Unrecognized Ebola hemorrhagic fever at Mosango Hospital during the 1995 epidemic in Kikwit, Democratic Republic of the Congo.

Letters observed, X1 and X2, which differed by 5 to 6 bands. Furthermore, outbreak isolates X3 and X4 were closely related to X1, differing by four and three DNA fragments, respectively. Similar results were obtained after digestion with a second restriction endonuclease, SpeI (5'-ACTAGT-3'; pattern designation S). Although fewer bands were seen compared to PFGE, ribotyping of these isolates using SpeI-digested genomic DNA largely confirmed the PFGE results in that the sporadic isolates gave unique profiles and only three closely related ribotype profiles were detected among the outbreak isolates. Two Malaysian isolates of S. paratyphi A included for comparison gave patterns very different from the Indian isolates by both PFGE (F = 0.44-0.65) and ribotyping. Also, it was determined that isolates A-117 (X1/S1) and A-123 (X2/S2) belonged to the index cases and that, as the outbreak progressed, other patterns (X3/S3 and X4/S4), which differed from the original patterns by one to four bands, appeared during weeks 2 to 3 of the outbreak. Notably, patterns X1 and X2 reappeared at the end of the outbreak. Although molecular analysis of S. typhi and S. paratyphi B by ribotyping (2,4) and PFGE (3) has been reported, to the best of our knowledge the present study is the first performed with S. paratyphi A. The data obtained agree with those observed for S. typhi (3) in that outbreak isolates are more clonal and limited in diversity, whereas sporadic isolates are more diverse genetically and belong to unrelated clones. According to the criteria of Tenover et al. (5), it seems likely that the present outbreak was associated with two distinct clones/strains of S. paratyphi A (X1/S1 and X2/S2) that are related (5) but have distinct PFGE profiles. This observation is perhaps not surprising given the fact that both clones are phage type 1 and that contaminated potable water was incriminated in the outbreak (1). The PFGE results were largely confirmed by ribotyping, although this technique appears to be slightly less sensitive and discriminating in that fewer bands were seen and the differences between outbreak isolates were much less obvious. We thus conclude that the outbreak in New Delhi, India, was caused by two related but distinct clones of S. paratyphi A. There also appears to be substantial genetic diversity among S. paratyphi A strains as the Malaysian isolates were very different from those from India. The data also suggested minor genetic changes among the S. …

among the S. paratyphi A isolates during the 2month outbreak. This observation agrees with the high mutation rates noted among pathogenic Salmonella spp. (6) and the plasticity of the genome of salmonellae associated with enteric fever (7). How these changes affected the biologic behavior of these isolates will be the subject of further study. Our study reaffirms the usefulness of PFGE and ribotyping in the molecular typing and discrimination of individual Salmonella isolates for epidemiologic investigations.

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in Mosango General Hospital that, retrospectively, was one of the first cases of the Ebola hemorrhagic fever outbreak in the Bandundu province of former Zaire in the spring of 1995 (1).

Case
On April 20, 1995, a 70-year-old nun, working as a nurse in Kikwit General Hospital, was admitted to Mosango General Hospital with a 5day history of fever, despite antimalarial treatment. The day before hospitalization she had profuse diarrhea, vomiting, high fever, and severe agitation with delirium. On arrival, quiet and apyretic, she complained of headache, loss of appetite, and severe asthenia, but she walked to her room without help. On examination, the only abnormalities recorded were severe dehydration and oral thrush-like lesions, raising a suspicion of candidiasis. Pulse rate was 80/min and blood pressure 120/80. Medical history included an amebiasis liver abscess 15 years ago and chronic coronaritis since 1990.
Later during the day, high fever (40°C) and severe diarrhea with melena developed; the pulse rate was normal (80/min). Typhoid fever was suspected despite the lack of hepatosplenomegaly; Widal test was not available for confirmation. Treatment was started with intravenous (i.v.) amoxicillin (1g/6h during the first 24 h and then 1g/4h) and i.v. chloramphenicol (2g/24h). Subsequently, coagulation abnormalities developed in addition to the melena; vitamin K and epsilon amino caproic acid were added to i.v. therapy. Watery vomits remained frequent and abundant, and the patient's condition was unresponsive to treatment.
On hospitalization day 2, the clinical picture remained the same, with severe asthenia, anorexia, abundant blackish diarrhea, and watery vomits. An intractable hiccup developed. The fever remained in plateau around 40°C with spikes. Obnubilation occurred during episodes of high fever. Pulse and blood pressure remained stable. ECG showed no modifications. Cutaneous examination detected for the first time a maculopapular rash and petechiae on flanks and limbs, and the patient complained of gastric pain for which the neurologic examination was normal. Urine was abundant and clear.
On hospitalization day 3, high fever continued, with some defervescence during which the patient regained lucidity, although she responded only with monosyllables because of the extreme asthenia and somnolence; diarrhea persisted but without hemorrhage. The patient had less vomiting. Laboratory data showed ESR 35 mm/h; BT 10 min; CT 12 min; WBC 12.6x10 9 /L (70% neutrophils, 24% lymphocytes, 2% eosinophils, 1% basophils, 3% mastocytes). During the night, the patient maintained a high temperature, still with temperature-pulse disparity. The diagnosis of typhoid fever was questioned, and other diagnostic possibilities were reconsidered (shigellosis, mononucleosis); leukocytosis was considered against the possibility of Ebola hemorrhagic fever. Chloramphenicol was switched to rifampicin (1,200 mg/24h).
On April 23, the patient's status was unchanged with fever, asthenia, and diarrhea. Later in the day, her condition deteriorated: petechiae could be seen on the entire body, and for the first time, bruises and bleeding at injection sites were observed and precluded intramuscular injections. The patient had bleeding cracks on the lips and diffuse bleeding in the oral cavity (i.e., gums, tongue). The volume of urine was low, and antibiotic therapy was changed to cephalosporin.
On hospitalization day 5, hemorrhages increased, and fever remained high until the end of the day, when it started to normalize. Urine volume was still low (verified by vesical catheter) despite the i.v. rehydration of 4 L/day. Fresh blood transfusion (300 ml) did not slow the hemorrhaging; disseminated intravascular coagulation was suspected, and heparin treatment was started. The patient became comatose. The laboratory results showed ESR 55mm/h and WBC 30.2x10 9 / L with an unchanged formula. No coagulation was observed on BT and CT. Blood pressure fell (80/50); the clinical status remained unchanged until the patient's death on April 25 at 10:00 a.m.

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No special nursing precautions were taken either during the hospitalization or after the death, and the body was transferred to Kikwit to be buried. On April 30, another nun who took care of the index patient during the night of April 23 became ill with fever, headache, and myalgia. Over the next few days, the second patient had a clinical picture identical to that of the index patient, including high fever, severe asthenia, vomiting, hiccups, and diarrhea. On May 5, epistaxis and coagulation abnormalities developed, followed by other clinical signs of the hemorrhagic syndrome. The second patient was transferred to Kikwit General Hospital, where she died 6 days later. A laboratory confirmation of Ebola hemorrhagic fever was made on a blood specimen collected on May 5 and sent to Special Pathogens Branch (Centers for Disease Control and Prevention, Atlanta, GA).
These cases of unrecognized Ebola hemorrhagic fever were part of the hospital outbreak that precipitated and mobilized international community efforts (2). Retrospectively, the clinical symptoms observed were typical of Ebola hemorrhagic fever (3,4) and were described again in subsequent patients during this outbreak (5). In tropical Africa, the presence of hemorrhagic symptoms in the course of a febrile illness should raise the possibility of one of the viral hemorrhagic fever diseases. In viral hemorrhagic fevers, maculopapular rash is constantly observed only in filovirus disease. Typically, the clinical laboratory findings include an early lymphopenia and marked thrombocytopenia. Containment and barrier nursing procedures should be initiated until the diagnosis of viral hemorrhagic fever can be ruled out. The index patient described here was the third patient transferred from Kikwit General Hospital in less than 1 month to die of a hemorrhagic illness after a few days of an unexplained febrile syndrome. Two patients were health-care workers in Kikwit General Hospital. This cluster of hemorrhagic illness and possible human-tohuman transmission, particularly among hospital staff, was (and should always be) sufficient to suspect a viral hemorrhagic fever. The laboratory confirmation of this presumptive diagnosis was the clenching factor in the multinational effort in Kikwit.