother-to-child transmission can be prevented by giving antiviral drugs to HIV-positive mothers during their pregnancy and to their newborn children. But, although most mothers in developed countries have access to this intervention, fewer than half of HIV-positive mothers in low- and middle-income countries receive this treatment and, every year, nearly half a million children become infected with HIV.
Why Was This Study Done?
It is generally thought that HIV infections in infants progress rapidly and that half of the children who acquire HIV from their mothers will die before their second birthday if not treated with antiretroviral drugs. However, as the AIDS epidemic matures, more children are surviving to adolescence with untreated, vertically acquired HIV infection in sub-Saharan Africa, the region where most children with HIV/AIDS live. Little is known about the burden of HIV infection and its contribution to illness and death in adolescents in sub-Saharan Africa but this information is needed to help health care providers prepare for this new aspect of the AIDS epidemic. In this study, the researchers examine the causes of acute hospital admissions (admissions for conditions with a sudden onset and usually a short course) among adolescents in Zimbabwe, a country where the HIV epidemic started early and where one in seven adults is HIV-positive and more than 17,000 children are infected with HIV every year, mainly through vertical transmission.
What Did the Researchers Do and Find?
The researchers recruited 301 10–18-year olds who were admitted to each of the two public hospitals in Harare (Zimbabwe) for acute illnesses between September 2007 and April 2008. Each patient completed a questionnaire about themselves and their health and underwent standard investigations, including HIV testing. Nearly half the participants were HIV positive; about a quarter of these HIV-positive individuals only found out about their status during the study. HIV-positive participants were more likely to be stunted, to have pubertal delay, and to be maternal orphans or have an HIV-infected mother than HIV-negative participants. 69% of HIV-positive participants were admitted to hospital because of infections, often tuberculosis or pneumonia whereas only 19% of the HIV-negative participants were admitted for infections. More than a quarter of all the participants had underlying heart, lung, or other chronic conditions. Finally, 22% of the HIV-positive participants died while in hospital compared to only 7% of the HIV-negative participants. Factors that increased the risk of death among all the participants were advanced HIV infection, pubertal immaturity, and chronic conditions.
What Do These Findings Mean?
These findings indicate that HIV infection is the commonest cause of acute adolescent admission to hospital in Harare (and probably elsewhere in Zimbabwe). Most of these admissions are due to opportunistic infections similar to those seen in HIV-positive adults and to long-term complications of having HIV/AIDS as an infant such as delayed puberty. Other findings indicate that most of the HIV-positive adolescents who participated in this study were infected via vertical transmission, which supports the idea that long-term survival after vertical infection is possible. Because the AIDS epidemic started early in Zimbabwe, there is likely to be a lag before adolescent survivors of vertical HIV transmission become common elsewhere. Nevertheless, all African countries and other places where HIV infection in adults is common need to recognize that the burden of HIV in their acutely unwell adolescents is likely to increase over the next few years. To deal with this emerging aspect of the AIDS epidemic, measures must be introduced to ensure early diagnosis of HIV in this previously neglected age group so that treatment can be started before HIV-positive adolescents become critically ill.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000178.
This study is further discussed in a PLoS Medicine Perspective by Glenda Gray
Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS
HIV InSite has comprehensive information on all aspects of HIV/AIDS, including a list of articles and other sources of information about the primary care of adolescents with HIV
Information is available from Avert, an international AIDS charity on many aspects of HIV/AIDS, including information on the HIV and AIDS in Zimbabwe, and on children, HIV, and AIDS (in English and Spanish)
UNICEF also has information about children and HIV and AIDS (in several languages)
doi:10.1371/journal.pmed.1000178
PMCID: PMC2814826  PMID: 20126383
15.  A Genetic Association Study of Serum Acute-Phase C-Reactive Protein Levels in Rheumatoid Arthritis: Implications for Clinical Interpretation 
PLoS Medicine  2010;7(9):e1000341.
A genetic association study by Timothy Vyse and colleagues suggests that there is a significant association between CRP variants and acute-phase serum CRP concentrations in patients with rheumatoid arthritis, including those with chronic inflammation.
Background
The acute-phase increase in serum C-reactive protein (CRP) is used to diagnose and monitor infectious and inflammatory diseases. Little is known about the influence of genetics on acute-phase CRP, particularly in patients with chronic inflammation.
Methods and Findings
We studied two independent sets of patients with chronic inflammation due to rheumatoid arthritis (total 695 patients). A tagSNP approach captured common variation at the CRP locus and the relationship between genotype and serum CRP was explored by linear modelling. Erythrocyte sedimentation rate (ESR) was incorporated as an independent marker of inflammation to adjust for the varying levels of inflammatory disease activity between patients. Common genetic variants at the CRP locus were associated with acute-phase serum CRP (for the most associated haplotype: p = 0.002, p<0.0005, p<0.0005 in patient sets 1, 2, and the combined sets, respectively), translating into an approximately 3.5-fold change in expected serum CRP concentrations between carriers of two common CRP haplotypes. For example, when ESR = 50 mm/h the expected geometric mean CRP (95% confidence interval) concentration was 43.1 mg/l (32.1–50.0) for haplotype 1 and 14.2 mg/l (9.5–23.2) for haplotype 4.
Conclusions
Our findings raise questions about the interpretation of acute-phase serum CRP. In particular, failure to take into account the potential for genetic effects may result in the inappropriate reassurance or suboptimal treatment of patients simply because they carry low-CRP–associated genetic variants. CRP is increasingly being incorporated into clinical algorithms to compare disease activity between patients and to predict future clinical events: our findings impact on the use of these algorithms. For example, where access to effective, but expensive, biological therapies in rheumatoid arthritis is rationed on the basis of a DAS28-CRP clinical activity score, then two patients with identical underlying disease severity could be given, or denied, treatment on the basis of CRP genotype alone. The accuracy and utility of these algorithms might be improved by using a genetically adjusted CRP measurement.
Please see later in the article for the Editors' Summary
Editors' Summary
C-reactive protein (CRP) is a serum marker for inflammation or infection and acts by binding to a chemical (phosphocholine) found on the surface of dead or dying cells (and some types of bacteria) in order to activate the immune system (via the complement system). Fat cells release factors that stimulate the liver to produce CRP, and serum levels greater than 10 mg/l are generally considered indicative of an infectious or inflammatory process. After an inflammatory stimulus, serum CRP levels may exceed 500 times baseline, so CRP is used in all medical specialities to help diagnose inflammation and infection. Although patients with chronic inflammatory diseases, such as rheumatoid arthritis, have raised levels of CRP, levels of CRP are still highly variable. Some studies have suggested that there may be genetic variations of CRP (CRP variants) that determine the magnitude of the acute-phase CRP response, a finding that has important clinical implications: CRP thresholds are used as a diagnostic component of formal clinical algorithms and play an important role in a clinician's decision-making process when diagnosing inflammatory disease and choosing treatment options. Therefore, it is possible that false reassurance could be given to a patient with disease, or optimal treatment withheld, because some patients are genetically predisposed to have only a modest increase in acute-phase CRP.
Why Was This Study Done?
Although some studies have looked at the CRP gene variant response, few, if any, studies have examined the CRP gene variant response in the context of chronic inflammation, such as in rheumatoid arthritis. Therefore, this study aimed to determine whether CRP gene variants could also influence CRP serum levels in rheumatoid arthritis.
What Did the Researchers Do and Find?
The authors studied two independent sets of patients with chronic inflammation due to rheumatoid arthritis (total 695 patients): one patient set used a cohort of 281 patients in the UK, and the other patient set (used for replication) consisted of 414 patients from New Zealand and Australia. A genetic technique (a tagSNP approach) was used to capture common variations at the CRP locus (haplotype association analysis) at both the population and the individual level. The relationship between genotype and serum CRP was explored by linear modeling. The researchers found that common genetic variants at the CRP locus were associated with acute-phase serum CRP in both patient sets translating into an approximate 3.5-fold change in expected serum CRP between carriers of two common CRP variants. For example, when ESR = 50 mm/h the expected CRP serum level for one common CRP variant was 43.1 mg/l and for another CRP variant was 14.2 mg/l.
What Do These Findings Mean?
The findings of this study raise questions about the interpretation of acute-phase serum CRP, as they suggest that there is a significant association between CRP variants and acute-phase serum CRP concentrations in a group of patients with rheumatoid arthritis, including those with chronic active inflammation. The size of the genetic effect may be large enough to have a clinically relevant impact on the assessment of inflammatory disease activity, which in turn may influence therapeutic decision making. Failure to take into account the potential for genetic effects may result in the inappropriate reassurance or undertreatment of patients simply because they carry low-CRP–associated genetic variants. CRP is increasingly being incorporated into clinical algorithms to compare disease activity between patients and to predict future clinical events, so these findings impact on the use of such algorithms. The accuracy and utility of these algorithms might be improved by using a genetically adjusted CRP measurement.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000341
Lab Test Online provides information on CRP
The Wellcome Trust provides a glossary of genetic terms
Learn.Genetics provides access to the Genetic Science Learning Center, which is part of the human genome project
doi:10.1371/journal.pmed.1000341
PMCID: PMC2943443  PMID: 20877716
16.  Sepsis in AIDS patients: clinical, etiological and inflammatory characteristics 
Introduction
Intensive care mortality of HIV-positive patients has progressively decreased. However, critically ill HIV-positive patients with sepsis present a worse prognosis. To better understand this condition, we propose a study comparing clinical, etiological and inflammatory data, and the hospital course of HIV-positive and HIV-negative patients with severe sepsis or septic shock.
Methods
A prospective observational study enrolling patients with severe sepsis or septic shock associated or not with HIV infection, and admitted to intensive care unit (ICU). Clinical, microbiological and inflammatory parameters were assessed, including C-reactive protein (CRP), procalcitonin (PCT), interleukin-6, interleukin-10 and TNF-α. Outcome measures were in-hospital and six-month mortality.
Results
The study included 58 patients with severe sepsis/septic shock admitted to ICU, 36 HIV-positive and 22 HIV-negative. All HIV-positive patients met the criteria for AIDS (CDC/2008). The main foci of infection in HIV-positive patients were pulmonary and abdominal (p=0.001). Fungi and mycobacteria were identified in 44.4% and 16.7% of HIV-positive patients, respectively. In contrast, the main etiologies for sepsis in HIV-negative patients were Gram-negative bacilli (36.4%) and Gram-positive cocci (36.4%) (p=0.001). CRP and PCT admission concentrations were lower in HIV-positive patients (130 vs. 168 mg/dL p=0.005, and 1.19 vs. 4.06 ng/mL p=0.04, respectively), with a progressive decrease in surviving patients. Initial IL-10 concentrations were higher in HIV-positive patients (4.4 pg/mL vs. 1.0 pg/mL, p=0.005), with moderate accuracy for predicting death (area under receiver-operating characteristic curve =0.74). In-hospital and six-month mortality were higher in HIV-positive patients (55.6 vs. 27.3% p=0.03, and 58.3 vs. 27.3% p=0.02, respectively).
Conclusions
The course of sepsis was more severe in HIV-positive patients, with distinct clinical, etiological and inflammatory characteristics.
doi:10.7448/IAS.16.1.17344
PMCID: PMC3564973  PMID: 23374857
sepsis; HIV; AIDS; etiology; inflammatory markers; mortality
17.  Ambient Air Pollution Associated with Suppressed Serologic Responses to Pneumocystis jirovecii in a Prospective Cohort of HIV-Infected Patients with Pneumocystis Pneumonia 
PLoS ONE  2013;8(11):e80795.
Background
Ambient air pollution (AAP) may be associated with increased risk for Pneumocystis pneumonia (PCP). The mechanisms underlying this association remain uncertain.
Objectives
To determine if real-life exposures to AAP are associated with suppressed IgM antibody responses to P. jirovecii in HIV-infected (HIV+) patients with active PCP, and to determine if AAP, mediated by suppressed serologic responses to Pneumocystis, is associated with adverse clinical outcomes.
Methods
We conducted a prospective cohort study in HIV+ patients residing in San Francisco and admitted to San Francisco General Hospital with microscopically confirmed PCP. Our AAP predictors were ambient air concentrations of particulate matter of < 10 µm in diameter (PM10) and < 2.5 µm in diameter (PM2.5), nitrogen dioxide (NO2), ozone (O3), and sulfur dioxide (SO2) measured immediately prior to hospital admission and 2 weeks prior to admission. Our primary outcomes were the IgM serologic responses to four recombinant P. jirovecii major surface glycoprotein (Msg) constructs: MsgC1, MsgC3, MsgC8, and MsgC9.
Results
Elevated PM10 and NO2 exposures immediately prior to and two weeks prior to hospital admission were associated with decreased IgM antibody responses to P. jirovecii Msg. For exposures immediately prior to admission, every 10 µg/m3 increase in PM10 was associated with a 25 to 35% decrease in IgM responses to Msg (statistically significant for all the Msg constructs), and every 10 ppb increase in NO2 was associated with a 19-45% decrease in IgM responses to Msg (statistically significant for MsgC8 and MsgC9). Similar findings were seen with exposures two weeks prior to admission, but for fewer of the Msg constructs.
Conclusions
Real life exposures to PM10 and NO2 were associated with suppressed IgM responses to P. jirovecii Msg in HIV+ patients admitted with PCP, suggesting a mechanism of immunotoxicity by which AAP increases host susceptibility to pulmonary infection.
doi:10.1371/journal.pone.0080795
PMCID: PMC3827464  PMID: 24236202
18.  The impact of concomitant pulmonary infection on immune dysregulation in Pneumocystis jirovecii pneumonia 
BMC Pulmonary Medicine  2014;14(1):182.
Background
Concurrent infection may be found in Pneumocystis jirovecii pneumonia (PJP) of non-acquired immunodeficiency syndrome (AIDS) patients, however, its impact on immune dysregulation of PJP in non-AIDS patients remains unknown.
Methods
We measured pro-inflammatory cytokines including tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-8, IL-17, monocyte chemoattractant protein-1 (MCP-1) and anti-inflammatory cytokines including IL-10 and transforming growth factor (TGF)-β1 and IL-1 receptor antagonist (IL-1RA) and inflammatory markers including high mobility group box 1, Krebs von den Lungen-6, receptor for advanced glycation end product, advanced glycation end product, surfactant protein D in bronchoalveolar lavage fluid (BALF) and blood in 47 pure PcP and 18 mixed PJP and other pulmonary infections (mixed PJP) in non-AIDS immunocompromised patients and explored their clinical relevance. The burden of Pneumocystis jirovecii in the lung was determined by counting number of clusters of Pneumocystis jirovecii per slide and the concentration of β-D-glucan in BALF. PJP severity was determined by arterial oxygen tension/fraction of inspired oxygen concentration ratio, the need of mechanical ventilation and death.
Results
Compared with pure PJP group, mixed PJP group had significantly higher BALF levels of IL-1β, TNF-α and IL-8 and significantly higher blood levels of IL-8. The BALF ratios of TNF-α/IL-10, IL-8/IL-10, IL-1β/IL-10, TNF-α/TGF-β1, IL-8/TGF-β1, IL-1β/TGF-β1 and IL-1β/IL-1RA were significantly higher in mixed than in pure PJP patients. There was no significant difference in clinical features and outcome between pure and mixed PJP groups, including inflammatory biomarkers and the fungal burden. In pure PJP patients, significantly higher BALF levels of IL-8 and the ratios of IL-8/IL-10, IL-1β/TGF-β1, MCP-1/TGF-β1, MCP-1/IL1RA and IL-8/TGF-β1 were found in the patients requiring mechanical ventilation and in non-survivors.
Conclusions
In summary, concurrent pulmonary infection might enhance immune dysregulation of PJP in non-AIDS immunocompromised patients, but did not affect the outcome as evidenced by morbidity and mortality. Because of limited number of cases studied, further studies with larger populations are needed to verify these issues.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2466-14-182) contains supplementary material, which is available to authorized users.
doi:10.1186/1471-2466-14-182
PMCID: PMC4247696  PMID: 25409888
Anti-inflammatory cytokines; Bronchoalveolar lavage fluid; Non-acquired immunodeficiency syndrome; Pneumocystis jirovecii pneumonia; Pro-inflammatory cytokines
19.  Mycobacterial and nonbacterial pulmonary complications in hospitalized patients with human immunodeficiency virus infection: A prospective, cohort study 
Background
A prospective observational study was done to describe nonbacterial pulmonary complications in hospitalized patients with human immunodeficiency virus (HIV) infection.
Methods
The study included 1,225 consecutive hospital admissions of 599 HIV-infected patients treated from April 1995 through March 1998. Data included demographics, risk factors for HIV infection, Acute Physiology and Chronic Health Evaluation (APACHE) II score, pulmonary complications, CD4+ lymphocyte count, hospital stay and case-fatality rate.
Results
Patient age (mean ± SD) was 38.2 ± 8.9 years, 62% were men, and 84% were African American. The median APACHE II score was 14, and median CD4+ lymphocyte count was 60/μL. Pulmonary complications were Pneumocystis carinii pneumonia (85) in 78 patients, Mycobacterium avium complex (51) in 38, Mycobacterium tuberculosis (40) in 35, Mycobacterium gordonae (11) in 11, Mycobacterium kansasii (10) in 9, Cytomegalovirus (10) in 10, Nocardia asteroides (3) in 3, fungus ball (2) in 2, respiratory syncytial virus (1), herpes simplex virus (1), Histoplasma capsulatum (1), lymphoma (3) in 3, bronchogenic carcinoma (2) in 2, and Kaposi sarcoma (1). The case-fatality rate of patients was 11% with Pneumocystis carinii pneumonia; 5%, Mycobacterium tuberculosis; 6%, Mycobacterium avium complex; and 7%, noninfectious pulmonary complications.
Conclusion
Most pulmonary complications in hospitalized patients with HIV are from Pneumocystis and mycobacterial infection.
doi:10.1186/1471-2466-1-1
PMCID: PMC57813  PMID: 11602023
20.  Endothelial cell injury with inflammatory cytokine and coagulation in patients with sepsis 
BACKGROUND:
Current studies on CD62P have focused mainly on cardiovascular diseases, while only few studies have evaluated the effects of CD62P on the development of sepsis and the association between endothelial cell injury with inflammation and coagulation. This study attended to explore the association between endothelial cell injury with inflammation and coagulation by evaluating the expression of soluble CD62P (s-CD62P) in plasma and its mechanism in patients with sepsis, thus to provide the evidence of effective treatment of sepsis with anti-adhesion therapy targeted CD62P.
METHODS:
A total of 70 critically ill patients with systemic inflammatory response syndrome (SIRS) admitted to intensive care unit (ICU) between September 2009 and February 2010 were enrolled for a prospective and control study. According to the diagnostic criteria of sepsis/SIRS, the patients were divided into two groups: a sepsis group (n=38) and a SIRS group (n=32). Another 20 healthy volunteers served as a control group. Patients in the sepsis group and SIRS group were matched by clinical signs of high blood pressure, diabetes and its complications. The demographics of the patients including age, sex, body mass index (BMI), smoking and alcohol addict were compared among the groups. Six mL peripheral blood samples were collected within 24-hour admission in ICU for enzymelinked immunosorbent assay (ELISA) to detect the plasma levels of s-CD62P, TNF-α, and hs-CRP. And variables of coagulation function such as platelet (PLT), prothrombin (PT), activated partial thromboplastin time (APTT), D-dimer and antithrombin-III (AT-III) were analyzed during 24 hours after admission to ICU. Meanwhile sequential organ failure assessment (SOFA) score of critically ill patients was evaluated. Data were expressed as mean±standard deviation and were statistically analyzed by using SPSS 17.0 statistical software. The differences in plasma levels of s-CD62P of patients in each group were analyzed by ANOVA and the Kruskal-Wallis test. The relations between s-CD62P and inflammatory cytokines as well as with coagulation were determined by Pearson’s product moment correlation coefficient analysis. Changes were considered as statistically significant if P value was less than 0.05.
RESULTS:
Compared with the control group and SIRS group, the sepsis group demonstrated significantly higher levels of s-CD62P, TNF-α and highly sensitive C-reactive protein (hs-CRP) (P<0.05). The plasma levels of D-dimer, PT, and APTT in the sepsis and SIRS groups were significantly higher than those in the control group, while the platelet count and the activity of AT-III were obviously lower (P<0.05). In the sepsis group, the plasma levels of hs-CRP and TNF-α were positively correlated with PT, APTT, and D-dimer, and negatively correlated with AT-III and PLT (P<0.05). The plasma levels of s-CD62P were significantly correlated with the plasma levels of TNF-α, hs-CRP, D-dimer, PT, and APTT, whereas they were correlated negatively well with PLT and AT-III (P<0.05).
CONCLUSIONS:
The concentration of plasma s-CD62P is elevated as a early biomarker in patients with sepsis, and it serves as one of the pathogenic factors responsible for endothelial cell damage. Coagulation and mediators of inflammation promote each other, aggravating the severity of sepsis. Plasma s-CD62P may be an important factor for the development of coagulation and inflammatory reaction.
doi:10.5847/wjem.j.issn.issn.1920-8642.2013.04.008
PMCID: PMC4129900  PMID: 25215134
Sepsis; Endothelial cell injury; Plasma soluble CD62P; Inflammatory cytokine; Coagulation
21.  Pneumocystis jirovecii dihydropteroate synthase gene mutations in a group of HIV-negative immunocompromised patients with Pneumocystis pneumonia 
The purpose of this study was to investigate dihydropteroate synthase (DHPS) mutations and their clinical context in non-HIV-infected patients with Pneumocystis pneumonia (PCP). DHPS genes in respiratory samples collected from HIV-negative patients with PCP presented between January 2008 and April 2011 were amplified by polymerase chain reaction (PCR) and sequenced. Basic clinical data from the medical records of the patients were also reviewed. The most common point mutations, which result in Thr55Ala and Pro57Ser amino acid substitutions, were not detected in the Pneumocystis jirovecii sampled from the HIV-negative patients. Two other point mutations, which result in nonsynonymous mutation, Asp90Asn and Glu98Lys, were identified in P. jirovecii from two patients. Among the patients, the levels of lactate dehydrogenase (LDH), C-reactive protein (CRP) and plasma (1–3) β-D-glucan were elevated in 75, 92.31 and 42.86% of patients, respectively. The percentage of circulating lymphocytes was significantly lower in non-survivors than in survivors [4.2%, interquartile range (IQR) 2.4–5.85 versus 10.1%, IQR 5.65–23.4; P=0.019]. The neutrophil proportion in bronchoalveolar lavage fluid (BALF) was significantly higher in non-survivors than in survivors (49.78±27.67 versus 21.33±15.03%; P=0.047). Thirteen patients had received adjunctive corticosteroids (1 mg/kg/day prednisone equivalent) and nine (69.23%) of them eventually experienced treatment failure. No common DHPS gene mutations of P. jirovecii were detected in the HIV-negative PCP patients. However, other mutations did exist, the significance of which remains to be further identified. The elevation of neutrophil counts in BALF and reduction of the number of lymphocytes in peripheral blood may be associated with poor outcome. The efficacy of adjunctive steroid therapy in HIV-negative patients with P. jirovecii infection requires further investigation.
doi:10.3892/etm.2014.2002
PMCID: PMC4218695  PMID: 25371739
Pneumocystis jirovecii; drug resistance; dihydropteroate synthase gene; mutation
22.  Global, regional, and national estimates of pneumonia burden in HIV-infected children in 2010: a meta-analysis and modelling study 
The Lancet. Infectious Diseases  2014;14(12):1250-1258.
Summary
Background
Globally, pneumonia is a leading cause of mortality and morbidity in children younger than 5 years. Underlying HIV infection is an important risk factor for pneumonia morbidity and mortality in children. There are, however, no global or country level estimates of pneumonia burden in HIV-infected children. We assessed the role of HIV in pneumonia incidence and mortality and estimated the number of pneumonia cases and deaths in HIV-infected children younger than 5 years in 133 high pneumonia-burden countries in 2010.
Methods
We estimated the risk of hospital admission and case fatality rate caused by pneumonia in HIV-infected children compared with HIV-uninfected children from a systematic review of studies published in Medline, Embase, and Global Health between Jan 1, 1980, and Aug 31, 2013. We estimated nationwide pneumonia incidence and mortality with two different models that incorporated several risk factors for paediatric pneumonia hospital admission and mortality (including HIV infection). We then estimated the number of pneumonia episodes and deaths that occurred in HIV-infected children in 2010.
Findings
The odds ratio (OR) for hospital admission for all-cause pneumonia in HIV-infected children compared with HIV-uninfected children was 6·5 (95% CI 5·9–7·2). The risk of death was higher in children with pneumonia and HIV compared with those with pneumonia only (OR 5·9, 95% CI 2·7–12·7). In 2010, 1·4 million pneumonia episodes (uncertainty range [UR] 0·6 million to 3·3 million) and 88 000 pneumonia deaths (UR 47 400–153 000) occurred in HIV-infected children in low-income countries. Of these, 1·2 million pneumonia episodes (UR 0·5 million–2·7 million) and 85 400 deaths (UR 46 000–147 300) were directly attributable to HIV. 1·3 million (90%) pneumonia episodes and 82 400 (93%) pneumonia deaths in HIV-infected children aged younger than 5 years occurred in the WHO African region.
Interpretation
Globally, a small proportion of pneumonia episodes and pneumonia deaths occur in HIV-infected children. However, in the highest HIV-burden countries in sub-Saharan Africa (ie, Swaziland, Lesotho, and Zimbabwe) up to a fifth of all pneumonia cases and 60% of pneumonia deaths occur in HIV-infected children. In these countries, major reductions in child pneumonia mortality can be achieved only if the systemic challenges plaguing the health system (poor coverage of early infant testing for HIV, of antiretroviral drugs in pregnant women and young children, of co-trimoxazole prophylaxis, and of pneumococcal vaccination) can be overcome.
Funding
WHO.
doi:10.1016/S1473-3099(14)70990-9
PMCID: PMC4242006  PMID: 25455992
23.  Correlation between inflammatory factors and post-stroke pneumonia in diabetic patients 
Pneumonia is the most common cause of mortality in stroke patients and it has been demonstrated to contribute to mortality and poor functional outcome following stroke in the majority of clinical studies. The risk of infection may be attributed to stroke-induced immunodepression syndrome (SIDS). Cytokine production is increased in SIDS. However, the correlation between biomarkers and the risk of post-stroke pneumonia in patients with diabetes mellitus is not clear. The aim of this study was to determine the correlation between pneumonia and the levels of C-reactive protein (CRP) and interleukin-6 (IL-6), as well as to identify early predictors of pneumonia in acute ischemic stroke patients with diabetes mellitus. Additionally, we investigated the impact of pneumonia on functional outcome after 1 month. A total of 106 ischemic stroke patients with diabetes mellitus who were admitted after the onset of symptoms were included in the study. They were divided into two groups, the pneumonia and non-pneumonia groups. CRP, IL-6, white blood cells (WBCs), mean body temperature and National Institutes of Health Stroke Scale (NIHSS) score were measured at the time of admission. The modified Rankin Scale score was assessed at 30 days. The levels of IL-6, CRP and WBCs, as well as mean body temperature were significantly higher in the patients with pneumonia than in the patients without pneumonia. There were also significant differences between the pneumonia and non-pneumonia groups in age, admission NIHSS score, length of hospital stay and dysphagia. Pneumonia patients had worse outcomes compared with patients without pneumonia at 1 month. Age, NIHSS score and dysphagia were significantly associated with pneumonia. WBCs and mean body temperature were not significant predictors of pneumonia. Older patients with more severe ischemic stroke are more susceptible to the development of pneumonia during the stay in hospital. Pneumonia contributes to poor functional outcome. IL-6, CRP, age, NIHSS score and dysphagia may predict the occurrence of pneumonia on the day of stroke symptom onset.
doi:10.3892/etm.2013.1103
PMCID: PMC3735628  PMID: 23935729
acute ischemic stroke; C-reactive protein; interleukin-6; pneumonia; diabetes mellitus
24.  Study of internal transcribed spacer and mitochondrial large-subunit genes of Pneumocystis carinii hominis isolated by repeated bronchoalveolar lavage from human immunodeficiency virus-infected patients during one or several episodes of pneumonia. 
Journal of Clinical Microbiology  1997;35(7):1687-1690.
The objective of this study was to type, analyze, and compare Pneumocystis carinii hominis strains obtained from different samples during a given or recurrent episodes of P. carinii pneumonia (PCP) for epidemiologic purposes. We studied 36 bronchoalveolar lavage (BAL) or induced sputum (IS) samples from 16 human immunodeficiency virus-infected patients with one or several episodes of PCP. PCR amplification and direct sequencing were performed on the two internal transcribed spacers (ITS1 and ITS2) of P. carinii hominis rRNA genes by using DNA extracted from BAL or IS samples, and the sequences were compared to the mitochondrial large-subunit (mt LSU) gene sequence determined in a previous study in our laboratory. The studies of the mt LSU and ITS sequences showed that some patients (n = 10) were infected with the same strains of P. carinii hominis during a given episode of PCP. In one patient infected with strains with identical sequences in several episodes, the recurrence could have been due to reactivation of organisms not eliminated by treatment during the first episode or to de novo infection by an identical strain. In five patients infected with strains with different sequences in each episode, recurrence was due to de novo infection. Sequence analysis of these two P. carinii hominis gene regions showed that de novo infection can occur in AIDS patients with recurrent PCP.
PMCID: PMC229822  PMID: 9196174
25.  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

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