ng-Ming Chu

Clinical progression and viral load in a community outbreak of coronavirus-associated SARS pneumonia: a prospective study

n Summaryn n Backgroundn We investigated the temporal progression of the clinical, radiological, and virological changes in a community outbreak of severe acute respiratory syndrome (SARS).n n n Methodsn We followed up 75 patients for 3 weeks managed with a standard treatment protocol of ribavirin and corticosteroids, and assessed the pattern of clinical disease, viral load, risk factors for poor clinical outcome, and the usefulness of virological diagnostic methods.n n n Findingsn Fever and pneumonia initially improved but 64 (85%) patients developed recurrent fever after a mean of 8.9 (SD 3.1) days, 55 (73%) had watery diarrhoea after 7.5 (2.3) days, 60 (80%) had radiological worsening after 7.4 (2.2) days, and respiratory symptoms worsened in 34 (45%) after 8.6 (3.0) days. In 34 (45%) patients, improvement of initial pulmonary lesions was associated with appearance of new radiological lesions at other sites. Nine (12%) patients developed spontaneous pneumomediastinum and 15 (20%) developed acute respiratory distress syndrome (ARDS) in week 3. Quantitative reverse-transcriptase (RT) PCR of nasopharyngeal aspirates in 14 patients (four with ARDS) showed peak viral load at day 10, and at day 15 a load lower than at admission. Age and chronic hepatitis B virus infection treated with lamivudine were independent significant risk factors for progression to ARDS (p=0.001). SARS-associated coronavirus in faeces was seen on RT-PCR in 65 (97%) of 67 patients at day 14. The mean time to seroconversion was 20 days.n n n Interpretationn The consistent clinical progression, shifting radiological infiltrates, and an inverted V viral-load profile suggest that worsening in week 2 is unrelated to uncontrolled viral replication but may be related to immunopathological damage.n Published online May 9, 2003 http://image.thelancet.com/extras/03art4432web.pdfn n

Characterization and Complete Genome Sequence of a Novel Coronavirus, Coronavirus HKU1, from Patients with Pneumonia

ABSTRACT Despite extensive laboratory investigations in patients with respiratory tract infections, no microbiological cause can be identified in a significant proportion of patients. In the past 3 years, several novel respiratory viruses, including human metapneumovirus, severe acute respiratory syndrome (SARS) coronavirus (SARS-CoV), and human coronavirus NL63, were discovered. Here we report the discovery of another novel coronavirus, coronavirus HKU1 (CoV-HKU1), from a 71-year-old man with pneumonia who had just returned from Shenzhen, China. Quantitative reverse transcription-PCR showed that the amount of CoV-HKU1 RNA was 8.5 to 9.6 × 106 copies per ml in his nasopharyngeal aspirates (NPAs) during the first week of the illness and dropped progressively to undetectable levels in subsequent weeks. He developed increasing serum levels of specific antibodies against the recombinant nucleocapsid protein of CoV-HKU1, with immunoglobulin M (IgM) titers of 1:20, 1:40, and 1:80 and IgG titers of <1:1,000, 1:2,000, and 1:8,000 in the first, second and fourth weeks of the illness, respectively. Isolation of the virus by using various cell lines, mixed neuron-glia culture, and intracerebral inoculation of suckling mice was unsuccessful. The complete genome sequence of CoV-HKU1 is a 29,926-nucleotide, polyadenylated RNA, with G+C content of 32%, the lowest among all known coronaviruses with available genome sequence. Phylogenetic analysis reveals that CoV-HKU1 is a new group 2 coronavirus. Screening of 400 NPAs, negative for SARS-CoV, from patients with respiratory illness during the SARS period identified the presence of CoV-HKU1 RNA in an additional specimen, with a viral load of 1.13 × 106 copies per ml, from a 35-year-old woman with pneumonia. Our data support the existence of a novel group 2 coronavirus associated with pneumonia in humans.

Clinical and Molecular Epidemiological Features of Coronavirus HKU1–Associated Community-Acquired Pneumonia

Abstract BackgroundRecently, we described the discovery of a novel group 2 coronavirus, coronavirus HKU1 (CoV-HKU1), from a patient with pneumonia. However, the clinical and molecular epidemiological features of CoV-HKU1–associated pneumonia are unknown MethodsProspectively collected (during a 12-month period) nasopharyngeal aspirates (NPAs) from patients with community-acquired pneumonia from 4 hospitals were subjected to reverse-transcription polymerase chain reaction, for detection of CoV-HKU1. The epidemiological, clinical, and laboratory characteristics of patients with CoV-HKU1–associated pneumonia were analyzed. The pol spike (S), and nucleocapsid (N) genes were also sequenced ResultsNPAs from 10 (2.4%) of 418 patients with community-acquired pneumonia were found to be positive for CoV-HKU1. All 10 cases occurred in spring and winter. Nine of these patients were adults, and 4 had underlying diseases of the respiratory tract. In the 6 patients from whom serum samples were available, all had a 4-fold change in immunoglobulin (Ig) G titer and/or presence of IgM against CoV-HKU1. The 2 patients who died had significantly lower hemoglobin levels, monocyte counts, albumin levels, and oxygen saturation levels on admission and had more-extensive involvement visible on chest radiographs. Sequence analysis of the pol S, and N genes revealed 2 genotypes of CoV-HKU1 ConclusionsCoV-HKU1 accounts for 2.4% of community-acquired pneumonia, with 2 genotypes in the study population. Without performance of diagnostic tests, the illness was clinically indistinguishable from other community-acquired pneumonia illnesses

Readmission rates and life threatening events in COPD survivors treated with non-invasive ventilation for acute hypercapnic respiratory failure

Background: Non-invasive ventilation (NIV) has been shown to reduce intubation and in-hospital mortality in patients with chronic obstructive pulmonary disease (COPD) and acute hypercapnic respiratory failure (AHRF). However, little information exists on the outcomes following discharge. A study was undertaken to examine the rates of readmission, recurrent AHRF, and death following discharge and the risk factors associated with them. Methods: A cohort of COPD patients with AHRF who survived after treatment with NIV in a respiratory high dependency unit was prospectively followed from July 2001 to October 2002. The times to readmission, first recurrent AHRF, and death were recorded and analysed against potential risk factors collected during the index admission. Results: One hundred and ten patients (87 men) of mean (SD) age 73.2 (7.6) years survived AHRF after NIV during the study period. One year after discharge 79.9% had been readmitted, 63.3% had another life threatening event, and 49.1% had died. Survivors spent a median of 12% of the subsequent year in hospital. The number of days in hospital in the previous year (pu200a=u200a0.016) and a low Katz score (pu200a=u200a0.018) predicted early readmission; home oxygen use (pu200a=u200a0.002), APACHE II score (pu200a=u200a0.006), and a lower body mass index (pu200a=u200a0.041) predicted early recurrent AHRF or death; the MRC dyspnoea score (p<0.001) predicted early death. Conclusions: COPD patients with AHRF who survive following treatment with NIV have a high risk of readmission and life threatening events. Further studies are urgently needed to devise strategies to reduce readmission and life threatening events in this group of patients.

Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical findings

Background: The clinical response of patients with severe acute respiratory syndrome (SARS) to a combination of lopinavir/ritonavir and ribavirin was examined after establishing the in vitro antiviral susceptibility of the SARS associated coronavirus to a panel of antiviral agents. Methods: The in vitro susceptibility of the prototype of SARS associated coronavirus to a panel of nucleoside analogues and protease inhibitors currently licensed for clinical use was studied. Forty one patients with SARS followed for 3 weeks were treated with a combination of lopinavir/ritonavir and ribavirin. The clinical progress and virological outcomes were monitored and compared with 111 patients treated with ribavirin only who served as historical controls. Results: In vitro antiviral activity against SARS associated coronavirus was demonstrated for lopinavir and ribavirin at concentrations of 4 µg/ml and 50 µg/ml, respectively, only at 48 hours. The adverse clinical outcome (ARDS or death) was significantly lower in the treatment group than in the historical controls (2.4% v 28.8%, p<0.001) at day 21 after the onset of symptoms. The adverse outcome remained significantly lower in the treatment group than in the controls—both those diagnosed early (p<0.001) and those diagnosed later in the course of the epidemic (pu200a=u200a0.002)—but there was no significant difference in adverse outcome rates between the two time periods (pu200a=u200a0.548). No time related difference in outcome was observed in the control groups. A reduction in steroid usage and nosocomial infections was seen in patients initially treated with lopinavir/ritonavir, and these patients had a decreasing viral load and rising peripheral lymphocyte count. Multivariate analysis showed that age, hepatitis B carrier status, and lack of treatment with this antiviral combination were independent predictors of an adverse outcome. Lopinavir/ritonavir treatment was associated with a better outcome even when adjusted for baseline lactate dehydrogenase level. Conclusions: The apparent favourable clinical response with lopinavir/ritonavir and ribavirin supports further randomised placebo controlled trials in patients with SARS.

Alleviation of sleep apnea in patients with chronic renal failure by nocturnal cycler-assisted peritoneal dialysis compared with conventional continuous ambulatory peritoneal dialysis.

Nocturnal hemodialysis has been shown to improve sleep apnea in patients who receive conventional hemodialysis. It was hypothesized that nocturnal peritoneal dialysis (NPD) also is effective in correcting sleep apnea in patients who receive continuous ambulatory PD (CAPD). Overnight polysomnography (PSG) was performed in 46 stable NPD and CAPD patients who were matched for demographic and clinical attributes. The prevalence of sleep apnea, defined as an apnea-hypopnea index (AHI; or frequency of apnea and hypopnea per hour of sleep) > or =15, was 52% for NPD patients and 91% for CAPD patients (P = 0.007). The mean (+/-SD) AHI in NPD and CAPD patients was 31.6 +/- 25.6 and 50.9 +/- 26.4 (P = 0.025), respectively. For validation of the efficacy of NPD in alleviating sleep apnea, a fixed sequence intervention study was performed in which 24 incident PD patients underwent one PSG study during mandatory cycler-assisted NPD while awaiting their turn for CAPD training and a second PSG recording shortly after they were established on stable CAPD. The prevalence of sleep apnea was 4.2% during NPD and 33.3% during CAPD (P = 0.016). AHI increased from 3.4 +/- 1.34 during NPD to 14.0 +/- 3.46 during CAPD (P < 0.001). With the use of bioelectrical impedance analysis, total body water content was significantly lower during stable NPD than CAPD (32.8 +/- 7.37 versus 35.1 +/- 7.35 L; P = 0.004). NPD delivered greater reductions in total body water (-2.81 +/- 0.45 versus -1.34 +/- 0.3 L; P = 0.015) and hydration fraction (-3.63 +/- 0.64 versus -0.71 +/- 0.52%; P = 0.005) during sleep. Pulmonary function tests remained unchanged before and after conversion from NPD to CAPD. These findings suggest that NPD may have a therapeutic edge over CAPD in sleep apnea that is associated with renal failure as a result of better fluid clearance during sleep.

Viral loads in clinical specimens and SARS manifestations.

The number of anatomical sites with detectable viral loads by RT-qPCR appeared to correlate with death risk.

Prevention of Acute Myocardial Infarction and Stroke among Elderly Persons by Dual Pneumococcal and Influenza Vaccination: A Prospective Cohort Study

BACKGROUNDnDespite World Health Organization recommendations, the rate of 23-valent pneumococcal (PPV) and influenza (TIV) vaccination among elderly persons in Hong Kong, China, is exceptionally low because of doubts about effectiveness of vaccination. The efficacy of dual vaccination remains unknown.nnnMETHODSnFrom 3 December 2007 to 30 June 2008, we conducted a prospective cohort study by recruiting outpatients aged ≥65 years with chronic illness to participate in a PPV and TIV vaccination program. All were observed until 31 March 2009. The outcome of subjects, including the rates of death, hospitalization, pneumonia, ischemic stroke, acute myocardial infarction, and coronary and intensive care admissions, were determined.nnnRESULTSnOf the 36,636 subjects recruited, 7292 received both PPV and TIV, 2076 received TIV vaccine alone, 1875 received PPV alone, and 25,393 were unvaccinated, with a duration of follow-up of 45,834 person-years. Baseline characteristics were well matched between the groups, except that there were fewer male patients in the PPV and TIV group and fewer cases of comorbid chronic obstructive pulmonary disease among unvaccinated persons. At week 64 from commencement of the study, dual-vaccinees experienced fewer deaths (hazard ratio [HR], 0.65; 95% confidence interval [CI], 0.55-0.77]; P<.001) and fewer cases of pneumonia (HR, 0.57; 95% CI, 0.51-0.64; P<.001), ischemic stroke (HR, 0.67; 95% CI, 0.54-0.83; P<.001), and acute myocardial infarction (HR, 0.52; 95% CI, 0.38-0.71; P<.001), compared with unvaccinated subjects. Dual vaccination resulted in fewer coronary (HR, 0.59; 95% CI, 0.44-0.79; P<.001) and intensive care admissions (HR, 0.45; 95% CI, 0.22-0.94; P=.03), compared with among unvaccinated subjects.nnnCONCLUSIONSnDual vaccination with PPV and TIV is effective in protecting elderly persons with chronic illness from developing complications from respiratory, cardiovascular, and cerebrovascular diseases, thereby reducing hospitalization, coronary or intensive care admissions, and death.

Noninvasive ventilation in patients with acute hypercapnic exacerbation of chronic obstructive pulmonary disease who refused endotracheal intubation.

ObjectiveTo determine the long-term outcome of noninvasive ventilation in chronic obstructive pulmonary disease patients who refused intubation for acute hypercapnic respiratory failure. DesignProspective, observational study. SettingNoninvasive ventilation unit in an acute regional hospital in Hong Kong. MethodsThe study recruited 37 chronic obstructive pulmonary disease patients who had the do-not-intubate code and developed acute hypercapnic respiratory failure. They were offered noninvasive ventilation, and their long-term outcomes were followed. Survival and event-free survival (an event is death or recurrent acute hypercapnic respiratory failure) were analyzed by survival analysis. Their disease profile and outcome were compared with another 43 chronic obstructive pulmonary disease patients without the do-not-intubate codes, who had acute hypercapnic respiratory failure and received noninvasive ventilation during the study period (usual care group). ResultsPatients in the do-not-intubate group were significantly older (p = .029), had worse dyspnea score (p < .001), worse Katz Activities of Daily Living score (p < .001), worse comorbidity score (p = .024), worse Acute Physiology and Chronic Health Evaluation II score (p = .032), lower hemoglobin (p = .001), and longer stay in the hospital during the past year (p = .001) than patients who received usual care. In the do-not-intubate group, the median survival was 179 days, and 1-yr actuarial survival was 29.7%; in the usual care group, the median survival was not reached during follow-up, and 1-yr actuarial survival was 65.1% (p < .0001). In the do-not-intubate group, the median event-free survival was 102 days, and 1-yr event-free survival was 16.2%; in the usual care group, median event-free survival was 292 days, and 1-yr event-free survival was 46.5% (p = .0004). ConclusionsA 1-yr survival of about 30% was recorded in chronic obstructive pulmonary disease patients with the do-not-intubate code who developed acute hypercapnic respiratory failure requiring noninvasive ventilation. The majority of survivors developed another life-threatening event in the following year. Information generated from this study is important to physicians and chronic obstructive pulmonary disease patients when they are considering using noninvasive ventilation as a last resort.

Viral replication in the nasopharynx is associated with diarrhea in patients with severe acute respiratory syndrome

Abstract The role of severe acute respiratory syndrome (SARS) coronavirus as an enteric pathogen was investigated in a cohort of 142 patients with SARS who were treated with a standard treatment protocol. Data from daily hematological, biochemical, radiological, and microbiological investigations were prospectively collected, and the correlation of these findings with diarrhea was retrospectively analyzed. Sixty-nine patients (48.6%) developed diarrhea at a mean (± standard deviation [SD]) of 7.6 ± 2.6 days after the onset of symptoms. The diarrhea was most severe at a mean (±SD) of 8.8 ± 2.4 days after onset, with a maximum frequency of 24 episodes per day (median, 5 episodes; range, 3–24 episodes). A higher mean virus load in nasopharyngeal specimens obtained on day 10 after the onset of symptoms was significantly associated with the occurrence of diarrhea (3.1 log10 vs. 1.8 log10 copies/mL; P = .01) and mortality (6.2 vs. 1.7 log10 copies/mL; P < .01). However, diarrhea was not associated with mortality. The lung and the gastrointestinal tract may react differently to SARS coronavirus infection. Additional investigation of the role of SARS coronavirus in the pathogenesis of diarrhea in patients with SARS should be conducted.