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Iranian Journal of Clinical Infectious Diseases
2009;4(3):189-193
©2009 IDTMRC, Infectious Diseases and Tropical Medicine Research Center
REVIEW ARTICLE
Ten years after the beginning of Crimean-Congo hemorrhagic fever
outbreak in Iran: A promising report
Batool Sharifi-Mood, Roya Alavi-Naini, Maliheh Metanat*
Research Center for Infectious Diseases and Topical Medicine, Zahedan University of Medical Sciences, Zahedan, Iran
INTRODUCTION
1
Crimean-Congo hemorrhagic fever (CCHF) is
a fatal viral infection described in about 30
countries. It has the most extensive geographic
distribution of the medically important tick-borne
viral diseases (1-6). Human can be infected through
tick bites, by crushing infected ticks, after contact
with a patient with CCHF during the acute phase of
infection, or by contact with blood or tissues from
viremic livestock. Health-care workers have a
serious risk of infection, particularly during care of
patients with hemorrhages from the nose, mouth,
gums, vagina, and injection sites (4-8).
Following an incubation period of two to
fourteen days, clinical features commonly show a
dramatic progression characterized by hemorrhage,
myalgia, and fever. Petechial rash and hemorrhagic
signs such as hematemesis, melena and intracranial
hemorrhage could be other presenting sings (6-10).
Mortality rate of CCHF is up to 80% of clinically
apparent cases, however, despite this high lethality
rate, up to 80% of the infections may be subclinical
(5-7). The levels of liver enzymes, creatinine
phosphokinase, and lactate dehydrogenase are
raised, and prolongation of bleeding markers are
another laboratory findings. Infection of the
endothelium has a major pathogenic role. Besides
Received: 19 June 2009 Accepted: 9 July 2009
Reprint or Correspondence: Maliheh Metanat, MD.
Department of Infectious Diseases and Tropical Medicine,
Boo-Ali Hospital, Zahedan, Iran
E-mail: [email protected]
direct infection of the endothelium, indirect
damage by viral factors or virus-mediated hostderived soluble factors that cause endothelial
activations and dysfunction are thought to occur (49). Although the first human cases of CCHF in Iran
were identified in the eastern and central regions of
the country in spring 1999, thereafter endemic
areas have substantially increased in several
provinces of Iran with an increasing morbidity
rate and approximately high fatalities (up to 26.5%)
in the first few years of the first decade (1,3,10).
About 67% of all confirmed cases in Iran have
been reported from Sistan and Baluchestan
province located in southeast of Iran (9). Now,
according to the current experiences from this
endemic region (Sistan and Baluchestan), there are
a few clinical and confirmed cases which need to
be highlighted about their results (11). The
objective of this review is to demonstrate our
experiences, especially in management and
treatment of CCHF patients with oral ribavirin.
Diagnosis
CCHF infection should be suspected in any
patient who have:
1- Clinical manifestations including acute onset
of fever, headache, myalgia and bleeding.
2- Epidemiologic risk factors including a
history of recent travel to an endemic region, living
in an endemic area, history of tick bite, and
Iranian Journal of Clinical Infectious Disease 2009;4(3):189-193
190 CCHF in Iran
exposure to blood or tissues of an infected patient
or animal.
3- Laboratory findings such as leucopenia or
leukocytosis, thrombocytopenia and increased level
of creatine phosphokinase, transaminases, and
prolongation of prothombin time (PT).
Methods for diagnosis of CCHF virus include
antibody
detection
by
enzyme-linked
immunosorbent assay (ELISA), antigen detection,
virus isolation, and a molecular method for
detecting the viral genome by reverse transcriptionpolymerase chain reaction (RT-PCR). Diagnosis of
suspected CCHF is performed in speciallyequipped, high biosafety level laboratories. IgG
and IgM antibodies may be detected in serum by
enzyme-linked immunoassay (ELISA) from about
day six of illness. IgM can be detectable for four
months, and IgG levels gradually decline but
remain detectable for up to five years. Patients with
fatal CCHF do not usually develop a measurable
antibody response and in these persons, in the first
few days of illness, diagnosis is made by virus
detection in blood or tissue samples. The virus may
be detected in blood or tissue specimens in the first
five days of illness, and grown in cell culture. Viral
antigens may sometimes be shown in tissue
samples using immunofluorescence or ELISA.
What to do when a physician
faces a CCHF patient
First Step
If clinicians feel that CCHF is a likely
diagnosis, they should isolate the patient, and then
report it to the local CDC and health departments.
Patients with CCHF syndrome generally have
significant quantities of virus in their blood and
other secretions. Therefore, caution should be
exercised in evaluating and treating patients with
suspected CCHF. At least, these should include the
following: stringent barrier nursing; wearing glove,
mask, gown, needle precautions; hazard-labeling of
specimens; restricted accessing to the patient; and
disinfecting of contaminated materials by using
hypochlorite or phenolic disinfectants or
autoclaving.
Second step: Management of hemorrhagic
syndrome.
Patients should be monitored carefully and
closely, in a high dependency or intensive care
setting. Complete blood count, liver function test,
serum electrolyte levels, blood urea nitrogen,
creatinin, PT and PTT should be monitored at least
daily in the early phase of the illness. Optimum
fluid and electrolyte balance should be targeted.
Replacement with blood products such as fresh
frozen plasma, erythrocyte and platelet should be
considered based on patient laboratory results.
Intramuscular injections and use of anti-platelet
agents such as aspirin or other non-steroidal antiinflammatory drugs should be avoided during the
bleeding period. Proton pump inhibitors or H2
receptor antagonists are indicated in severe cases
and those who have upper GI bleeding. Use of
platelets and FFP should be considered based on
platelet count and coagulation status.
Third step
There is an urgent need for a close collaboration
between hospitals, academic centers, health care
centers and other wards to recognize the magnitude
and future of the epidemic.
Fourth Step
One of the most important steps in the
management of CCHF patients is early oral
ribavirin treatment especially, in the first few days
of illness that showed a significant positive effect
on survival. It is essential to make an early
diagnosis of CCHF and start treatment and
preventive measures for all suspected cases without
waiting for confirmation of the diagnosis. In this
regard, there are several clinical surveys in this
region that revealed patients treated with oral
ribavirin had clinical improvement as well as a
decreased in the mortality rate from 26.5% in the
first years to less than 3% during the last few years
of the recent decade.
Iranian Journal of Clinical Infectious Disease 2009;4(3):189-193
Sharifi-Mood B. et al 191
A review of studies during last
decade
In Alavi-Naini and colleagues study in Sistan
and Baluchestan, among 255 patients with CCHF,
22% died (9). Thereafter, in 2006, Metanat et al
showed that of 184 CCHF patients, 89 (48.5%)
have been treated by ribavirin during the first 72
hours of the disease of whom 75 (84%) survived
and 14 (16%) died. Moreover, of 95 patients
treated after 72 hours following the disease onset,
74% survived and 26% died. Recovery rate was
higher in those who were treated during the first
three days (10).
Another study in 2006 on 29 children with
CCHF also demonstrated that recovery rate was
higher among patients who were treated during the
initial 3 days of illness (3). Indeed, of 29 children,
25 were treated by oral ribavirin within the first
three days, 2 were treated after this time and 2
received nothing because of misdiagnosis.
Unfortunately, both of these 2 untreated cases as
well as another child who received therapy 6 days
following the disease onset and 4 (16%) children
who received early therapy died. Therefore, a
fatality rate of 24% was calculated, however,
recovery rate was still higher among those who
were treated during the initial 3 days (3).
A study in the beginning of the recent outbreak
showed that of 91 patients who were treated with
ribavirin, 73 (80%) survived and 18 (20%) died
(11). Among the survived patients, 58 (79%) were
treated during the initial 72 hours and 15 were
treated thereafter, however, 16 patients who
received treatment after this period died. The
mortality rate was lower in those who were treated
during the initial three days (2% vs. 16%) (11).
Between 2005 and 2007, of 32 patients who were
treated within three days of the onset of the disease,
only one (3%) died. There was a significant
difference in the recovery rate between the two
groups who were treated at the beginning of the
outbreak and during the years 2005 to 2007
(p=0.001) (11). A study conducted by Izadi et al
revealed that of 113 patients admitted to a hospital
in Zahedan, all except 5 were treated with oral
ribavirin within 2 hours of hospitalization (12).
Patients who survived began oral ribavirin 24 hours
earlier than those who died. This study defined that
the cases who were treated during the first 4 days
had a better outcome than those who were treated
after this time (p=0.004). The results of the study
also showed early therapy with oral ribavirin
reduced bleeding tendency (12).
In another survey, a total of 34 non-adult
confirmed CCHF patients were evaluated (13). The
mean age of the studied subjects was 13.3±4.6
years (range, 5–18 years). Fourteen (41.2%)
patients were 12 years-old or younger. The casefatality ratio in this study was 26.5% (9 of 34). In
fatal cases, the median time from onset of
symptoms until death was 7 days (range, 5–11
days).
In
univariate
analyses,
impaired
consciousness,
petechia,
hemorrhagic
manifestations, and jaundice were more frequent in
dead subjects than in survivors. Those who
survived received earlier treatment with oral
ribavirin (13).
Ribavirin is a WHO recommended anti-viral
medication for CCHF (11-13). The recommended
dose is an initial dose of 30mg/kg followed by
15mg/kg for four days and then 7.5mg/kg for six
days for a total of 10 days (10-18). Unfortunately,
ribavirin has not been included in the official list of
pharmaceutical companies for use in CCHF and
companies promote this drug for hepatitis C
management. Intravenous form of the drug which
was first recommended for ill patients, is not
available for patients who can not tolerate the drug
orally (18-28). Usually the affected population is
from rural areas with low economical situation. It
is suggested that drugs for these patients be easily
available and accessible so that patients with
positive clinical features and epidemiological
factors could receive oral ribavirin with the onset
of disease without any delay.
Iranian Journal of Clinical Infectious Disease 2009;4(3):189-193
192 CCHF in Iran
In conclusion, clinicians should consider oral
ribavirin in the treatment of CCHF patients in the
beginning of illness. Early diagnosis and treatment
of CCHF are potentially associated with a lower
mortality and decreased chance of secondary
spread of infection.
ACKNOWLEDGEMENT
The authors wish to thank the cooperation of all
laboratory and health care staff during the recent
years, without their help gathering associated data
was impossible.
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