حمى الوادي المتصدع "Rift Valley Fever" كيف ينتشر الفيروس وكيف تتم الوقاية؟

Quote: Clinical Infectious Diseases 2003;36:245–252 © 2003 by the Infectious Diseases Society of America. All rights reserved. 1058-4838/2003/3603-0001$15.00 DOI: 10.1086/345671 MAJOR ARTICLE Epidemic Rift Valley Fever in Saudi Arabia: A Clinical Study of Severe Illness in Humans Mohammed Al-Hazmi,1 Ephraim Ayobanji Ayoola,1 Mahmoud Abdurahman,1 Subodh Banzal,1 Jammal Ashraf,1 Adil El-Bushra,1 Ali Hazmi,2 Mohammed Abdullah,1 Hamid Abbo,1 Abdulhadi Elamin,1 El-Tayeb Al-Sammani,1 Mohammed Gadour,1 Chandra Menon,1 Mirghani Hamza,1 Inam Rahim,1 Magdy Hafez,1 Manish Jambavalikar,1 Haider Arishi,3 and Ali Aqeel3 Departments of 1Medicine, 2Ophthalmology, and 3Pediatrics, King Fahd Central Hospital, Gizan, Saudi Arabia Received 26 June 2002; accepted 8 October 2002; electronically published 17 January 2003. Reprints or correspondence: Prof. E. A. Ayoola, PO Box 235 Abu-Arish, Gizan Province, Saudi Arabia ([email protected] or [email protected]). We describe the clinical patterns and case-fatality rate associated with severe Rift Valley fever (RVF) in patients who were admitted to the Gizan regional referral hospital during an outbreak of RVF in Saudi Arabia from September through November 2000. A total of 165 consecutive patients (136 men and 29 women) were prospectively studied; all were identified according to a strict case definition, were confirmed to have RVF by serologic testing, and were treated according to a predetermined protocol. The major clinical characteristics of RVF included a high frequency of hepatocellular failure in 124 patients (75.2%), acute renal failure in 68 patients (41.2%), and hemorrhagic manifestations in 32 patients (19.4%). Sixteen patients had retinitis and 7 patients had meningoencephalitis as late complications in the course of the disease. A total of 56 patients (33.9%) died. Hepatorenal failure, shock, and severe anemia were major factors associated with patient death. The Rift Valley fever (RVF) virus of the family Bunyaviridae is a cause of zoonotic viral disease that predominantly causes abortion and death among domestic ruminants; it is characterized by necrotic hepatitis with or without a hemorrhagic state [1, 2]. Infection in humans is acquired through mosquito bites or through contact with tissues of infected animals, and it is usually associated with uncomplicated acute febrile illness. However, severe complications, such as hemorrhagic disease, meningoencephalitis, and retinitis, occur in a minority of clinical cases [1]. Since the 1930s, when the first isolation of the virus occurred and the first detailed description of the disease in animals in the Rift Valley of Kenya was reported, there have been several epizootics in South Africa (1975), West Africa (1987), Madagascar (1990), Egypt (1977 and 1993), and, most recently, in Kenya (1977–1998) [1–4]. Serologic evidence that the virus existed throughout sub-Saharan Africa and Madagascar led to the prediction that the infection might subsequently extend beyond continental Africa and spread to the Middle Eastern countries [5]. In September 2000, an outbreak that caused unexplained hemorrhagic fever in humans and that was associated with deaths and abortions among animals in the far western Saudi-Yemen border region was subsequently confirmed to be an outbreak of RVF; this outbreak represented the first cases of RVF reported on the Arabian Peninsula [4]. In subsequent months, 516 clinical cases of RVF were identified in Saudi Arabia [6]. We report the results of a prospective study designed to determine the clinical pattern of RVF, the frequency of its complications, and the associated case-fatality rates among patients in Saudi Arabia. Patients and Methods Gizan province is a relatively small area of the southwestern part of Saudi Arabia adjacent to the Yemen border. It consists of a coastal plain with a mountainous hinterland rising >300 m above sea level. The province is relatively dense in population and is noted for its extensive agriculture and traditional irrigation practices. King Fahd Central Hospital, located in Gizan, is a well-equipped 500-bed referral center for the 14 general hospitals and many primary health care centers that serve the estimated 1 million inhabitants of the Gizan province. Patients. Patients with RVF were identified through an elaborate preexisting system of primary health care centers that refer acutely ill persons to general hospitals for assessment of hepatitis and other criteria for admission as RVF case patients (table 1) [4]. Of the 516 case patients in Saudi Arabia who were described during the epidemic, the largest number of case patients () was reported from the southwestern province of Gizan, and 122 case patients from the contiguous Asir region were described [6]. From the general hospitals in the Gizan region, critically ill patients were referred to the regional hospital, King Fahd Central Hospital in Gizan, for specialized care. Table 1. Case definition of Rift Valley fever. The subjects of the study were 165 consecutively seen patients who were treated from September through November 2000. At the time of admission to the hospital, a questionnaire was completed that detailed, for each patient, history of possible exposure to sick animals, travel out of the region or country, duration of symptoms, and medical history. A comprehensive examination that included indirect ophthalmoscopy was performed by one of the investigators (A.H.). Laboratory evaluation. The following laboratory values were assessed at the time of admission and then daily or more frequently as needed: complete blood count; prothrombin time; partial thromboplastin time; and levels of serum electrolytes, urea, creatinine, calcium, phosphate, blood sugar, liver enzymes (i.e., bilirubin, alkaline phosphate, alanine aminotransferase [ALT], and aspartate aminotransferase [AST]), total serum protein and albumin, creatine phosphokinase, lactic dehydrogenase, amylase, and lipase. Other tests, which were performed where indicated, included analysis of arterial blood gases, peripheral blood smears for the detection of malaria parasites, and examination of stool and urine samples for blood and pathogens. Chest radiography, abdominal ultrasound, abdominal CT, MRI of the CNS, and echocardiography were performed as indicated. Virologic and serologic tests. Serum samples obtained from all patients were tested for RVF antigen (RVFAg) and for IgM and IgG antibody to RVF virus (IgM-RVFAb and IgG-RVFAb). During the initial stage of the epidemic, the first few patients were tested by PCR for RVF RNA and virologic typing, as reported elsewhere [4, 6]. Markers of viral hepatitis A–C comprising IgM antibody to hepatitis A virus (IgM anti-HAV), hepatitis B surface antigen (HBsAg), IgM antibody to hepatitis B core antigen (IgM anti-HBc), and antibody to hepatitis C virus (anti-HCV) were tested by ELISA with commercial kits. Treatment. All patients were treated in the special RVF unit, where strict barrier and isolation nursing care were provided and where intravenous transfusion of fresh frozen plasma, blood, and albumin was performed as necessary. None of the patients was treated with ribavirin or any other antiviral agent. Bacterial superinfection was treated with antibiotics as necessary. Patients who had severe acute renal failure underwent hemodialysis as indicated. Other intensive care and supportive measures, such as mechanical ventilation, were provided as indicated. Statistical analysis. Descriptive statistics were used to summarize the demographic data at baseline. Continuous variables were presented as mean ± SD. Discrete or categorical variables were expressed as percentages. Comparison of data in proportions was performed using analysis, Fisher's exact test, or analysis of variance. Groups of continuous data were compared using Student's t test for parametric data and nonparametric data. was statistically significant. Results Demographic characteristics of the patients. A total of 165 patients (136 men and 29 women) were treated during the study period and comprised 127 Saudis, 35 Yemenis, and 3 non-Saudis aged 15–95 years (mean age, 47.5 years; median age, 50 years) (table 2). A total of 99 patients (60%) reported having had direct contact either with infected and sick relatives or with sick, aborted, or dead animals. A total of 52 patients (31.5%) had slept in the open air most of the time, and 132 (80%) had frequently sustained mosquito bites. Only 15 patients (9.1%) had traveled out of the country during the 6 months before admission to the hospital; 21 patients (12.7%) had ingested raw milk frequently. Table 2. Demographic characteristics of and clinical outcome for 165 patients in Saudi Arabia with Rift Valley fever. Clinical features of RVF. The mean duration (±SD) from the onset of symptoms to hospitalization was days (range, 1–15 days; median, 4 days). There was little variation in the clinical findings for the patients. Major symptoms and signs of RVF are summarized in table 3. Nausea or vomiting (in 151 patients) and fever (in 122 patients) were the most common symptoms. A total of 31 of 122 patients with fever experienced associated chills or rigors. Abdominal pain was poorly localized. In addition to significant anemia (in 55 patients), the major physical signs were hepatomegaly (in 21 patients) and splenomegaly (in 20 patients). Other features at presentation included altered sensorium (confusion, drowsiness, and coma) in 29 patients and shock in 21 patients. Table 3. Major clinical features of moderate to severe Rift Valley fever in 165 patients in Saudi Arabia. Laboratory investigations. The most prominent abnormal findings of the laboratory investigations were marked elevations of serum levels of ALT (range, 17–16,662 IU/L) and AST (range, 12–40,560 IU/L). Elevation of the lactic dehydrogenase level was found in 71 (44%) of 163 patients, and elevation of the creatine phosphokinase level was found in 50 (32.3%) of 155 patients. Thrombocytopenia and anemia occurred frequently (table 4). Table 4. Laboratory findings for patients in Saudi Arabia with severe Rift Valley fever. Hepatitis and hepatic failure. Abnormal levels of serum AST or ALT indicative of liver damage were present in 152 (95%) of 160 patients. A total of 142 patients (88.8%) had an AST level that was >3 times the upper limit of the range of AST levels considered to be normal (median AST level, 984.5 IU/L; mean AST level, 2088 IU/L) (table 5). Hepatic failure was diagnosed in 124 (75.2%) of 165 patients and was associated with hepatic encephalopathy in 74 patients, a finding that indicated a fulminant course. In 18 patients (16 males and 2 females), ALT and AST levels were less than the cutoff values, and, in 10 of them, such levels were within the range considered to be normal. Comparison of this subgroup with the subgroup that had high aminotransferase levels () did not show any difference with regard to the frequencies of the presenting clinical features, such as fever (13 vs. 108), myalgia (11 vs. 55), diarrhea (12 vs. 59), or oliguria (4 vs. 31), and the occurrence of major nonhepatic complications. These complications included renal failure (in 6 patients), retinitis (in 1 patient), meningoencephalitis (in 1 patient), and both retinitis and meningoencephalitis (in 1 patient). Two of the 18 patients demonstrated hemorrhagic manifestations. One of them had concomitant renal failure, shock, and disseminated intravascular coagulopathy and was 1 of the 2 patients in this subgroup who died. The other was a 30-year-old patient who presented with vaginal bleeding. RVFAg and IgM antibody were detected in 4 and 14 patients, respectively. Among the patients with high aminotransferase levels, RVFAg and IgM antibody were detected in 36 and 104 patients, respectively. Seven patients in the latter subgroup had both the antigen and antibody. Table 5. Frequency of detection of abnormal levels, according to the case definition of Rift Valley fever, during laboratory testing. Renal failure. Impairment of renal function was demonstrated by 91 patients (55.2%) at the time of admission. The mean creatinine and urea levels were 361.9 μM and 18.2 mM, respectively, and 74 patients (44.8%) had serum creatinine levels >150 μM. The abnormality of renal function (prerenal azotemia) resulting from dehydration was reversible in 23 patients. Acute renal failure was established and severe (creatinine level, >600 μM) in 68 (41.2%) of 165 patients, and 32 of the 68 patients required hemodialysis. Hemorrhagic manifestations. A total of 32 patients (19.4%) presented with hemorrhagic manifestations at admission. These manifestations included hematemesis (in 8 patients), vaginal bleeding (in 2 patients), and severe hemoptysis (in 1 patient), in addition to bleeding from the gums and venipuncture sites, petechial rashes, and ecchymoses of the skin. For 3 patients, upper gastrointestinal endoscopy confirmed that the presence of erosive mucosal lesions was the cause of bleeding. Severe coagulopathy with marked prolongation of prothrombin time and partial thromboplastin time was found in 61 patients, 31 of whom had evidence of disseminated intravascular coagulopathy. Retinitis and encephalitis. Macular and paramacular retinitis were found in 16 patients during their hospitalization. These patients were 9 males and 7 females whose age range was 15–77 years. The lesions (figures 1 and 2) were bilateral in 11 patients. Three patients experienced permanent loss of vision, and 4 patients with concomitant meningoencephalitis died. Table 6 summarizes the clinical and laboratory findings for patients who had meningoencephalitis diagnosed 2–60 days after the onset of the infection. All the patients had fever. Diarrhea and myalgia occurred in 1 patient (patient 4). One patient (patient 6) experienced paralysis of the left sixth and seventh cranial nerves, concomitant hepatitis, retinitis, and ecchymosis. CT of the brain revealed no abnormal findings for 4 patients, but it demonstrated hypodense lesions in 2 patients (patients 6 and 7) and atrophic changes in 1 patient. RVFAg was detected in 1 patient (patient 6), and the remaining 6 patients were positive for IgM antibody to RVF. One of the 3 patients who survived (patient 1) remained in a vegetative state, and 1 patient was discharged with residual neurologic deficit and was lost to follow-up. Figure 1. (60 KB)Figure 1. Macular retinitis with exudates and hemorrhage in the macular and paramacular areas of a patient with Rift Valley fever. Figure 2. (39 KB)Figure 2. Scarring in the macular area of a patient with Rift Valley fever. Table 6. Clinical characteristics of and laboratory results for 7 patients with meningoencephalitis associated with Rift Valley fever (RVF) in Saudi Arabia. Case fatality. As summarized in table 2, the in-hospital case-fatality rate was 33.9% (56 of 165 patients died), with there being no difference with regard to the sex of the patient (33.8% of 136 men and 34.4% of 29 women died). Overall, the mean age of the survivors was significantly less than that of the patients who died (). Complications associated with death are shown in table 7. A total of 39 (70.9%) of 55 patients who had both hepatic and renal failure died, compared with 2 (7.1%) of 28 patients with neither of the complications, 12 (17.4%) of 69 patients with hepatic failure only, and 3 (23.1%) of 13 patients with renal failure only. The difference was statistically significant (). For a few patients who died, histopathologic examination of the liver revealed massive hepatic necrosis and inflammatory changes. Table 7. Major complications of Rift Valley fever in 165 patients in Saudi Arabia. Discussion The outbreak of RVF in the Gizan region of Saudi Arabia confirms the extension of its geographic distribution outside the continent of Africa into the Middle Eastern area of the world. It is evident that the RVF virus can establish itself wherever potential permissive vectors and animal reservoirs are present. The Gizan region is a rural area where the main occupations of the population include animal husbandry. The climate favors breeding of mosquitoes, and, despite the control measures instituted by the government, malaria transmission and severe clinical malaria continue to affect a significant proportion of the population in this area of Saudi Arabia [7]. The precise number of humans infected in the outbreak in Gizan is unknown. It was estimated that 20,000 people in the region might have been infected, with the majority of the infections being subclinical or mild in persons who did not seek care. RVF virus is perhaps unique in that it causes several different disease syndromes in humans, none of which seems to predispose to the other [1, 2]. All the clinical syndromes in humans usually begin with mild, nonfatal influenza-like illness. In a minority of patients, severe hepatic disease with hemorrhagic manifestations, encephalitis, and ocular lesions may complicate RVF [5, 8–14]. Our results indicate that the hepatic form of the disease was the predominant organ manifestation of RVF in the Saudi epidemic, occurring in 88% of the patients who were admitted with severe illness requiring management in a special unit for RVF. Clinical characteristics of the patients included marked elevations of aminotransferase levels, a high frequency of fulminant hepatic failure, and a high case-fatality rate. However, clinical and serologic profiles, the frequency of nonhepatic complications, and the case-fatality rate were similar among patients with lower aminotransferase levels and among those with severe hepatic damage. Our findings are consistent with previous observations that (1) hepatic necrosis is the most striking microscopic lesion, and (2) increased liver enzymes are early markers for fatal RVF in humans and are usually elevated 7–8-fold during the first 48 h of illness in the majority of cases [15]. Histopathologic examinations of liver samples obtained from patients who have died of RVF usually show striking hepatic necrosis with changes in the hepatocytes that include focal cytoplasmic degradation, formation of eosinophilic or dark bodies, and bizarre nuclear profiles similar to those observed previously in animals [16–18]. The lesions in target organs associated with acute infection are presumed to be the results of a direct lytic effect of the virus, and, on the basis of the results of titration of infectivity in organ homogenates, the liver and spleen are the major sites of viral replication [1, 18]. Renal impairment was a frequent occurrence among the patients studied, and it appeared to be the result of hypovolemia and multiple-organ dysfunction in the majority of patients. However, it is also possible that the renal failure might be related to a direct virus-related injury in a proportion of the patients. Inference from immunofluorescence studies showed that the sites of RVF viral replication corresponded to the glomerular lesions, in addition to necrosis of the lymphoid, adrenal, lung, and hepatic tissues, in animals and humans [1, 15, 18]. Schrire [19] and Freed [20] were the first to report ocular abnormalities leading to a loss of central vision in patients with RVF. Since the publication of those reports, there have been many more reports of ocular complications, which have been estimated to occur in association with 1% of all RVF infections [5, 11, 12]. Ten percent of Saudi patients studied were found to have retinitis that affected both eyes. Although ocular lesions occasionally may appear during the phase of acute febrile illness, they usually develop 4 weeks after the onset of illness. Therefore, a survey of hospitalized patients might have underestimated the prevalence of RVF-related retinitis. Another survey performed by the ophthalmologist on our team (A.H.), which assessed outpatients during follow-up, indicated that the prevalence was higher than that noted for hospitalized patients (A.H., personal communication) The high prevalence of ocular complications may be a unique feature of the Saudi epidemic. The clinical presentations vary from blurred vision to macular exudate-like lesions, retinal detachment, and retinitis [5, 11, 12, 19, 20]. The pathogenesis of the lesions is not well understood, but fluorescein angiography suggests that the lesions are often the result of primary occlusion of the retinal circulation, probably as a result of proliferation of virus particles on the endothelial cells [21]. A contributory role of the inflammatory process is suggested by the occurrence of maculopathy, vascular narrowing, sheathing, and retinal hemorrhages in some patients [12, 21]. Encephalitis, which was found in only 7 of our patients, is an uncommon and unpredictable complication of RVF infection occurring 1–4 weeks after the onset of RVF. It usually presents with variable clinical manifestations, including severe headache, confusion, disorientation, meningism, and coma [5, 11, 22, 23]. Although complete recovery from this complication is reported to occur, only one of our patients survived, and this patient remained in a vegetative state. It was interesting to note that 5 of the 7 patients had concurrent retinitis. Histopathologic characteristics include focal necrosis with leukocyte infiltration and perivascular cuffing [1]. These features and the delayed appearance of the clinical course of the disease suggest a complex interaction of immune-mediated and direct cytopathic effects of the virus as the underlying mechanism of this complication [1, 14, 24]. No brain tissue was obtained from any of our patients for histologic examination. Serologic analysis is a useful tool for the identification of RVF infection. However, some patients who have clinical features consistent with the infection may have negative results of serologic analysis. In the outbreak in Kenya, possible causes of the cases of fever with hemorrhagic syndromes in patients found to be negative for RVF included the use of extremely sensitive case definitions, improper sampling, the presence of other pathogens and toxins, and complications of malnutrition [25, 26]. In the Saudi epidemic, 95% of severely infected case patients were confirmed to have RVF by either viral antigen or IgM antibody testing, perhaps because of the application of a very strict case definition [6]. It is essential that RVF be distinguished from Crimean-Congo hemorrhagic fever (CCHF) and similar diseases [1]. CCHF is a tickborne viral zoonosis that occurs in Europe, Asia, and Africa [27]. Before the RVF epidemic, a study that used the reversed passive hemagglutination inhibition test detected antibodies in 3 (0.8%) of 354 humans tested in Saudi Arabia [28]. In the initial phase of the epidemic, serologic testing of the patients excluded CCHF as the cause of the illness. Generally, it was estimated that only approximately 1%–2% of infections result in fatal hemorrhagic fever or encephalitis [25]. The overall case-fatality rate in the Saudi outbreak was reported to be 17% (87 of 516 case patients died) [6]. The 33.3% case-fatality rate for our patients admitted to the special RVF unit was reflective of the severity of the illness, which necessitated specialized management. The lethality of RVF was first recognized when 7 deaths occurred during the epidemic in South Africa in 1974–1976 [10, 14]. Since then, many more deaths have been attributed to RVF. The outbreak in Egypt in 1977–1978 was associated with an estimated 18,000 infections and 598 deaths, for a case-fatality rate of 33.2 deaths per 1000 individuals [1, 11]. In contrast, only 5 human deaths were reported in Zimbabwe in 1978 [29]. In 1987, an estimated 224 deaths occurred in the Mauritanian epidemic. The case-fatality rate was estimated to be 1%, although higher estimates of 4.8%–13.9% were reported for 2 different populations surveyed [30]. It is difficult to compare these aforementioned rates because of the differences in the characteristics of these epidemics and, also, because some of the data on the number of deaths associated with these epidemics are estimates. Factors that contributed to a fatal outcome in these patients included hepatic failure, shock, and renal failure, findings that are in agreement with findings reported elsewhere [24]. Additional host-related factors might be contributory. For example, it was suggested that the unusually high mortality rate noted in the Egyptian epidemic could have been due to infection with a more virulent strain of RVF virus or to infections in a host population compromised by previous diseases, such as schistosomiasis or chronic hepatitis B or C [14]. The Gizan province of Saudi Arabia is similar to Egypt in terms of the high prevalence of subclinical liver diseases caused by schistosomiasis and viral hepatitis. Therefore, it is possible, although speculative, that these factors might have influenced the case-fatality rates among the Gizan patients. It was interesting to observe that 21% of our patients habitually consumed raw milk. It is unclear whether this was a contributing factor to the acquisition of infection by these patients, because the majority were exposed to infected animals or humans before they became ill. However, low concentrations of RVF virus were found in the milk and body fluids of domestic animals, and, in the Mauritania epidemic, it appeared that there might have been a connection between RVF infection in humans and the consumption of raw milk [1, 31–33]. Some authors have warned that the population of the entire Mediterranean littoral must be considered to be at risk for RVF disease [5, 34]. 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