Rity Y. K. Wong

Outcomes of adults hospitalised with severe influenza

Background The aim of this study was to investigate factors affecting clinical outcomes of adults hospitalised with severe seasonal influenza. Methods A prospective, observational cohort study was conducted over 24 months (2007–2008) in two acute, general hospitals. Consecutive, hospitalised adult patients were recruited and followed once their laboratory diagnosis of influenza A/B was established (based on viral antigen detection and virus isolation from nasopharyngeal aspirates collected per protocol). Outcomes studied included in-hospital death, length of stay and duration of oxygen therapy. Factors affecting outcomes were analysed using multivariate Cox proportional hazards models. Sequencing analysis on the neuraminidase gene was performed for available H1N1 isolates. Results 754 patients were studied (influenza A, n=539; >75% H3N2). Their mean age was 70±18 years; co-morbidities and serious complications were common (61–77%). Supplemental oxygen and ventilatory support was required in 401 (53.2%) and 41 (5.4%) patients, respectively. 39 (5.2%) patients died; pneumonia, respiratory failure and sepsis were the causes. 395 (52%) patients received antiviral (oseltamivir) treatment. Omission of antiviral treatment was associated with delayed presentation or negative antigen detection results. The mortality rate was 4.56 and 7.42 per 1000 patient-days in the treated and untreated patients, respectively; among those with co-morbidities, it was 5.62 and 11.64 per 1000 patient-days, respectively. In multivariate analysis, antiviral use was associated with reduced risk of death (adjusted HR (aHR) 0.27 (95% CI 0.13 to 0.55); p<0.001). Improved survival was observed with treatment started within 4 days from onset. Earlier hospital discharge (aHR 1.28 (95% CI 1.04 to 1.57); p=0.019) and faster discontinuation of oxygen therapy (aHR 1.30 (95% CI 1.01 to 1.69); p=0.043) was associated with early treatment within 2 days. Few (n=15) H1N1 isolates in this cohort had the H275Y mutation. Conclusions Antiviral treatment for severe influenza is associated with reduced mortality and improved clinical outcomes.

High Morbidity and Mortality in Adults Hospitalized for Respiratory Syncytial Virus Infections

BACKGROUND Better understanding of complications and outcomes of adults hospitalized with respiratory syncytial virus (RSV) infection is necessary. METHODS A retrospective cohort study was conducted on all adults (≥ 18 years) admitted to 3 acute care general hospitals in Hong Kong with virologically confirmed RSV infection during 2009-2011 (N = 607). Adults hospitalized for seasonal influenza during the period were used for comparison (n = 547). Both infections were prospectively diagnosed following a standard protocol. Independent reviews of chest radiographs were performed by radiologists. Main outcome measures were all-cause death, respiratory failure requiring ventilatory support, and hospitalization duration. Cox proportional hazards models were used for analyses. RESULTS The mean age of RSV patients was 75 (SD, 16) years; 87% had underlying conditions. Lower respiratory and cardiovascular complications were diagnosed in 71.9% (pneumonia, 42.3%; acute bronchitis, 21.9%; chronic obstructive pulmonary disease/asthma exacerbation, 27.3%) and 14.3% of patients, respectively; 12.5% had bacterial superinfections. Supplemental oxygen and ventilatory support were required in 67.9% and 11.1%, respectively. Crude all-cause mortality was 9.1% and 11.9% within 30 days and 60 days, respectively; mean length of stay of survivors was 12 (SD, 13) days. Advanced age, radiographic pneumonia, requirement for ventilation, bacterial superinfection, and elevated urea level and white blood cell count were independently associated with poorer survival. Systemic corticosteroid use was associated with longer hospitalization and secondary infections. The overall outcomes of survival and length of stay were not significantly different from those in influenza. CONCLUSIONS RSV can cause severe lower respiratory complications in older adults, resulting in respiratory failure, prolonged hospitalization, and high mortality similar to seasonal influenza. Corticosteroids did not seem to improve outcomes. The unmet need for antiviral therapy and vaccination against RSV in adults should be promptly addressed.

Cytokine response patterns in severe pandemic 2009 H1N1 and seasonal influenza among hospitalized adults.

Background Studying cytokine/chemokine responses in severe influenza infections caused by different virus subtypes may improve understanding on pathogenesis. Methods Adults hospitalized for laboratory-confirmed seasonal and pandemic 2009 A/H1N1 (pH1N1) influenza were studied. Plasma concentrations of 13 cytokines/chemokines were measured at presentation and then serially, using cytometric-bead-array with flow-cytometry and ELISA. PBMCs from influenza patients were studied for cytokine/chemokine expression using ex-vivo culture (Whole Blood Assay,±PHA/LPS stimulation). Clinical variables were prospectively recorded and analyzed. Results 63 pH1N1 and 53 seasonal influenza patients were studied. pH1N1 patients were younger (mean±S.D. 42.8±19.2 vs 70.5±16.7 years), and fewer had comorbidities. Respiratory/cardiovascular complications were common in both groups (71.4% vs 81.1%), although severe pneumonia with hypoxemia (54.0% vs 28.3%) and ICU admissions (25.4% vs 1.9%) were more frequent with pH1N1. Hyperactivation of the proinflammatory cytokines IL-6, CXCL8/IL-8, CCL2/MCP-1 and sTNFR-1 was found in pH1N1 pneumonia (2–15 times normal) and in complicated seasonal influenza, but not in milder pH1N1 infections. The adaptive-immunity (Th1/Th17)-related CXCL10/IP-10, CXCL9/MIG and IL-17A however, were markedly suppressed in severe pH1N1 pneumonia (2–27 times lower than seasonal influenza; P−values<0.01). This pattern was further confirmed with serial measurements. Hypercytokinemia tended to be sustained in pH1N1 pneumonia, associated with a slower viral clearance [PCR-negativity: day 3–4, 55% vs 85%; day 6–7, 67% vs 100%]. Elevated proinflammatory cytokines, particularly IL-6, predicted ICU admission (adjusted OR 12.6, 95%CI 2.6–61.5, per log10unit increase; P = 0.002), and correlated with fever, tachypnoea, deoxygenation, and length-of-stay (Spearmans rho, P-values<0.01) in influenza infections. PBMCs in seasonal influenza patients were activated and expressed cytokines ex vivo (e.g. IL-6, CXCL8/IL-8, CCL2/MCP-1, CXCL10/IP-10, CXCL9/MIG); their ‘responsiveness’ to stimuli was shown to change dynamically during the illness course. Conclusions A hyperactivated proinflammatory, but suppressed adaptive-immunity (Th1/Th17)-related cytokine response pattern was found in severe pH1N1 pneumonia, different from seasonal influenza. Cytokine/immune-dysregulation may be important in its pathogenesis.

Complications and Outcomes of Pandemic 2009 Influenza A (H1N1) Virus Infection in Hospitalized Adults: How Do They Differ From Those in Seasonal Influenza?

BACKGROUND It is unclear whether pandemic 2009 influenza A (pH1N1) infection caused more significant disease among hospitalized adults than seasonal influenza. METHODS A prospective, observational study was conducted in adults hospitalized with polymerase chain reaction-confirmed pH1N1 infection in 2 acute-care general hospitals from June 2009 to May 2010 (n = 382). Complications and outcomes were described and compared with those in a seasonal influenza cohort (2007-2008, same hospitals; n = 754). RESULTS Hospitalized patients with pH1N1 influenza were younger than those with seasonal influenza (mean age ± standard deviation, 47 ± 20 vs 70 ± 19 years) and fewer had comorbid conditions (48% vs 64%). The rate of positive immunofluorescence assay results was low (54% vs 84%), and antiviral use was frequent (96% vs 52%). Most patients in both cohorts developed complicated illnesses (67.8% vs 77.1%), but patients with pH1N1 influenza had higher rates of extrapulmonary complications (23% vs 16%; P = .004) and intensive care unit admission and/or death (patient age <35 years, 2.3% vs 0%; 35-65 years, 12.4% vs 3.2%; >65 years, 13.5% vs 8.5%; adjusted odds ratio [OR] 2.13; 95% confidence interval [CI], 1.25-3.62; P = .005). Patients who received antiviral treatment within 96 h after onset had better survival (log-rank test, P < .001). However, without timely treatment, the mortality risk was higher with pH1N1 infection (9.0% vs 5.8% for seasonal influenza; adjusted OR, 6.85; 95% CI, 1.64-28.65; P = .008]. Bacterial superinfection worsened outcomes. CONCLUSIONS Adults hospitalized for pH1N1 influenza had significant complications and mortality despite being younger than patients with seasonal influenza. Antiviral treatment within 96 h may improve survival.

Viral clearance and inflammatory response patterns in adults hospitalized for pandemic 2009 influenza A(H1N1) virus pneumonia.

BACKGROUND Little is known about the virological and inflammatory responses of severe pandemic 2009 influenza A(H1N1) virus pneumonia during antiviral treatment. METHODS In a prospective observational study, we recruited consecutive adults hospitalized with confirmed pandemic 2009 H1N1 infection during a 16-week period. Nasopharyngeal aspirate and non-respiratory samples (blood, stool and urine) were collected at presentation, and serial nasopharyngeal flocked swabs (NPFS) and tracheal aspirates (TA) were collected after initiating oseltamivir treatment for quantitative viral RNA assay, using real-time reverse transcriptase-PCR. Serial plasma samples were collected for cytokine/chemokine assay using cytometric bead array. Patients with severe pneumonia (lung infiltrates and hypoxaemia) were compared to those with milder illnesses. RESULTS A total of 66 patients were studied (mean age 43 ±20 years); 28 (42%) developed severe pneumonia, of whom 10 (15%) required intubation. Severe pneumonia was associated with older age, dyspnoea, delayed presentation >2 days from onset, extrapulmonary virus detection (13-28%) and higher viral concentration despite late-presentation (multiple linear regression, β=0.94, 95% confidence interval 0.15-1.74; P=0.02). Patients with severe pneumonia exhibited slow viral clearance with oseltamivir treatment, particularly in the lower respiratory tract (median [interquartile range] durations of RNA positivity after antiviral initiation were NPFS 6.0 days [3.0-8.0], TA 11.0 days [7.8-14.3] versus milder illness group NPFS of 2.0 days [1.0-3.0] days; P<0.01). High viral load in lower respiratory tract despite upper-tract RNA negativity and viral rebound after stopping treatment were noted in some patients. H275Y mutation was absent. High plasma levels of interleukin (IL)-6, CXCL-8 (IL-8), CCL2 (monocyte chemoattractant protein-1) and soluble tumour necrosis factor receptor-1 were observed, which correlated with the extent and progression of pneumonia in hospital. CONCLUSIONS In severe 2009 H1N1 pneumonia, viral clearance is slow with treatment, particularly in the lower respiratory tract. A more sustained antiviral regime appears warranted.

Use of convalescent plasma therapy in SARS patients in Hong Kong.

In order to evaluate the efficacy of convalescent plasma therapy in the treatment of patients with severe acute respiratory syndrome (SARS), 80 SARS patients were given convalescent plasma at Prince of Wales Hospital, Hong Kong, between 20 March and 26 May 2003. Good outcome was defined as discharge by day 22 following the onset of SARS symptoms. Poor outcome was defined as death or hospitalization beyond 22 days. A higher day-22 discharge rate was observed among patients who were given convalescent plasma before day 14 of illness (58.3% vs 15.6%; P<0.001) and among those who were PCR positive and seronegative for coronavirus at the time of plasma infusion (66.7% vs 20%; P=0.001).

Retrospective comparison of convalescent plasma with continuing high-dose methylprednisolone treatment in SARS patients.

ABSTRACT Treatment of severe acute respiratory syndrome (SARS) is experimental, and the effectiveness of ribavirin-steroid therapy is unclear. Forty SARS patients with progressive disease after ribavirin treatment and 1.5 g of pulsed methylprednisolone were given either convalescent plasma (n = 19) or further pulsed methylprednisolone (n = 21) in a retrospective non-randomised study. Good clinical outcome was defined as discharge by day 22 following the onset of symptoms. Convalescent plasma was obtained from recovered patients after informed consent. Patients in the plasma group had a shorter hospital stay (p 0.001) and lower mortality (p 0.049) than the comparator group. No immediate adverse effects were observed following plasma infusion.

A Prospective Intervention Study on Higher-Dose Oseltamivir Treatment in Adults Hospitalized With Influenza A and B Infections

BACKGROUND It is unclear if higher-dose oseltamivir provides benefit beyond the standard dose in influenza patients who require hospitalization. METHODS A prospective intervention study was performed in 2 acute care general hospitals in Hong Kong over 4 seasonal peaks (2010-2012). Adults (≥18 years) with laboratory-confirmed influenza (85 A/H3N2, 34 A/H1N1pdm09, 36 B) infections who presented within 96 hours were recruited. Study regimen of either 150 mg or 75 mg oseltamivir twice daily for 5 days was allocated by site, which was switched after 2 seasons. Subjects with preexisting renal impairment (creatinine clearance, 40-60 mL/minute) received 75 mg oseltamivir twice daily. Viral clearance by day 5 and clinical responses were compared between groups. Plasma steady-state trough oseltamivir carboxylate (OC) concentration was measured by high-performance liquid chromatography-tandem mass spectrometry. RESULTS Altogether, 41 and 114 patients received 150 mg and 75 mg twice-daily oseltamivir, respectively; their enrollment characteristics (mean age, 61 ± 18 vs 66 ± 16 years) and illness severity were comparable. Trough OC levels were higher in the 150-mg group (501.0 ± 237.0 vs 342.6 ± 192.7 ng/mL). There were no significant differences in day 5 viral RNA (44.7% vs 40.2%) or culture negativity (100.0% vs 98.1%), RNA decline rate, and durations of fever, oxygen supplementation, and hospitalization. Results were similar when analyzed by study arm (all cases and among those without renal impairment). Subanalysis of influenza B patients showed faster RNA decline rate (analysis of variance, F = 4.14; P = .05) and clearance (day 5, 80.0% vs 57.1%) with higher-dose treatment. No oseltamivir resistance was found. Treatments were generally well tolerated. CONCLUSIONS We found no additional benefit of higher-dose oseltamivir treatment in adults hospitalized with influenza A, but an improved virologic response in influenza B. CLINICAL TRIALS REGISTRATION ClinicalTrials.gov, NCT01052961.

Clinical and virological course of infection with haemagglutinin D222G mutant strain of 2009 pandemic influenza A (H1N1) virus

BACKGROUND Aspartic acid to glycine substitution (D222G) of haemagglutinin subunit (HA1) was associated with adverse outcomes in 2009 pandemic influenza A (H1N1) infections. OBJECTIVES To characterize the virological profile and antiviral response of patients infected with the HA1 D222G mutant. STUDY DESIGN Sixty-three adults admitted for pandemic influenza in Hong Kong were tested for D222G mutation by direct sequencing. Nasopharyngeal viral concentration on presentation was measured by real-time PCR to evaluate shedding from the upper respiratory tract. Serial upper and lower respiratory tract specimens were monitored to determine preferential tropism and document virological response to treatment. RESULTS The frequency of D222G infection was 17.4% among cases with severe pneumonia, and 26.7% among cases requiring intensive care. Altogether, four sporadic D222G cases spread across the first and second waves in Hong Kong were detected. A significant association between D222G infection with severe pneumonia (100% vs. 32.2%, P=0.015) and intensive care admission (100% vs. 18.6%, P=0.002) was observed. D222G was associated with lower concentrations of virus in the upper respiratory tract compared to wildtype, but persisted in the lower respiratory tract at high concentrations, despite clearance from the upper respiratory tract following antiviral treatment. CONCLUSIONS These observations suggest that D222G can arise de novo, sheds less virus from the upper respiratory tract and may be less transmissible, but more pneumotropic and more resistant to antiviral treatment. D222G is associated with a higher chance of developing critical disease. Lower respiratory tract specimen is needed for a reliable detection of this mutant.

Role of human Toll‐like receptors in naturally occurring influenza A infections

We investigated the roles of Toll‐like receptors (TLRs) in naturally occurring influenza.