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Imported epidemic typhus
CORRESPONDENCE
2 agonists and heart failure
Imported epidemic typhus Sir—D Raoult and colleagues (Aug 1, p 353)1 report an outbreak of epidemic typhus in Burundi, and cite the first confirmed case in a nurse returning to Switzerland from Burundi. The diagnosis of epidemic typhus in this patient alerted the international health community to the outbreak in Burundi, which ultimately affected more than 43 000 people. We report the clinical course and laboratory investigation that identified this sentinel case. The 38-year-old International Red Cross nurse cared for inmates in the N’Gozi prison in northern Burundi. During the last 2 months of her stay, an unexplained increase in mortality was observed among the prisoners. 2 3 days after her return to Switzerland, she developed high fever, chills, and myalgias, and was admitted to hospital 5 days later. Other than fever (39ºC), physical examination was unremarkable, with no evidence of a rash. Notable laboratory data included severe thrombocytopenia (50⫻109/L) and raised D-dimers (4·0 mg/L). Chest radiographs were clear and blood smears were negative for parasites, including Plasmodium spp. Blood and urine cultures were sterile. Initially, the patient’s condition was stable, apart from fever, and no antibiotics were administered. 3 days after admission, her platelet count dropped (16⫻109/L). Because of the patient’s travel history and worsening coagulopathy, the clinical differential centred on viral haemorrhagic fevers and typhoid fever; ciprofloxacin (500 mg twice daily) was administered. Her condition deteriorated rapidly, with onset of stupor, dyspnoea, shock and multiorgan failure. She died the following day and a necropsy was done. Histopathological findings include glial nodules in the central nervous system, suggestive of a rickettsial infection. Immunohistochemical staining for typhus group rickettsiae confirmed the diagnosis of typhus (figure). Subsequently, indirect fluorescence antibody testing of acute-phase serum revealed antibody reactive with Rickettsia prowazekii at a titre of 1:2048, and PCR analysis of blood amplified a DNA fragment of the 17 kDa rickettsial surface protein gene with 99·6% homology to R prowazekii. This sentinel case and the subsequent epidemic in Burundi shows us that epidemic typhus is endemic worldwide, with periodic
THE LANCET • Vol 352 • November 21, 1998
Immunostaining of typhus group rickettsial antigens in a glial (typhus) nodule in the cerebral cortex Original magnification ⫻158, immunoalkaline phosphatase stain with naphthol/fast red substrate and haematoxylin counterstain.
large-scale emergencies. This patient presented with a non-specific febrile illness, highlighting the potential difficulty in the clinical diagnosis of epidemic typhus. This diagnosis should be suspected in any febrile patients with or without a rash who has returned from an area where R prowazekii is endemic, or from a region where there is an epidemic of unknown febrile disease. This report shows how health-care workers are at increased risk for this infection, 3 particularly in conditions of overcrowding and poor hygiene, even if the exposure is only transient. Laboratory diagnostics for epidemic typhus seldom affects the management of patients; thus, the potentially rapid clinical progression and associated mortality of untreated epidemic typhus requires prompt administration of appropriate antirickettsial therapy. Although cirofloxacin may be effective, therapy for other select rickettsioses, tetracyclines and chloramphenicol are the drugs of choice in the treatment of epidemic typhus. *G Zanetti, P Francioli, D Tagan, C D Paddock, S R Zaki *Division of Infectious Diseases, Department of Internal Medicine, University Hospital, 1011 Lausanne, Switzerland; and Division of Viral and Rickettsial Diseases, Centers for Disease Control and Prevention, Atlanta, GA, USA 1
2
3
Raoult D, Ndihokubwayo JB, Tissot-Dupont H, et al. Outbreak of epidemic typhus associated with trench fever in Burundi. Lancet 1998; 352: 353–58. Bise G, Coninx R. Epidemic typhus in a prison in Burundi. Trans R Soc Trop Med Hyg 1997; 97: 133–34. Gear J. Typhus fever in the Transkei. S Afr Med J 1944; April 22: 144–48.
Sir—John W Jenne’s Oct 3 commentary1 comments on Martin and Dunn’s study2 on oral 2 agonists and heart failure. That study stemmed from the Drug Safety Research Unit in Southampton which used prescriptionevent monitoring (PEM) to compare the prevalence of cardiac failure in two cohorts (the drugs in question were salmeterol [Glaxo Wellcome UK] and bambuterol [Astra, Lund, Sweden]). Jenne states categorically that “every effort should be made to rule out cardiac disease before prescribing an oral 2-agonist”. However, the underlying scientific evidence does not support such a strong statement. PEM studies are not designed to study causal relations, but are used to generate hypotheses. In the two PEM cohorts in the DSRU study, data were missing for more than 40% of the prescriptions. Furthermore, the cohorts were collected at different times. Indeed, Jenne states that the comparison was probably not fair because of this issue, and we agree. In the bambuterol group the patients were older, the prevalence of asthma was lower, and the rate of other diagnoses was higher. Overall, the patients on bambuterol seemed to have more severe disorders than those in the salmeterol group. Thus, the populations were probably different before the study, so that little, if anything, can be inferred from the comparison of two such fundamentally different cohorts. In any event, this type of study can be used only for generating hypotheses and not to support the strong statement by Jenne. A review of preclinical studies, clinical studies, and postmarketing surveillance gives no support to an association between bambuterol and cardiac failure. According to the Drug Safety Research Unit, there have been no spontaneous reports of cardiac failure with bambuterol to the Committee on Safety of Medicines, which accords with data from the WHO database INTDIS showing no reports of cardiac failure with bambuterol, in contrast to ten reports for salmeterol. The datasheet of most if not all 2 agonists gives precautions about use in patients with severe cardiovascular disease, and bambuterol and salmeterol are not exempted from this rule. Evidence-based medicine is nowadays recommended for clinical decisions. The statement by Jenne seems to favour practising hypothesis-
1709
2 agonists and heart failure
Imported epidemic typhus Sir—D Raoult and colleagues (Aug 1, p 353)1 report an outbreak of epidemic typhus in Burundi, and cite the first confirmed case in a nurse returning to Switzerland from Burundi. The diagnosis of epidemic typhus in this patient alerted the international health community to the outbreak in Burundi, which ultimately affected more than 43 000 people. We report the clinical course and laboratory investigation that identified this sentinel case. The 38-year-old International Red Cross nurse cared for inmates in the N’Gozi prison in northern Burundi. During the last 2 months of her stay, an unexplained increase in mortality was observed among the prisoners. 2 3 days after her return to Switzerland, she developed high fever, chills, and myalgias, and was admitted to hospital 5 days later. Other than fever (39ºC), physical examination was unremarkable, with no evidence of a rash. Notable laboratory data included severe thrombocytopenia (50⫻109/L) and raised D-dimers (4·0 mg/L). Chest radiographs were clear and blood smears were negative for parasites, including Plasmodium spp. Blood and urine cultures were sterile. Initially, the patient’s condition was stable, apart from fever, and no antibiotics were administered. 3 days after admission, her platelet count dropped (16⫻109/L). Because of the patient’s travel history and worsening coagulopathy, the clinical differential centred on viral haemorrhagic fevers and typhoid fever; ciprofloxacin (500 mg twice daily) was administered. Her condition deteriorated rapidly, with onset of stupor, dyspnoea, shock and multiorgan failure. She died the following day and a necropsy was done. Histopathological findings include glial nodules in the central nervous system, suggestive of a rickettsial infection. Immunohistochemical staining for typhus group rickettsiae confirmed the diagnosis of typhus (figure). Subsequently, indirect fluorescence antibody testing of acute-phase serum revealed antibody reactive with Rickettsia prowazekii at a titre of 1:2048, and PCR analysis of blood amplified a DNA fragment of the 17 kDa rickettsial surface protein gene with 99·6% homology to R prowazekii. This sentinel case and the subsequent epidemic in Burundi shows us that epidemic typhus is endemic worldwide, with periodic
THE LANCET • Vol 352 • November 21, 1998
Immunostaining of typhus group rickettsial antigens in a glial (typhus) nodule in the cerebral cortex Original magnification ⫻158, immunoalkaline phosphatase stain with naphthol/fast red substrate and haematoxylin counterstain.
large-scale emergencies. This patient presented with a non-specific febrile illness, highlighting the potential difficulty in the clinical diagnosis of epidemic typhus. This diagnosis should be suspected in any febrile patients with or without a rash who has returned from an area where R prowazekii is endemic, or from a region where there is an epidemic of unknown febrile disease. This report shows how health-care workers are at increased risk for this infection, 3 particularly in conditions of overcrowding and poor hygiene, even if the exposure is only transient. Laboratory diagnostics for epidemic typhus seldom affects the management of patients; thus, the potentially rapid clinical progression and associated mortality of untreated epidemic typhus requires prompt administration of appropriate antirickettsial therapy. Although cirofloxacin may be effective, therapy for other select rickettsioses, tetracyclines and chloramphenicol are the drugs of choice in the treatment of epidemic typhus. *G Zanetti, P Francioli, D Tagan, C D Paddock, S R Zaki *Division of Infectious Diseases, Department of Internal Medicine, University Hospital, 1011 Lausanne, Switzerland; and Division of Viral and Rickettsial Diseases, Centers for Disease Control and Prevention, Atlanta, GA, USA 1
2
3
Raoult D, Ndihokubwayo JB, Tissot-Dupont H, et al. Outbreak of epidemic typhus associated with trench fever in Burundi. Lancet 1998; 352: 353–58. Bise G, Coninx R. Epidemic typhus in a prison in Burundi. Trans R Soc Trop Med Hyg 1997; 97: 133–34. Gear J. Typhus fever in the Transkei. S Afr Med J 1944; April 22: 144–48.
Sir—John W Jenne’s Oct 3 commentary1 comments on Martin and Dunn’s study2 on oral 2 agonists and heart failure. That study stemmed from the Drug Safety Research Unit in Southampton which used prescriptionevent monitoring (PEM) to compare the prevalence of cardiac failure in two cohorts (the drugs in question were salmeterol [Glaxo Wellcome UK] and bambuterol [Astra, Lund, Sweden]). Jenne states categorically that “every effort should be made to rule out cardiac disease before prescribing an oral 2-agonist”. However, the underlying scientific evidence does not support such a strong statement. PEM studies are not designed to study causal relations, but are used to generate hypotheses. In the two PEM cohorts in the DSRU study, data were missing for more than 40% of the prescriptions. Furthermore, the cohorts were collected at different times. Indeed, Jenne states that the comparison was probably not fair because of this issue, and we agree. In the bambuterol group the patients were older, the prevalence of asthma was lower, and the rate of other diagnoses was higher. Overall, the patients on bambuterol seemed to have more severe disorders than those in the salmeterol group. Thus, the populations were probably different before the study, so that little, if anything, can be inferred from the comparison of two such fundamentally different cohorts. In any event, this type of study can be used only for generating hypotheses and not to support the strong statement by Jenne. A review of preclinical studies, clinical studies, and postmarketing surveillance gives no support to an association between bambuterol and cardiac failure. According to the Drug Safety Research Unit, there have been no spontaneous reports of cardiac failure with bambuterol to the Committee on Safety of Medicines, which accords with data from the WHO database INTDIS showing no reports of cardiac failure with bambuterol, in contrast to ten reports for salmeterol. The datasheet of most if not all 2 agonists gives precautions about use in patients with severe cardiovascular disease, and bambuterol and salmeterol are not exempted from this rule. Evidence-based medicine is nowadays recommended for clinical decisions. The statement by Jenne seems to favour practising hypothesis-
1709