Loutfy MR, Blatt LM, Siminovitch KA, Ward S, Wolff B, Lho H, Pham DH, Deif H, LaMere EA, Chang M, Kain KC, Farcas GA, Ferguson P, Latchford M, Levy G, Dennis JW, Lai EKY, Fish EN. Interferon Alfacon-1 Plus Corticosteroids in Severe Acute Respiratory SyndromeA Preliminary Study. JAMA. 2003;290(24):3222-3228. doi:10.1001/jama.290.24.3222
Author Affiliations: North York General Hospital (Drs Loutfy, Wolff, Lho, Pham, Deif, LaMere, Chang, and Lai and Mss Ferguson and Latchford), Toronto General Research Institute and University of Toronto (Drs Siminovitch, Kain, Levy, and Fish and Mss Ward and Farcas), and Mt Sinai Hospital and University of Toronto (Dr Dennis), Toronto, Ontario; and Intermune Corp, Brisbane, Calif (Dr Blatt).
Context Severe acute respiratory syndrome (SARS) is a new clinical entity for
which no effective therapeutic strategy has been developed.
Objective To provide preliminary results on the potential therapeutic benefit
and tolerability of interferon alfacon-1 plus corticosteroids for SARS.
Design, Setting, and Patients Open-label study of 22 patients diagnosed as having probable SARS at
North York General Hospital, Toronto, Ontario, between April 11 and May 30,
Interventions Thirteen patients were treated with corticosteroids alone and 9 patients
were treated with corticosteroids plus subcutaneous interferon alfacon-1.
Main Outcome Measures Clinical parameters, including oxygen saturation and requirement, laboratory
measures, and serial chest radiography results.
Results Resolution of fever and lymphopenia were similar between the 2 treatment
groups. Of the 13 patients treated with corticosteroids alone, 5 (38.5%) were
transferred to the intensive care unit, 3 (23.1%) required intubation and
mechanical ventilation, and 1 (7.7%) died. Of the 9 patients in the interferon
alfacon-1 treatment group, 3 (33.3%) were transferred to the intensive care
unit, 1 (11.1%) required intubation and mechanical ventilation, and none died.
The interferon alfacon-1 treatment group had a shorter time to 50% resolution
of lung radiographic abnormalities (median time, 4 days vs 9 days; P = .001), had better oxygen saturation (P =
.02), resolved their need for supplemental oxygen more rapidly (median, 10
days vs 16 days; P = .02), had less of an increase
in creatine kinase levels (P = .03), and showed a
trend toward more rapid resolution of lactate dehydrogenase levels compared
with the group receiving corticosteroids alone.
Conclusions In this preliminary, uncontrolled study of patients with SARS, use of
interferon alfacon-1 plus corticosteroids was associated with reduced disease-associated
impaired oxygen saturation, more rapid resolution of radiographic lung abnormalities,
and lower levels of creatine kinase. These findings suggest that further investigation
may be warranted to determine the role of interferon alfacon-1 as a therapeutic
agent for the treatment of SARS.
Severe acute respiratory syndrome (SARS) is a new infectious disease,
probable cases of which are defined by the Centers for Disease Control and
Prevention and World Health Organization criteria of fever (temperature >38°C),
lower respiratory tract symptoms, abnormal chest radiograph results, and laboratory
evidence of the Urbani strain of SARS-associated coronavirus infection (SARS-CoV).1,2 As of September 26, 2003, the World
Health Organization had recorded a cumulative number of 8098 SARS cases and
774 SARS-related deaths from 27 countries.3 Treatment
strategies have included empirical antibiotic therapy, intravenous and oral
ribavirin, corticosteroids, and intravenous immunoglobulin.4- 6 However,
no compelling evidence exists that these strategies improve clinical outcome,
and use of ribavirin has been associated with significant toxic effects.6
Hyperimmuneglobulin, protease inhibitors, fusion inhibitors, and interferons
represent other therapeutic options for treating SARS patients.7 Among
these possibilities, interferon alfa is a potential candidate agent and has
been recognized to play critical roles in host resistance to viral infection.8- 11 Interferons
inhibit viral infection by inducing both innate and adaptive immune responses
(eg, by altering the intracellular environment to restrict viral replication,
and inducing signaling events that activate immune cell populations and thereby
elicit an antiviral immune response).
Interferon alfas have been shown to be of value in the treatment of
hepatitis B and C12,13 and to
induce inhibition of respiratory coronavirus infections, albeit unrelated
to the Urbani strain of SARS-CoV.14- 17 In
in vitro experiments, interferons were effective in inhibiting SARS-CoV,18 with interferon alfacon-1 exhibiting the highest
antiviral activity compared with interferon gamma (Jason Paragas, PhD, US
Army Medical Research Institute of Infectious Diseases, unpublished data,
May 2003). Interferon alfacon-1 (Infergen, Intermune Corp, Brisbane, Calif)
is a synthetic interferon alfa designed to represent a consensus interferon
alfa19 that has been shown in both cell culture
systems20 and comparative clinical trials21 to inhibit viral replication more potently than other
type 1 interferons.
This preliminary pilot study was initiated to evaluate the potential
clinical benefit and safety of interferon alfacon-1 in SARS treatment.
The study population involved 22 patients who were admitted to North
York General Hospital (NYGH), Toronto, Ontario, between April 11 and May 30,
2003, and met the Centers for Disease Control and Prevention and World Health
Organization criteria for probable SARS.1,2 Inclusion
criteria for interferon alfacon-1 therapy were (1) symptom onset within 10
days of the Health Canada approval date (May 29, 2003) for use of interferon
alfacon-1 in SARS patients; (2) progressive radiological deterioration over
the preceding 48 hours, with greater than 20% involvement of lung fields;
(3) progressive deterioration of clinical respiratory status over the preceding
48 hours (decreasing oxygen saturation, increasing respiratory rate, or worsening
dyspnea); and (4) patient informed consent for use of interferon alfacon-1.
Exclusion criteria included (1) symptom onset more than 10 days before the
Health Canada approval date; (2) mechanically assisted ventilation in the
intensive care unit (ICU); and (3) contraindication to use of interferon alfacon-1.
Nine patients met the inclusion criteria for interferon alfacon-1 treatment.
Patients with probable SARS who were admitted to NYGH during the same
period and were administered corticosteroids but not ribavirin served as a
comparison group. After May 29, interferon alfacon-1 was offered to all patients
who met inclusion criteria. Eleven patients who were admitted prior to May
30 and 2 who declined interferon alfacon-1 treatment comprise the comparison
group. All patients admitted prior to April 11, 2003, were excluded because
they were included in a previously published study and received ribavirin.6
Oral prednisone, 50 mg twice per day, or intravenous methylprednisolone,
40 mg every 12 hours, was administered to all patients who had abnormal chest
radiographs. After May 26, 2003, patients exhibiting progressive disease,
as characterized by worsening chest radiographs, decreasing oxygen saturation,
and worsening dyspnea, received pulsed high-dose intravenous methylprednisolone,
500 mg once per day, for 3 days, followed by a taper and a step down to oral
prednisone to complete a 20-day course similar to the previously described
protocol.5 Patients who required at least 6
L/min of oxygen via nasal prongs to maintain oxygen saturation of at least
92% were transferred to the ICU.
Following Health Canada approval for interferon alfacon-1 use in SARS
treatment (May 29, 2003), interferon alfacon-1 was offered through a special
access program to all patients who met inclusion criteria for interferon alfacon-1
treatment. Because this study represented the first use of interferon for
SARS treatment, the Health Canada provisions for its use in these patients
included consultation with an immunologist and submission of a report of adverse
events. Institutional research ethics boards for NYGH and the University Health
Network reviewed and approved the study protocol and written informed consent
was obtained from all participants who received interferon alfacon-1.
Patients were administered subcutaneous interferon alfacon-1 for a total
of 10 days, beginning with 9 µg/d for a minimum of 2 days and increased
to 15 µg/d if no clinical response was observed. Of the 9 patients treated
with interferon alfacon-1, 7 received only the 9-µg dose and 2 received
the 15-µg doses. Because of concerns about possible viral and disease
rebound if interferon alfacon-1 treatment was stopped before cessation of
corticosteroids, a more rapid steroid taper was introduced and interferon
alfacon-1 treatment was continued for 1 day after corticosteroid termination.
Because of the variable stages of steroid tapering, the interferon alfacon-1
treatment courses ranged from 8 to 13 days. Patients were not discharged to
home while still receiving interferon alfacon-1. Patients in the comparison
group received corticosteroids but not ribavirin while at NYGH. These patients
were chosen prior to data analysis. In both groups, supplemental oxygen therapy
was withdrawn when oxygen saturation increased to at least 99% with 1 L/min
of oxygen via nasal prongs and at the discretion of treating physicians.
Laboratory investigations included serial hematological and biochemical
assays. Acute and convalescent serum samples were tested for SARS-CoV–associated
IgG, using both an enzyme-linked immunosorbent assay and an indirect immunofluorescent
assay targeted to the SARS-CoV propagated in Vero E6 cells (National Reference
Laboratory, Winnipeg, Manitoba). Serial chest radiographs were obtained from
a total of 31 patients at NYGH, including the 22 study patients and 9 additional
radiological controls. Radiological controls were randomly chosen from a list
of patients investigated for but found not to have SARS and were included
to ensure blinding to the disease and the treatment (results of these radiological
controls are not included in the data analysis).
Each radiograph was obtained in the frontal projection and was retrospectively
reviewed independently by 3 radiologists who were blinded to the identity,
diagnosis, and treatment protocol of each patient. For each radiograph, description
and an approximate size estimation of the abnormalities, based on percentage
of lung involvement, were recorded. For quantitative assessment of radiographic
disease progression, the mean percentage of lung involvement reported by the
3 readers was calculated for each radiograph. The radiographic end point used
for the analysis was decided prior to any data analysis and was defined as
the time from maximum to 50% improved chest radiographic abnormalities. Complete
resolution of abnormalities was not considered a practical end point because
most patients (18/22) had some residual radiographic findings on the last
radiograph, and some did not achieve complete resolution even when followed
up beyond the study time frame, up to several months.
Baseline characteristics and treatment of the 2 groups are presented
as medians and ranges for continuous variables and as numbers and percentages
for categorical variables.22 Comparisons were
made using the Wilcoxon rank sum test and the Fisher exact test, respectively.22 Serial laboratory tests, oxygen saturation, and temperature
were plotted for the 2 groups and compared using repeated-measures analysis
of variance.22 Missing data were imputed using
the last-value-carried-forward technique.22 Kaplan-Meier
methods were used to analyze time to 50% resolution of peak lung involvement
and time to cessation of supplemental oxygen; significance was calculated
using the log-rank test.22 Patients were censored
if at the end of follow-up they had not reached the end point. The data set
was created and closed prior to any data analysis. Statistical analyses were
completed using SAS statistical software, version 8.2 (SAS Institute Inc,
Cary, NC). P<.05 was considered significant for
The study population included 16 women and 6 men aged 16 to 86 years.
SARS-CoV–associated IgG seroconversion was confirmed in all study patients
except 1 who received corticosteroids alone, from whom no convalescent serum
sample was obtained. Treatment subgroups did not differ in either demographic
or clinical features at post–symptom onset day 7 (Table 1). This comparison was made at day 7 because it is 1 day
prior to the median start date of interferon alfacon-1 treatment (day 8; range,
days 4-10) and frequently approximates the time of peak disease.23 The
2 concurrent patients in the comparison group who received high-dose steroids
were considered for interferon alfacon-1 therapy but one refused and the other
was late in the course of disease. The latter patient was transferred from
another Toronto hospital and had received intravenous ribavirin, 400 mg every
8 hours, at that hospital for 3 days. Ribavirin was discontinued on admission
to NYGH and this patient was intubated and received high-dose methylprednisolone.
Of the 13 patients treated with corticosteroids alone, 5 (38.5%) were
transferred to the ICU, 3 (23.1%) required intubation and mechanical ventilation,
and 1 (7.7%) died. Two patients were transferred to the ICU on days 5 and
10 after disease onset and remained in the ICU for 2 and 3 days, respectively.
The former patient subsequently died. The other 3 patients were transferred
on days 8, 10, and 12 after disease onset and remained there for 10, 14, and
14 days, respectively. These 3 patients were intubated for 9, 5, and 12 days,
Of the 9 patients treated with interferon alfacon-1, 3 (33.3%) were
transferred to the ICU, 1 (11.1%) subsequently required intubation and mechanical
ventilation, and none died. Of these patients, 1 who started interferon alfacon-1
on day 8 after disease onset was transferred to the ICU on day 9 and released
from the ICU within 24 hours. A second patient received interferon alfacon-1
on day 6 and was transferred to the ICU on day 6, remaining there for 6 days.
These 2 patients did not require intubation or ventilation. The third patient
started interferon alfacon-1 on day 8 after disease onset, was transferred
to the ICU on day 9, was intubated for 14 days, and remained in the ICU for
a total of 17 days.
Length of time to discharge was not included as a study outcome because
patients receiving interferon alfacon-1 were kept in the hospital for monitoring
for the duration of therapy, regardless of clinical status. Patients tolerated
interferon alfacon-1 treatment well, with minimal adverse events. The single
clinical adverse event reported was fever, which led to discontinuation of
the drug in 1 patient. The fever persisted for 1 week after drug discontinuation
and was likely due to the underlying disease. None of the patients receiving
interferon alfacon-1 developed flulike symptoms, myalgias, or depression.
One patient experienced neutropenia with an absolute neutrophil count (ANC)
of less than 1000/µL on the last day of treatment. Interferon alfacon-1
was generally associated with a minor transient decrease in ANC (Figure 1A) and elevation of serum transaminase
levels (Figure 1D), both of which
resolved within 1 to 2 days of drug discontinuation and appeared to be of
no clinical consequence. Decreases in ANC and increases in serum transaminase
levels are frequently observed in patients with chronic hepatitis C who are
receiving interferon therapy.24,25
Follow-up of the 9 interferon alfacon-1 patients to day 60 revealed
no evidence of rebound fever or recurrent disease. There was no worsening
on chest radiographs, no requirement for supplemental oxygen, and no rehospitalization
after cessation of interferon alfacon-1 therapy.
The data in Figure 1 and Figure 2 record the changes in mean values
of specific clinical measurements and laboratory test results, obtained for
both the interferon alfacon-1 and comparison groups over the course of disease.
Analysis of these data with the last-value-carried-forward method and with
no data imputation yielded identical results. Time-course plots for mean hemoglobin,
calcium, total bilirubin, alkaline phosphatase, aspartate aminotransferase,
and creatinine values remained within normal range and were similar among
all patients (data not shown). The time course for resolution of fever during
the course of disease was indistinguishable between the interferon alfacon-1
and comparison groups (Figure 2A).
As in other studies, lymphopenia was observed in all patients.23,26,27 However, the absolute
lymphocyte counts were indistinguishable between the 2 groups and returned
to normal levels during the course of disease (Figure 1B). The ANC increased in the comparison group (Figure 1A) and initially in the interferon
alfacon-1 group. However, continued interferon alfacon-1 treatment was associated
with a decrease in ANC that improved after the drug was discontinued. The
interferon alfacon-1–treated group also showed less thrombocytosis during
recovery than the comparison group (Figure
1C), possibly because of myelosuppression.
Elevated lactate dehydrogenase (LDH) is a consistent laboratory feature
of SARS6,28 and may represent
a marker for lung parenchymal damage. Lactate dehydrogenase increased over
time in all patients, but a trend toward faster nomalization appeared in the
interferon alfacon-1 group (Figure 1E).
Creatine kinase (CK) levels, which were highly elevated in the comparison
group during the mid course of disease, were minimally altered during the
entire course of disease in the interferon alfacon-1–treated patients
(P = .03 by repeated-measures analysis of variance)
The initial chest radiographs were obtained 3 to 12 days (median, 3
days) and the final radiographs were obtained 7 to 50 days (median, 21 days)
after symptom onset. The median number of radiographs obtained per patient
was similar in the 2 groups: 11 (range, 7-12) for interferon alfacon-1 patients
and 9 (range, 3-12) for the comparison group. The median number of days to
peak abnormalities for all patients was 10, with no difference between the
interferon alfacon-1 group (median, 11 days; range, 9-12 days) and comparison
group (median, 10 days; range, 6-14 days). The median time from peak chest
radiographic abnormalities to 50% improvement for interferon alfacon-1 patients
was 4 days (range, 2-5 days) and for patients receiving corticosteroids alone
was 9 days (range, 4-12 days) (P = .001 by log-rank
test) (Figure 3A).
Consistent with these findings, higher oxygen saturation levels were
observed in interferon alfacon-1 patients compared with the comparison group
(Figure 2B) (P = .02 by repeated-measures analysis of variance). The need for supplemental
oxygen resolved significantly faster in interferon alfacon-1 patients than
in the comparison group (median, 10 days [range, 0-17 days] vs 16 days [range,
0-21 days]; P = .02 by log-rank test). Fifty percent
of patients in the comparison group were still receiving supplemental oxygen
by day 21, while none of the interferon alfacon-1 patients required oxygen
beyond day 17 (Figure 3B).
This article reports the clinical features and outcomes observed in
a SARS patient cohort treated with corticosteroids alone or in combination
with interferon alfacon-1. These preliminary findings suggest that treatment
with interferon alfacon-1 and steroids was associated with more rapid resolution
of radiographic lung abnormalities and better oxygen saturation levels than
treatment with corticosteroids alone. In addition, in contrast with this comparison
group, in whom the disease was associated with considerable increases in CK
and LDH levels, interferon alfacon-1 patients showed less increases in CK
levels and a more rapid return of LDH to normal levels. As morbidity and mortality
in SARS are directly related to pulmonary space infiltration and LDH and CK
levels are thought to represent indicators of lung parenchymal damage and
poor prognosis, respectively,6,23,27 these
findings provide preliminary evidence that interferon alfacon-1 therapy may
help ameliorate lung parenchymal disease in SARS.
Interferon alfacon-1 therapy was well tolerated by SARS patients and,
at least in the group studied herein, did not induce increases in headache,
fever, chills, or myalgia—adverse events reported with interferon treatment
in other clinical settings.29 The lack of these
adverse events is likely due to the concurrent use of steroids in the patient
population in this study. Although interferon alfacon-1 therapy was associated
with mild neutropenia and some elevation of serum transaminase levels, these
changes were clinically insignificant and resolved with drug discontinuation.
The current study was undertaken for the purpose of providing preliminary
data on the tolerability, safety, and potential therapeutic benefit of interferon
alfacon-1 in SARS patients when administered in combination with corticosteroids.
Although steroid use at high or low doses does not appear to induce severe
complications in SARS patients, it is currently unclear whether disease course
or outcomes are significantly altered by it. However, to conform to the standard
of care, corticosteroid treatment was administered in all study patients.
The findings of improved resolution of radiographic abnormalities, higher
oxygen saturation, and reduced CK elevation in interferon alfacon-1 patients
cannot, therefore, be attributed solely to interferon alfacon-1, independent
of corticosteroids. Emerging data suggest that the clinical progression of
SARS involves an initial phase when viral replication contributes to the cytolytic
damage and immunopathological response, followed by pathological lung damage
caused by an overexuberant host immune response.23 Interferon
alfacon-1 may effectively limit viral load, thereby decreasing the subsequent
immunpathological damage. Moreover, interferon alfacon-1 may act synergistically
with steroids to immunosuppress the host response.
The dosage of interferon alfacon-1 used in this study was selected in
consideration of SARS as an acute viral infection and the consequent aim of
achieving high enough interferon alfacon-1 levels to effect viral clearance.
Data from studies of patients with hepatitis C treated with interferon alfacon-1
have revealed that daily dosing at 9 µg provides a sustained antiviral
response21,29 and that effectiveness
in terms of viral clearance increases with 15-µg and 30-µg doses.30 It is in this context that the 9-µg and 15-µg
doses were used in the current study. The 15-µg dose appeared to be
well tolerated and may prove to be the more appropriate dose to use in SARS
treatment. The optimal dose, as well as the effect of monotherapy with interferon
alfacon-1 in the absence of steroids for the management of SARS, needs to
be further evaluated in clinical studies.
Furthermore, the findings reported herein need to be cautiously interpreted
in view of lack of randomization, the restrospective study design, and limited
sample size. However, despite the limitations of this open-label, uncontrolled
study, these data suggest that interferon alfacon-1 may be of value in the
treatment of SARS and indicate that its use for this purpose merits further
evaluation. To this end, a protocol for a randomized controlled clinical trial,
the primary objective of which is to evaluate the safety and virologic efficacy
of interferon alfacon-1 in the treatment of probable and suspected SARS cases
compared with observation and supportive therapy, has been submitted to and
approved by Health Canada.