OBJECTIVES: To describe the immunological responses and clinical outcome of coronavirus (SARS) infected healthcare workers (HCW) who had been administered with convalescent plasma as a treatment.
METHODS: Convalescent plasma (500 mL) was obtained from each of three SARS patients and transfused into the three infected HCW. Donors were blood type O and seronegative for hepatitis B and C, HIV, syphilis and human T-cell lymphotropic virus types I and II (HTLV-I and -II). Serum antibody (IgG) titre was >640. Apharesis was performed with a CS 3000 plus cell separator followed by the forming of the convalescent phase plasma. As part of the routine check with donated plasma, the convalescent plasma was confirmed free of residual SARS-CoV by RT-PCR. Serial serum samples obtained from the recipients of the convalescent plasma were collected to undertake real-time quantitative RT-PCR for SARS-CoV for direct measurement of viral concentration. Specific immunoglobulin IgM and IgG concentrations were titrated using an antigen microarray developed in-house.
RESULTS: Viral load dropped from 495 x 10(3), 76 x 10(3) or 650 x 10(3) copies/mL to zero or 1 copy/mL one day after transfusion. Anti-SARS-CoV IgM and IgG also increased in a time-dependent manner following transfusion. All three patients survived. One HCW became pregnant subsequently, delivering 13 months after discharge. Positive anti-SARS-CoV IgG was detected in the newborn. Passive transfer of anti-SARS-CoV antibody from the mother was considered as a possibility.
CONCLUSIONS: All infected HCW whose condition had progressed severely and who had failed to respond to the available treatment, survived after transfusion with convalescent plasma.
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).
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 micro g/ml and 50 micro g/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 (p = 0.002)-but there was no significant difference in adverse outcome rates between the two time periods (p = 0.548). 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.
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.
OBJECTIVE: Ribavirin is a broad spectrum nucleoside analogue efficacious in the treatment of several viral infections. In the recent severe acute respiratory syndrome (SARS) outbreak, ribavirin was used in various countries against this novel coronavirus. We conducted a retrospective analysis to assess the efficacy of ribavirin in the treatment of SARS in Singapore.
METHODS: A total of 229 cases were analysed. Ninety-seven (42.4%) patients received ribavirin at a mean of 6.4 days of illness. Clinical and laboratory parameters taken at the start of ribavirin treatment were compared with day 5, 6 or 7 parameters of those patients not on treatment. The two groups were compared using Fisher's exact test and Student's t-test. Multivariate analysis was performed using Cox regression model with death as the outcome of interest.
RESULTS: The treatment group had younger women with more symptoms of myalgia (P < 0.001). The crude death rate was 12.9% in the control and 10.3% (P = 0.679) in the treatment group. After correction for age, male sex, lactate dehydrogenase levels and steroid use, the hazard ratio was 1.03 (95% CI: 0.44-2.41, P = 0.939).
CONCLUSION: In this retrospective, uncontrolled cohort analysis, use of ribavirin did not appear to confer any benefit for patients with SARS.
BACKGROUND: The outcome is reported of a prospective uncontrolled study based on a stepwise treatment protocol during an outbreak of severe acute respiratory syndrome (SARS) in Hong Kong.
METHOD: One hundred and thirty eight patients were treated with broad spectrum antibiotics, a combination of ribavirin and low dose corticosteroid, and then intravenous high dose methylprednisolone according to responses. Sustained response to treatment was defined as (1) defervescence for > or =4 consecutive days, (2) resolution of lung consolidation by >25%, and (3) oxygen independence by the fourth day without fever. Patients with defervescence who achieved either criterion 2 or 3 were classified as partial responders. Patients who fell short of criteria 2 and 3 were non-responders.
RESULTS: Laboratory confirmation of SARS coronavirus infection was established in 132 (95.7%). None responded to antibiotics but 25 (18.1%) responded to ribavirin + low dose corticosteroid. Methylprednisolone was used in 107 patients, of whom 95 (88.8%) responded favourably. Evidence of haemolytic anaemia was observed in 49 (36%). A high level of C-reactive protein at presentation was the only independent predictor for use of methylprednisolone (odds ratio 2.18 per 10 mg/dl increase, 95% confidence interval 1.12 to 4.25, p = 0.02). Thirty seven patients (26.8%) required admission to the intensive care unit and 21 (15.2%) required invasive mechanical ventilation. There were 15 deaths (mortality rate 10.9%), most with significant co-morbidities, whereas 122 (88.4%) had been discharged home 4 months after the outbreak onset.
CONCLUSION: The use of high dose pulse methylprednisolone during the clinical course of a SARS outbreak was associated with clinical improvement, but randomised controlled trials are needed to ascertain its efficacy in this condition.
BACKGROUND: Severe acute respiratory syndrome (SARS) is a condition of unknown cause that has recently been recognized in patients in Asia, North America, and Europe. This report summarizes the initial epidemiologic findings, clinical description, and diagnostic findings that followed the identification of SARS in Canada.
METHODS: SARS was first identified in Canada in early March 2003. We collected epidemiologic, clinical, and diagnostic data from each of the first 10 cases prospectively as they were identified. Specimens from all cases were sent to local, provincial, national, and international laboratories for studies to identify an etiologic agent.
RESULTS: The patients ranged from 24 to 78 years old; 60 percent were men. Transmission occurred only after close contact. The most common presenting symptoms were fever (in 100 percent of cases) and malaise (in 70 percent), followed by nonproductive cough (in 100 percent) and dyspnea (in 80 percent) associated with infiltrates on chest radiography (in 100 percent). Lymphopenia (in 89 percent of those for whom data were available), elevated lactate dehydrogenase levels (in 80 percent), elevated aspartate aminotransferase levels (in 78 percent), and elevated creatinine kinase levels (in 56 percent) were common. Empirical therapy most commonly included antibiotics, oseltamivir, and intravenous ribavirin. Mechanical ventilation was required in five patients. Three patients died, and five have had clinical improvement. The results of laboratory investigations were negative or not clinically significant except for the amplification of human metapneumovirus from respiratory specimens from five of nine patients and the isolation and amplification of a novel coronavirus from five of nine patients. In four cases both pathogens were isolated.
CONCLUSIONS: SARS is a condition associated with substantial morbidity and mortality. It appears to be of viral origin, with patterns suggesting droplet or contact transmission. The role of human metapneumovirus, a novel coronavirus, or both requires further investigation.
BACKGROUND: We investigated the temporal progression of the clinical, radiological, and virological changes in a community outbreak of severe acute respiratory syndrome (SARS).
METHODS: 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.
FINDINGS: 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.
INTERPRETATION: 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.
In March 2003, an outbreak of severe acute respiratory syndrome started in Hong Kong. A 57-year-old woman had a typical presentation, including fever, non-productive cough, malaise, lymphopenia, and raised liver aminotransferases. The clinical course and successful treatment with convalescent plasma, ribavirin, and corticosteroids are discussed.
OBJECTIVES: To investigate the possible benefits and adverse effects of the addition of lopinavir/ritonavir to a standard treatment protocol for the treatment of severe acute respiratory syndrome.
DESIGN: Retrospective matched cohort study.
SETTING: Four acute regional hospitals in Hong Kong.
PATIENTS AND METHODS: Seventy-five patients with severe acute respiratory syndrome treated with lopinavir/ritonavir in addition to a standard treatment protocol adopted by the Hospital Authority were matched with controls retrieved from the Hospital Authority severe acute respiratory syndrome central database. Matching was done with respect to age, sex, the presence of co-morbidities, lactate dehydrogenase level and the use of pulse steroid therapy. The 75 patients treated with lopinavir/ritonavir were divided into two subgroups for analysis: lopinavir/ritonavir as initial treatment, and lopinavir/ritonavir as rescue therapy. These groups were compared with matched cohorts of 634 and 343 patients, respectively. Outcomes including overall death rate, oxygen desaturation, intubation rate, and use of pulse methylprednisolone were reviewed.
RESULTS: The addition of lopinavir/ritonavir as initial treatment was associated with a reduction in the overall death rate (2.3%) and intubation rate (0%), when compared with a matched cohort who received standard treatment (15.6% and 11.0% respectively, P<0.05) and a lower rate of use of methylprednisolone at a lower mean dose. The subgroup who had received lopinavir/ritonavir as rescue therapy, showed no difference in overall death rate and rates of oxygen desaturation and intubation compared with the matched cohort, and received a higher mean dose of methylprednisolone.
CONCLUSION: The addition of lopinavir/ritonavir to a standard treatment protocol as an initial treatment for severe acute respiratory syndrome appeared to be associated with improved clinical outcome. A randomised double-blind placebo-controlled trial is recommended during future epidemics to further evaluate this treatment.
To describe the immunological responses and clinical outcome of coronavirus (SARS) infected healthcare workers (HCW) who had been administered with convalescent plasma as a treatment.
METHODS:
Convalescent plasma (500 mL) was obtained from each of three SARS patients and transfused into the three infected HCW. Donors were blood type O and seronegative for hepatitis B and C, HIV, syphilis and human T-cell lymphotropic virus types I and II (HTLV-I and -II). Serum antibody (IgG) titre was >640. Apharesis was performed with a CS 3000 plus cell separator followed by the forming of the convalescent phase plasma. As part of the routine check with donated plasma, the convalescent plasma was confirmed free of residual SARS-CoV by RT-PCR. Serial serum samples obtained from the recipients of the convalescent plasma were collected to undertake real-time quantitative RT-PCR for SARS-CoV for direct measurement of viral concentration. Specific immunoglobulin IgM and IgG concentrations were titrated using an antigen microarray developed in-house.
RESULTS:
Viral load dropped from 495 x 10(3), 76 x 10(3) or 650 x 10(3) copies/mL to zero or 1 copy/mL one day after transfusion. Anti-SARS-CoV IgM and IgG also increased in a time-dependent manner following transfusion. All three patients survived. One HCW became pregnant subsequently, delivering 13 months after discharge. Positive anti-SARS-CoV IgG was detected in the newborn. Passive transfer of anti-SARS-CoV antibody from the mother was considered as a possibility.
CONCLUSIONS:
All infected HCW whose condition had progressed severely and who had failed to respond to the available treatment, survived after transfusion with convalescent plasma.
