Robert F. Miller

Effect of an Indwelling Pleural Catheter vs Chest Tube and Talc Pleurodesis for Relieving Dyspnea in Patients With Malignant Pleural Effusion: The TIME2 Randomized Controlled Trial

CONTEXT Malignant pleural effusion causes disabling dyspnea in patients with a short life expectancy. Palliation is achieved by fluid drainage, but the most effective first-line method has not been determined. OBJECTIVE To determine whether indwelling pleural catheters (IPCs) are more effective than chest tube and talc slurry pleurodesis (talc) at relieving dyspnea. DESIGN Unblinded randomized controlled trial (Second Therapeutic Intervention in Malignant Effusion Trial [TIME2]) comparing IPC and talc (1:1) for which 106 patients with malignant pleural effusion who had not previously undergone pleurodesis were recruited from 143 patients who were treated at 7 UK hospitals. Patients were screened from April 2007-February 2011 and were followed up for a year. INTERVENTION Indwelling pleural catheters were inserted on an outpatient basis, followed by initial large volume drainage, education, and subsequent home drainage. The talc group were admitted for chest tube insertion and talc for slurry pleurodesis. MAIN OUTCOME MEASURE Patients completed daily 100-mm line visual analog scale (VAS) of dyspnea over 42 days after undergoing the intervention (0 mm represents no dyspnea and 100 mm represents maximum dyspnea; 10 mm represents minimum clinically significant difference). Mean difference was analyzed using a mixed-effects linear regression model adjusted for minimization variables. RESULTS Dyspnea improved in both groups, with no significant difference in the first 42 days with a mean VAS dyspnea score of 24.7 in the IPC group (95% CI, 19.3-30.1 mm) and 24.4 mm (95% CI, 19.4-29.4 mm) in the talc group, with a difference of 0.16 mm (95% CI, −6.82 to 7.15; P = .96). There was a statistically significant improvement in dyspnea in the IPC group at 6 months, with a mean difference in VAS score between the IPC group and the talc group of −14.0 mm (95% CI, −25.2 to −2.8 mm; P = .01). Length of initial hospitalization was significantly shorter in the IPC group with a median of 0 days (interquartile range [IQR], 0-1 day) and 4 days (IQR, 2-6 days) for the talc group, with a difference of −3.5 days (95% CI, −4.8 to −1.5 days; P < .001). There was no significant difference in quality of life. Twelve patients (22%) in the talc group required further pleural procedures compared with 3 (6%) in the IPC group (odds ratio [OR], 0.21; 95% CI, 0.04-0.86; P = .03). Twenty-one of the 52 patients in the catheter group experienced adverse events vs 7 of 54 in the talc group (OR, 4.70; 95% CI, 1.75-12.60; P = .002). CONCLUSION Among patients with malignant pleural effusion and no previous pleurodesis, there was no significant difference between IPCs and talc pleurodesis at relieving patient-reported dyspnea. TRIAL REGISTRATION isrctn.org Identifier: ISRCTN87514420.

Asymptomatic carriage of Pneumocystis jiroveci in subjects undergoing bronchoscopy: a prospective study

Background: The opportunistic fungus Pneumocystis jiroveci is a common cause of respiratory infection in immunocompromised patients. By contrast, pneumocystis pneumonia (PCP) occurs only rarely in immunocompetent individuals. Asymptomatic colonisation with P jiroveci has recently been described in patients who are either minimally immunosuppressed or who have underlying lung disorders such as bronchiectasis. We sought to determine the prevalence of asymptomatic colonisation by P jiroveci in a cohort of adult patients undergoing diagnostic bronchoscopy. Methods: A prospective observational cohort study was performed in patients who required bronchoscopy and bronchoalveolar lavage (BAL) as part of their routine clinical assessment. All the samples underwent standard microbiological analysis and a Grocott methenamine silver stain was performed where clinically indicated to detect the presence of P jiroveci. Polymerase chain reaction for detection of P jiroveci specific DNA was also performed. Results: Ninety three consecutive BAL fluid samples were analysed, 17 (18%) of which contained P jiroveci DNA. Of the potential predictors examined, only glucocorticoid use was significantly associated with detectable P jiroveci DNA. Eighteen patients were receiving oral glucocorticoids (equivalent to >20 mg/day prednisolone) at the time of bronchoscopy, of whom eight (44%) had detectable P jiroveci DNA. In contrast, P jiroveci was detected in only nine of 75 patients (12%) who were not receiving glucocorticoids (difference between proportions 32%, 95% CI 8 to 57; p=0.004, two tailed Fisher’s exact test). Conclusions:P jiroveci colonisation, as determined by detection of P jiroveci DNA in BAL fluid, is common in HIV negative patients with primary respiratory disorders undergoing bronchoscopy and BAL. The higher prevalence in patients receiving corticosteroids suggests that oral glucocorticoid therapy is an independent risk factor for colonisation. In contrast, underlying lung cancer or COPD did not appear to be risk factors.

Differential susceptibility of PCR reactions to inhibitors: an important and unrecognised phenomenon

BackgroundPCR inhibition by nucleic acid extracts is a well known yet poorly described phenomenon. Inhibition assessment generally depends on the assumption that inhibitors affect all PCR reactions to the same extent; i.e. that the reaction of interest and the control reaction are equally susceptible to inhibition. To test this assumption we performed inhibition assessment on DNA extracts from human urine samples, fresh urine and EDTA using different PCR reactions.ResultsWhen copurified inhibitors were assessed using two different PCR reactions one reaction appeared to be inhibited whilst the other was not. Further experiments using various concentrations of unextracted urine to inhibit six different PCR reactions revealed that susceptibility to inhibition was highly variable between reactions. Similar results were obtained using EDTA as the PCR inhibitor. We could find no obvious explanation why one reaction should be more susceptible to inhibition than another, although a possible association with amplicon GC content was noted.ConclusionThese findings have serious implications for all PCR-based gene expression studies, including the relatively new PCR array method, and for both qualitative and quantitative PCR-based molecular diagnostic assays, suggesting that careful consideration should be given to inhibition compatibility when conducting PCR analyses. We have demonstrated unequivocally that it is not safe to assume that different PCR reactions are equally susceptible to inhibition by substances co-purified in nucleic acid extracts.

Performance of a T-cell-based diagnostic test for tuberculosis infection in HIV-infected individuals is independent of CD4 cell count

The performance characteristics of the enzyme-linked immunospot assay (ELISPOT) assay (T-SPOT TB) for the diagnosis of latent tuberculosis infection in HIV-infected individuals are unknown. Given that ELISPOT enumerates Mycobacterium tuberculosis antigen-specific IFN-γ-secreting T cells, HIV-associated immunosuppression might adversely affect test performance. However, we found that 28 out of 29 HIV-positive individuals (97%) gave evaluable test results, and performance was independent of the CD4 T-cell count. ELISPOT test performance appears to be independent of HIV-associated immunosuppression.

Pneumocystis carinii f. sp. hominis DNA in Immunocompetent Health Care Workers in Contact with Patients with P. carinii Pneumonia

ABSTRACT The possible transmission of Pneumocystis carinii f. sp. hominis from patients with P. cariniipneumonia to asymptomatic health care workers (HCW), with or without occupational exposure to human immunodeficiency virus (HIV)-infected patients with P. carinii pneumonia, was examined. HCW in a specialist inpatient HIV-AIDS facility and a control group in the general medical-respiratory service in the same hospital provided induced sputum and/or nasal rinse samples, which were analyzed for the presence of P. carinii f. sp.hominis DNA by using DNA amplification (at the gene encoding the mitochondrial large subunit rRNA [mt LSU rRNA]).P. carinii f. sp. hominis DNA was detected in some HCW samples; those with the closest occupational contact were more likely to have detectable P. carinii DNA. P. carinii DNA was detected in one HCW who carried out bronchoscopy over a 2-year period. P. carinii-positive samples were genotyped by using DNA sequence variations at the internal transcribed spacer (ITS) regions of the nuclear rRNA operon, along with bronchoalveolar lavage samples from patients with P. carinii pneumonia hospitalized at the same time. Genotyping identified 31 different P. cariniif. sp. hominis ITS genotypes, 26 of which were found in the patient samples. Five of the eight ITS genotypes detected in HCW samples were not observed in the patient samples. The results suggested that HCW in close occupational contact with patients who had P. carinii pneumonia may have become colonized with P. carinii. Carriage was asymptomatic and did not result in the development of clinical disease.

Sequence Polymorphisms in the Pneumocystis carinii Cytochrome b Gene and Their Association with Atovaquone Prophylaxis Failure

Atovaquone (Mepron, 566c80) is an effective agent against Pneumocystis carinii, which probably acts by binding to cytochrome b and inhibiting electron transport. To assess the possibility that atovaquone resistance might be developing, the genes for the cytochrome b from P. carinii sp. f. carinii and P. carinii sp. f. hominis were partially sequenced. Eight of 10 patient isolates had cytochrome b genes with the same amino acid sequence. The P. carinii cytochrome b genes from 2 of 4 patients who had atovaquone prophylaxis failure contained mutations resulting in amino acid changes in one of the ubiquinone (coenzyme Q) binding sites (Qo). These mutations are homologous to mutations in other microorganisms that confer resistance to similar inhibitors. Variations in the sequence of the P. carinii cytochrome b gene suggest but do not prove the development of drug resistance.

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.

Adverse events and treatment interruption in tuberculosis patients with and without HIV co-infection

Background: Serious treatment associated adverse events are thought to occur more frequently in individuals with tuberculosis (TB) who are co-infected with HIV. A study was undertaken to assess the frequency of serious (grade III/IV) adverse events and interruption of anti-TB treatment in the era of effective antiretroviral therapy. Methods: The incidence of serious adverse events was retrospectively compared in 312 individuals treated for TB, 156 of whom were co-infected with HIV. Results: 111 HIV infected individuals (71%) received highly active antiretroviral therapy at the same time as anti-TB treatment. Serious adverse events were recorded in 40% HIV infected and 26% HIV uninfected individuals (p = 0.008). Peripheral neuropathy and persistent vomiting were more common in co-infected patients (p<0.001; p = 0.006), although all cause interruption of anti-TB treatment occurred with similar frequency in the two groups (13% in HIV infected patients and 15% in HIV uninfected patients; p = 0.74). In 85% of HIV infected patients and 87% of HIV uninfected individuals this was due to hepatotoxicity, which typically presented within 2 months of starting treatment. The median delay in restarting treatment was 4 weeks, so most individuals required full TB re-treatment. Conclusion: Despite a greater rate of serious (grade III/IV) adverse events among HIV infected individuals, discontinuation of anti-TB treatment occurred with a similar frequency in HIV infected and HIV uninfected individuals.

Dihydropteroate synthase gene mutations in Pneumocystis and sulfa resistance

We review studies of dihydropteroate synthase gene mutations in Pneumocystis jirovecii and summarize the evidence for resistance to sulfamethoxazole and dapsone.

Cerebral CD8+ lymphocytosis in HIV-1 infected patients with immune restoration induced by HAART

In HIV infected persons, highly active antiretroviral therapy (HAART) has reduced both the morbidity and incidence of several disorders. Its effects on direct HIV-induced damage to the CNS remain controversial. In addition, HAART may provoke an “immune reconstitution inflammatory syndrome” (IRIS). Herein we report two patients who, despite HAART, developed a diffuse encephalopathy. Their clinical, radiological and neuropathological features are described. Immunohistochemical and PCR analyses were used to detect HIV and to exclude other viruses in brain tissue. The unusual inflammatory reaction in the brain tissue was defined by immunohistochemistry. Both patients had advanced HIV disease with low CD4 counts and high HIV “viral loads” before starting HAART. In both, HAART induced an increase in CD4 count and a marked reduction in HIV viral load, which was accompanied, in patient one, by worsening of pre-existing, and, in patient two, by development of, acute encephalopathy. At post-mortem examination, the brain of patient one showed HIV encephalitis. In addition, the brains of both patients revealed HIV–DNA by PCR, diffuse microglial hyperplasia and massive and diffuse perivascular and intraparenchymal infiltration by CD8+/CD4− lymphocytes. We suggest that the rapid immune reconstitution induced by HAART in these two patients led to a redistribution of lymphocytes into peripheral blood. This was followed by recruitment of CD8+ lymphocytes into the brain, which resulted in the diffuse infiltration described. The appearances in patient two further suggest that HIV brain infection, even without encephalitis, is sufficient to trigger this response.