Maria Angeles Marcos

Hepatotoxicity in HIV-1-infected patients receiving nevirapine-containing antiretroviral therapy

ObjectivesTo assess the incidence and risk factors for hepatotoxicity associated with nevirapine. DesignA prospective cohort study in a teaching and referral hospital involving all consecutive patients who were prescribed a nevirapine-containing antiretroviral regimen between September 1997 and May 2000. MethodCutaneous and hepatic adverse reactions and clinical hepatitis were assessed. Blood analysis including plasma HIV-1 RNA CD4 cell counts, liver chemistry tests, and serology for hepatitis B and C viruses. Hepatotoxicity was defined as an increase of at least threefold in serum alanine aminotransferase or aspartate aminotransferase levels compared with baseline values. ResultsOf a total of 610 patients, 82 (13.4%) were antiretroviral naive when commencing nevirapine, and 46.2 and 8.9% were coinfected with hepatitis C and B viruses, respectively. Median duration of exposure to nevirapine was 8.7 months (interquartile range 3.4–14.3). Hepatotoxicity developed in 76 (12.5%), an incidence of 13.1/100 person-years. Kaplan–Meier estimated incidence of hepatotoxicity at 3, 6 and 12 months was 3.7, 9.7 and 20.1%, respectively. In seven (1.1%) patients, hepatotoxicity was associated with clinical hepatitis, which was reversible upon discontinuation of therapy. Multivariate analysis identified the duration of prior exposure to antiretroviral drugs, hepatitis C virus, and higher baseline levels of alanine aminotransferase as independent risk factors for hepatotoxicity. ConclusionsHepatotoxicity but not clinical hepatitis was common in HIV-1-infected patients receiving nevirapine-containing regimens and the incidence steadily increased over time. Prolonged exposure to any antiretroviral therapy, coinfection with hepatitis C virus and abnormal baseline levels of alanine aminotransferase identified patients at a higher risk.

Biomarkers improve mortality prediction by prognostic scales in community-acquired pneumonia

Background: Prognostic scales provide a useful tool to predict mortality in community-acquired pneumonia (CAP). However, the inflammatory response of the host, crucial in resolution and outcome, is not included in the prognostic scales. Methods: The aim of this study was to investigate whether information about the initial inflammatory cytokine profile and markers increases the accuracy of prognostic scales to predict 30-day mortality. To this aim, a prospective cohort study in two tertiary care hospitals was designed. Procalcitonin (PCT), C-reactive protein (CRP) and the systemic cytokines tumour necrosis factor α (TNFα) and interleukins IL6, IL8 and IL10 were measured at admission. Initial severity was assessed by PSI (Pneumonia Severity Index), CURB65 (Confusion, Urea nitrogen, Respiratory rate, Blood pressure, ≥65 years of age) and CRB65 (Confusion, Respiratory rate, Blood pressure, ≥65 years of age) scales. A total of 453 hospitalised CAP patients were included. Results: The 36 patients who died (7.8%) had significantly increased levels of IL6, IL8, PCT and CRP. In regression logistic analyses, high levels of CRP and IL6 showed an independent predictive value for predicting 30-day mortality, after adjustment for prognostic scales. Adding CRP to PSI significantly increased the area under the receiver operating characteristic curve (AUC) from 0.80 to 0.85, that of CURB65 from 0.82 to 0.85 and that of CRB65 from 0.79 to 0.85. Adding IL6 or PCT values to CRP did not significantly increase the AUC of any scale. When using two scales (PSI and CURB65/CRB65) and CRP simultaneously the AUC was 0.88. Conclusions: Adding CRP levels to PSI, CURB65 and CRB65 scales improves the 30-day mortality prediction. The highest predictive value is reached with a combination of two scales and CRP. Further validation of that improvement is needed.

Rapid urinary antigen test for diagnosis of pneumococcal community-acquired pneumonia in adults

Streptococcus pneumoniae is suspected to cause an important proportion of community-acquired pneumonia (CAP) whose aetiology cannot be detected with conventional tests. In this study, the authors evaluated the diagnostic yield of a new immunochromatographic membrane test (ICT) for the detection of the S. pneumoniae antigen in the urine of patients admitted with diagnosed CAP. ICT was performed in unconcentrated and concentrated urine from all the patients. ICT was repeated 1 month after discharge in a group initially testing positive. The authors also studied the ICT in clinically stable human immunodeficiency virus type 1 (HIV1)-infected patients. S. pneumoniae antigen was detected in all of the 68 (100%) patients tested with definitive pneumococcal pneumonia. In five of these cases ICT was only positive when it had been performed on the patients. The S. pneumoniae antigen was also detected in 36 (69.2%) of 52 patients with probable pneumococcal pneumonia and in 50 of 277 (18%) patients without pneumococcal pneumonia. ICT remained positive in 16 (69.5%) of 23 patients, 1 month after hospital discharge. Nasopharyngeal colonisation with S. pneumoniae was detected in 8 (12%) of 68 clinically stable HIV1 infected patients, but none tested ICT positive. The Binax NOW® immunochromatographic membrane test is a rapid, sensitive and specific test for detecting pneumococcal community-acquired pneumonia in adults. The test may remain positive for several weeks after pneumococcal pneumonia.

Markers of treatment failure in hospitalised community acquired pneumonia

Background: Lack of response to treatment in community acquired pneumonia (CAP) worsens outcome. We evaluated the systemic cytokine profile (tumour necrosis factor α, interleukin (IL)1, IL6, IL8 and IL10), C reactive protein (CRP) and procalcitonin (PCT) in patients with CAP who had treatment failure. Methods: A prospective study was performed in hospitalised patients with CAP. Cytokines, PCT and CRP measurements were obtained on day 1 and after 72 h of treatment. Treatment failure was the endpoint evaluated, with separation of those with early (⩽72 h) or late failure. Results: 453 patients were included: 84 (18%) had treatment failure, of whom 38 (8%) were early failures. Median levels of IL6, PCT and CRP on days 1 and 3 and median levels of IL8 on day 1 were significantly higher in patients with any treatment failure. Logistic regression analysis demonstrated that values above the cut-off points for IL6 (⩾169 pg/ml), IL8 (⩾14 pg/ml) and CRP (⩾21.9 mg/dl) on day 1 had independent predictive value for any treatment failure after adjustment for initial severity; relative risks (OR) found were 1.9, 2.2 and 2.6, respectively. Increased levels for CRP and PCT on day 1 were also independent predictors for early failure. Increased levels for IL6 and CRP were the best predictors of late failure. Conclusions: Serum levels of CRP, IL6 and PCT on days 1 and 3 were independently associated with a higher risk of any treatment failure. Low levels of PCT and CRP on day 1 had a high negative predictive value for early failure.

Microbial aetiology of community-acquired pneumonia and its relation to severity

Background The distribution of the microbial aetiology and mortality of community-acquired pneumonia (CAP) was investigated in relation to the clinical setting and severity scores (pneumonia severity index (PSI) and confusion, blood urea nitrogen, respiratory rate, blood pressure, age (CURB-65)). Methods 3523 patients with CAP were included (15% outpatients, 85% inpatients). The distribution of the microbial aetiology in relation to the clinical setting and severity scores (PSI, CURB-65) and the relative mortality of different aetiologies across the severity scores were analysed. Results The aetiology was established in 1463 patients (42%), of whom 257 died (7%). The ranking of aetiologies varied according to site of care, with increasing frequency of Streptococcus pneumoniae and mixed aetiologies and decreasing frequency of atypical pathogens in hospitalised patients and those in ICUs. The distribution of aetiologies according to severity scores showed corresponding patterns; however, the severity scores were more sensitive to Gram-negative enteric bacilli (GNEB) and Pseudomonas aeruginosa and less sensitive in identifying mixed aetiologies as moderate- and high-risk conditions. Mortality rates according to aetiology and severity scoring showed increasing mortality rates for all pathogens except atypical pathogens. S pneumoniae had the highest number of deaths while GNEB, P aeruginosa, Staphylococcus aureus and mixed aetiologies had the highest mortality rates. Legionella pneumophila was similarly distributed according to site of care and prognostic scores. Conclusions CAP due to atypical bacterial pathogens is recognised both clinically and by severity scoring as a low-risk condition. Severity scores are more sensitive in identifying patients with GNEB and P aeruginosa as moderate- and high-risk aetiologies whereas mixed aetiologies may be underestimated.

A comparative study of different PCR-based DNA fingerprinting techniques for typing of the Acinetobacter calcoaceticus-A. baumannii complex

Different PCR-based DNA fingerprinting techniques were evaluated for typing 26 clinical isolates belonging to the Acinetobacter calcoaceticus-A. baumannii complex. Seven isolates belonged to a previously defined outbreak while 19 isolates were unrelated epidemiologically. The PCR-based DNA fingerprinting techniques used were: (i) repetitive extragenic palindromic (REP) PCR; (ii) enterobacterial repetitive intergenic consensus (ERIC) PCR; (iii) randomly amplified polymorphic DNA with M13 forward primer; (iv) restriction analysis of the amplified 16S rRNA gene (ARDRA-16S); and (v) restriction analysis of an amplified region containing the 16S-23S rRNA spacer region and part of the 23S rRNA gene (ARDRA 23S + spacer). The discrimination index for the PCR-based DNA fingerprinting techniques was: 0.99 for REP; 0.94 for ERIC; 0.87 for M13; 0.60 for ARDRA-16S digested with Hpa II and <0.50 for ARDRA 23S + spacer. It was concluded that REP-PCR possessed high discriminatory power and reproducibility in comparison with the other PCR-based DNA fingerprinting techniques, and is a simple and rapid typing method for use in epidemiological studies of isolates belonging to the A. calcoaceticus-A. baumannii complex.

Lower mortality among patients with community-acquired pneumonia treated with a macrolide plus a beta-lactam agent versus a beta-lactam agent alone

A cohort of 1,391 patients with community-acquired pneumonia of unknown etiology, atypical pneumonia, Legionella pneumophila pneumonia, viral pneumonia, or pneumococcal pneumonia was studied according to a standard protocol to analyse whether the addition of a macrolide to β-lactam empirical treatment decreases mortality rates. Patients admitted to the intensive care unit were excluded. Severity was assessed using the PORT score. An etiological diagnosis was achieved in 498 (35.8%) patients (292 infections due to Streptococcus pneumoniae). Treatment was chosen by the attending physician according to his/her own criteria: β-lactam agent in 270 and β-lactam agent plus a macrolide in 918 cases. The mortality rate was 13.3% in the group treated with a β-lactam agent alone and 6.9% in the group treated with a β-lactam agent plus a macrolide (p=0.001). The percentage of PORT-group V patients was 32.6% in the group treated with a beta-lactam agent alone compared to 25.7% in the group who received a β-lactam agent plus a macrolide (p=0.02). After controlling for PORT score, the odds of fatal outcome was two times higher in patients treated with a beta-lactam agent alone than in those treated with a β-lactam agent plus a macrolide (adjusted OR = 2, 95%CI 1.24–3.23). The results suggest that the addition of a macrolide to an initial β-lactam-based antibiotic regimen is associated with lower mortality in patients with community-acquired pneumonia, independent of severity of infection, thus supporting the recommendation of a β-lactam-agent plus a macrolide as empirical therapy.

Nursing home-acquired pneumonia: a 10 year single-centre experience

Background Pneumonia among nursing home (NH) residents has increased considerably in recent years, but it remains unclear whether it should be considered as community-acquired pneumonia (CAP) or a new category of infection. Methods 150 consecutive cases of NH-acquired pneumonia (NHAP) (from 1 February 1997 to 1 July 2007) were analysed. Results Patients (median age, 82 years; range, 77–87 years) showed numerous co-morbidities, (neurological, 55%; pulmonary, 38%; cardiac, 35%) and severe disability for daily activities (partial, 32%; total, 31%). Cases of NHAP were mainly classified as mild to moderate according to the CRB-65 score (CRB-65 classes 0–1 and 2, 41% each). In-hospital and 30-day mortality were 8.7% and 20%, respectively. Aetiology was defined in 57 cases (38%). The most common isolates were Streptococcus pneumoniae (58%), Enterobacteriaceae (Gram-negative bacteria (GNB)) (9%), atypical bacteria (7%), respiratory viruses (5%), methicillin-resistant Staphylococcus aureus (MRSA) (5%) and Legionella pneumophila (5%). The most frequent causes of treatment inadequacy were use of β-lactams alone (25%) and lack of aspiration assessment (15%). Prognostic factors of 1-month mortality were neurological comorbidities (OR 4.5; 95% CI 1.3 to 15.7; p=0.020), septic shock (OR 6.6; 95% CI 1.3 to 34.0; p=0.025), pleural effusion (OR 3.6; 95% CI 1.1 to 11.7; p=0.036) and isolation of GNB or MRSA (OR 16.4; 95% CI 2.1 to 128.9; p=0.008). Conclusions The patients show clinical characteristics (eg, age and co-morbidities) comparable with those with hospital-acquired pneumonia. However, microbiological and mortality data of patients with NHAP are more similar to the data of those with CAP. Isolation of GNB or MRSA was associated with increased mortality risk. CAP empirical antibiotic coverage is still indicated in NHAP, although specific risk factors for multidrug-resistant infections should be assessed on an individual basis.

Host adaptive immunity deficiency in severe pandemic influenza

IntroductionPandemic A/H1N1/2009 influenza causes severe lower respiratory complications in rare cases. The association between host immune responses and clinical outcome in severe cases is unknown.MethodsWe utilized gene expression, cytokine profiles and generation of antibody responses following hospitalization in 19 critically ill patients with primary pandemic A/H1N1/2009 influenza pneumonia for identifying host immune responses associated with clinical outcome. Ingenuity pathway analysis 8.5 (IPA) (Ingenuity Systems, Redwood City, CA) was used to select, annotate and visualize genes by function and pathway (gene ontology). IPA analysis identified those canonical pathways differentially expressed (P < 0.05) between comparison groups. Hierarchical clustering of those genes differentially expressed between groups by IPA analysis was performed using BRB-Array Tools v.3.8.1.ResultsThe majority of patients were characterized by the presence of comorbidities and the absence of immunosuppressive conditions. pH1N1 specific antibody production was observed around day 9 from disease onset and defined an early period of innate immune response and a late period of adaptive immune response to the virus. The most severe patients (n = 12) showed persistence of viral secretion. Seven of the most severe patients died. During the late phase, the most severe patient group had impaired expression of a number of genes participating in adaptive immune responses when compared to less severe patients. These genes were involved in antigen presentation, B-cell development, T-helper cell differentiation, CD28, granzyme B signaling, apoptosis and protein ubiquitination. Patients with the poorest outcomes were characterized by proinflammatory hypercytokinemia, along with elevated levels of immunosuppressory cytokines (interleukin (IL)-10 and IL-1ra) in serum.ConclusionsOur findings suggest an impaired development of adaptive immunity in the most severe cases of pandemic influenza, leading to an unremitting cycle of viral replication and innate cytokine-chemokine release. Interruption of this deleterious cycle may improve disease outcome.

C-reactive protein levels in community-acquired pneumonia

The diagnostic value of C-reactive protein (CRP) admission serum levels as an indicator of the aetiology of community-acquired pneumonia (CAP) was evaluated. A cohort of 1,222 patients with CAP was assessed. CRP levels were analysed in 258 patients with a single aetiological diagnosis. The mean CRP values in patients with pyogenic, atypical, viral and Legionella pneumophila pneumonia were: 16 mg·dL−1, 13 mg·dL−1, 14 mg·dL−1 and 25 mg·dL−1, respectively. CRP levels were not significantly different among patients outcome research team (PORT) groups (19 mg·dL−1 in groups I–II, 16 mg·dL−1 in group III and 16 mg·dL−1 in groups IV–V. A cut-off point of 25 mg·dL−1 had a sensibility, specificity, positive predictive value and negative predictive value of 0.6, 0.83, 0.3, and 0.94, respectively. After controlling for age and PORT score, the odds of having a CRP level >25 mg·dL−1 was 6.9 times higher in patients with L. pneumophila pneumonia than in those with non-L. pneumophila pneumonia. Patients with Legionella pneumophila pneumonia had higher C-reactive protein levels than those with pneumonia of any other aetiology, independently of severity of infection. Being a cheap and readily available test, C-reactive protein may be a useful adjunctive procedure in the diagnosis of community-acquired pneumonia.