Casi nosocomiali (aprile 2003 - aprile 2012)
Instability of Gait as an Extrapulmonary Sequela in Acute Legionella Pneumonia: A Case Report
Department of Respiratory Disease, Physiopathology and Rehabilitation, Second University of Naples (SUN), AORN "Monaldi Hospital", Naples, Italy.
J Emerg Med. 2013 Jan;44(1):e13-5.
ABSTRACT: BACKGROUND: Legionnaires disease is a potentially fatal infection often associated with permanent pulmonary fibrosis in survivors. Although neurological complications are not infrequent, chronic peripheral neuropathy in the absence of pulmonary abnormalities is an uncommon consequence of Legionnaires disease.CASE REPORT: A 51-year-old woman was admitted to the Emergency Department due to acute respiratory failure. Chest computed tomographic (CT) scan revealed bilateral consolidation shadows suggestive of acute respiratory disease syndrome (ARDS). Urine culture was evaluated and empiric therapy was administered due to a clinical suspicion of acute legionella pneumonia. Acute flaccid paralysis of the limbs and cutaneous rash complicated the clinical course. Treatment with appropriate antibiotics and steroids resulted in complete recovery of pulmonary damage, whereas mild ataxic gait was present at 1-year follow-up.CONCLUSIONS: The outcome of this case confirms that the early exudative phase of ARDS in the absence of bronchial dilatation on chest CT scan is not always related to pulmonary fibrosis in survivors at follow-up. It also demonstrates that peripheral neuropathy can persist despite tailored treatment.
An outbreak of legionnaires disease associated with a decorative water wall fountain in a hospital
Haupt TE, Heffernan RT, Kazmierczak JJ, Nehls-Lowe H, Rheineck B, Powell C, Leonhardt KK, Chitnis AS, Davis JP.
Wisconsin Division of Public Health, Madison, Wisconsin 53701, USA. firstname.lastname@example.org
Infect Control Hosp Epidemiol. 2012 Feb;33(2):185-91.
ABSTRACT: Objective: To detect an outbreak-related source of Legionella, control the outbreak, and prevent additional Legionella infections from occurring.
Design and setting: Epidemiologic investigation of an acute outbreak of hospital-associated Legionnaires disease among outpatients and visitors to a Wisconsin hospital.
Patients: Patients with laboratory-confirmed Legionnaires disease who resided in southeastern Wisconsin and had illness onsets during February and March 2010.
Methods: Patients with Legionnaires disease were interviewed using a hypothesis-generating questionnaire. On-site investigation included sampling of water and other potential environmental sources for Legionella testing. Case-finding measures included extensive notification of individuals potentially exposed at the hospital and alerts to area healthcare and laboratory personnel.
Results: Laboratory-confirmed Legionnaires disease was diagnosed in 8 patients, all of whom were present at the same hospital during the 10 days prior to their illness onsets. Six patients had known exposure to a water wall-type decorative fountain near the main hospital entrance. Although the decorative fountain underwent routine cleaning and maintenance, high counts of Legionella pneumophila serogroup 1 were isolated from cultures of a foam material found above the fountain trough. Conclusion: This outbreak of Legionnaires disease was associated with exposure to a decorative fountain located in a hospital public area. Routine cleaning and maintenance of fountains does not eliminate the risk of bacterial contamination. Our findings highlight the need to evaluate the safety of water fountains installed in any area of a healthcare facility.
Legionella pneumophila serogroup 3 pneumonia in a patient with low-grade 4 non-Hodgkin lymphoma: a case report
Mencacci A, Corbucci C, Castellani A, Furno P, Bistoni F, Vecchiarelli A.
Department of Experimental Medicine and Biochemical Sciences, Microbiology Section, University of Perugia, Via del Giochetto, Perugia 06122, Italy. email@example.com
J Med Case Reports. 2011 Aug 17;5(1):387.
ABSTRACT: INTRODUCTION: Nosocomial legionellosis has generally been described in immunodepressed patients, but Legionella pneumophila serogroup 3 has rarely been identified as the causative agent. CASE PRESENTATION: We report the case of nosocomial L. pneumophila serogroup 3 pneumonia in a 70-year-old Caucasian man with non-Hodgkin lymphoma. Diagnosis was carried out by culture and real-time polymerase chain reaction of bronchoalveolar lavage fluid. The results of a urinary antigen test were negative. A hospital environmental investigation revealed that the hospital water system was highly colonized by L. pneumophila serogroups 3, 4, and 8. The hospital team involved in the prevention of infections was informed, long-term control measures to reduce the environmental bacterial load were adopted, and clinical monitoring of legionellosis occurrence in high-risk patients was performed. No further cases of Legionella pneumonia have been observed so far. CONCLUSIONS: In this report, we describe a case of legionellosis caused by L. pneumophila serogroup 3, which is not usually a causative agent of nosocomial infection. Our research confirms the importance of carrying out cultures of respiratory secretions to diagnose legionellosis and highlights the limited value of the urinary antigen test for hospital infections, especially in immunocompromised patients. It also indicates that, to reduce the bacterial load and prevent nosocomial legionellosis, appropriate control measures should be implemented with systematic monitoring of hospital water systems.
Epidemiological investigation of a case of nosocomial Legionnaires' disease in Taiwan: implications for routine environmental surveillance
Chien ST, Hsueh JC, Lin HH, Shih HY, Lee TM, Ben RJ, Chou ST, Fong CM, Lin YE, Tseng LR, Chiang CS.
Kaohsiung Armed Forces General Hospital, Kaohsiung, Taiwan. firstname.lastname@example.org
Clin Microbiol Infect. 2010 Jun;16(6):761-3.
ABSTRACT: An epidemiological investigation with Legionella and molecular subtyping was conducted to determine the source of a case of nosocomial Legionnaires' disease (LD) who was hospitalized in three hospitals within a month. Legionella pneumophila serogroup 3, an uncommon serogroup for infection, was isolated from the patient's sputum. Environmental surveillance revealed Legionella colonization in all three hospitals; the patient isolate matched the isolate from the first hospital by molecular typing. Culturing the hospital water supply for Legionella is a pro-active strategy for detection of nosocomial LD even in hospitals experiencing no previous cases.
Fulminant legionellosis in two patients treated with infliximab for Crohn's disease: case series and literature review
Hofmann A, Beaulieu Y, Bernard F, Rico P.
Department of General Internal Medicine, McGill University Faculty of Medicine, Montreal, Quebec, Canada. email@example.com
Can J Gastroenterol. 2009 Dec;23(12):829-33.
ABSTRACT: Two cases of fulminant pulmonary legionellosis, complicated by prolonged intensive care unit stays and acute respiratory distress syndrome, and who were recently treated with infliximab for Crohn's disease, are described. A review of the literature revealed three additional cases in patients with inflammatory bowel disease, and a total of 22 cases of Legionella pneumophila pneumonia in the context of treatment with antitumour necrosis (TNF)-alpha medications. The median age of the patients was 49 years, and men and women were affected equally. The case fatality rate was 14% (three of 22). Early recognition and treatment of this anti-TNF-alpha-related complication would likely result in reduced mortality and morbidity. Physicians prescribing anti-TNF-alpha drugs should be aware of this association.
An unusual case of hospital-acquired infection: Legionella Longbeachae
Dhillon R, Bastiampillai T, Hong S.
Australas Psychiatry. 2009;17(4):337-8.
A cluster of cases of nosocomial legionnaires disease linked to a contaminated hospital decorative water fountain
Palmore TN, Stock F, White M, Bordner M, Michelin A, Bennett JE, Murray PR, Henderson DK.
Warren Grant Magnusen Clinical Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892-1888, USA. firstname.lastname@example.org
Infect Control Hosp Epidemiol. 2009;30(8):764-8.
BACKGROUND: Nosocomial outbreaks of Legionnaires disease have been linked to contaminated water in hospitals. Immunocompromised patients are particularly vulnerable and, when infected, have a high mortality rate. We report the investigation of a cluster of cases of nosocomial pneumonia attributable to Legionella pneumophila serogroup 1 that occurred among patients on our stem cell transplantation unit. METHODS: We conducted a record review to identify common points of potential exposure, followed by environmental and water sampling for Legionella species from those sources. We used an air sampler to in an attempt to detect aerosolized Legionella and pulsed-field gel electrophoresis to compare clinical and environmental isolates. RESULTS: The most likely sources identified were the water supply in the patients' rooms and a decorative fountain in the radiation oncology suite. Samples from the patients' rooms did not grow Legionella species. Cultures of the fountain, which had been restarted 4 months earlier after being shut off for 5 months, yielded L. pneumophila serogroup 1. The isolates from both patients and the fountain were identical by pulsed-field gel electrophoresis. Both patients developed pneumonia within 10 days of completing radiation therapy, and each reported having observed the fountain at close range. Both patients' infections were identified early and treated promptly, and both recovered. CONCLUSIONS: This cluster was caused by contamination of a decorative fountain despite its being equipped with a filter and ozone generator. Fountains are a potential source of nosocomial Legionnaires disease despite standard maintenance and sanitizing measures. In our opinion, fountains present unacceptable risk in hospitals serving immunocompromised patients.
Fatal nosocomial Legionella pneumophila infection due to exposure to contaminated water from a washbasin in a hematology unit
Brûlet A, Nicolle MC, Giard M, Nicolini FE, Michallet M, Jarraud S, Etienne J, Vanhems P.
Service d'Hygiène, Epidémiologie et Prévention, Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France. email@example.com
Infect Control Hosp Epidemiol. 2008 Nov;29(11):1091-3.
ABSTRACT: A fatal nosocomial infection with Legionella pneumophila serogroup 5 occurred in a patient with leukemia. Isolates recovered from both the potable water supply and the patient showed an identical genomic profile. With no other exposure identified, the water from the washbasin was evidently the source of infection.
Legionnaire's disease: a nosocomial outbreak in Turkey
Ozerol IH, Bayraktar M, Cizmeci Z, Durmaz R, Akbas E, Yildirim Z, Yologlu S.
Department of Medical Microbiology, Faculty of Medicine, Inonu University, Malatya, Turkey.
J Hosp Infect. 2006 Jan; 62(1): 50-7.
ABSTRACT: Six nosocomial cases of Legionella pneumophila occurred over a two-week period, with one further case being diagnosed retrospectively after 30 days. Strains isolated from the hospital water system were clonally related to a single sputum isolate. A sero-epidemiological investigation into legionella exposure amongst staff and inpatients was undertaken at the eight-year-old Inonu University Medical Centre in Turkey, which has 600 beds and central air conditioning. There is no disinfection programme for the hospital water system. A total of 500 serum samples (400 hospital staff and 100 inpatients) were screened for antibody to L. pneumophila by enzyme-linked immunosorbent assay (ELISA). Seroreactive cases were confirmed by a four-fold antibody rise in ELISA, a high indirect immunofluorescent assay (IFA) antibody titre or a positive urinary antigen test. ELISA showed that 24 (6%) of the 400 hospital staff and seven (7%) of the 100 inpatients had antibody titres higher than the cut-off value. ELISA-seroreactive cases were followed for two to four weeks. Of these subjects, seven (three patients and four staff) showed a four-fold rise in antibody titre by ELISA, six (three patients and three staff) had a high IFA titre, three patients with pneumonia had a positive urinary antigen test, and one of these patients also had a positive sputum culture. In addition, 22 water distribution systems were screened for the presence of L. pneumophila by culture. L. pneumophila was isolated from 15 sites. Pulsed-field gel electrophoresis typing indicated that all strains isolated from water systems were identical and clonally related to the strain isolated from sputum. Superheating and flushing of water systems were undertaken with legionella being re-isolated from four sites. Repeated superheating and flushing eliminated legionella completely. This study demonstrated that rapid detection of L. pneumophila and adequate superheating and flushing of water systems are effective for elimination and reduction of spread of this organism.
Legionnaires' disease in long-term care facilities: overview and proposed solutions
Seenivasan MH, Yu VL, Muder RR.
From the Department of Veterans Affairs Pittsburgh Healthcare System and University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
J Am Geriatr Soc. 2005 May;53(5):875-80.
ABSTRACT: Pneumonia is a leading cause of morbidity and mortality in nursing home patients. In acute care hospitals, there is considerable evidence to indicate that Legionnaires' disease is a significant cause of nosocomial pneumonia, the source of which is the potable water system. A relatively limited amount of data exists as to the role of Legionnaires' disease as a cause of pneumonia acquired in long-term care residents. Several lines of evidence suggest that Legionnaires' disease may be an important but underrecognized cause of pneumonia in long-term care residents. These include reports of outbreaks, prospective studies of community-acquired pneumonia that include nursing home patients, and prospective studies of individual long-term care facilities linking Legionnaires' disease to colonization of the potable water system with Legionella. Multiinstitutional studies combining environmental and clinical surveillance for Legionella are needed to further confirm the relationship between colonization of potable water and the occurrence of disease in the long-term care facilities. Until these studies are completed, it is recommended that individual facilities undertake annual sampling of the potable water system for Legionella, coupled with introduction of the rapid Legionella urinary antigen test should L. pneumophila serogroup 1 be found.
One-year surveillance of legionellosis in burned patients and Legionella environmental monitoring
Franzin L, Stella M, Zaccaria T, Cabodi D, Pastoris MC.
Infectious Diseases Unit, University of Turin, Corso Svizzera 164, 10149 Turin, Italy.
Burns. 2005 Feb;31(1):50-4.
ABSTRACT: Burned patients have a theoretically high risk of Legionella infection because burns produce a compromised immune system. Cutaneous surfaces are without protective barriers, and bathing tank water is frequently used for washing and caring. A one-year surveillance study was performed on 65 burned patients by antibody determination and by culture of bronchial aspirates. Environmental culturing for Legionella was done in the patients' care areas every four months during the same period. Low titers ranging from 8 to 32 were found in 30 (46.1%) subjects against 18 antigens including several Legionella species. No increase in antibody titers was shown in 193 patients' sera. Cultures of respiratory samples were negative. L. pneumophila serogroups 4, 5, 6 and 8 and L. rubrilucens were isolated from 55.5% of water samples. Despite no evidence of Legionella infection among patients included in this study, the authors believe it to be advisable to improve control measures in hospital water supplies, used by burned patients, to minimise the risk of legionellosis.
Multicenter Study of Hospital-Acquired Pneumonia in Non-ICU Patients
Sopena N, Sabria M.
Unitat de Malalties Infeccioses. Hospital Universitari Germans Trias i Pujol, C/Canyet s/n,
CP 08916 ( Badalona ), Barcelona Spain.
Chest. 2005 Jan;127(1):213-9.
ABSTRACT: To know the incidence, epidemiology, etiology, and outcome of hospital-acquired pneumonia (HAP) in non-ICUs adult patients. SETTING: Twelve Spanish teaching hospitals. INTERVENTIONS: From April 1999 to November 2000, non-ICU HAP was prospectively studied by active, bimonthly 1-week surveillance. Epidemiologic data, etiology, and evolution of pneumonia were recorded. Blood and sputum cultures and Legionella pneumophila and Streptococcus pneumoniae urinary antigen tests were performed. RESULTS: We included 186 patients, with complete data available in 165 patients (70.3% male gender; mean age, 63.7 +/- 16.9 years [ +/- SD]) The mean incidence of HAP was 3 +/- 1.4 cases/1,000 hospital admissions. Most patients (64.2%) were in medical wards, had severe underlying diseases (66.6%), and had a hospital stay > 5 days (76.4%). Blood cultures were performed in 139 patients (84.2%), sputum cultures were performed in 89 patients (53.9%), and urinary antigen detection was performed in 123 patients (74.5%). An etiologic diagnosis was obtained in 60 cases (36.4%), and 31 were definitive. The most frequent etiologies were S pneumoniae (16 cases, 14 definitive), L pneumophila (7 cases, 7 definitive), Aspergillus sp (7 cases, 3 definitive), Pseudomonas aeruginosa (7 cases, 2 definitive), and several Enterobacteriaceae (8 cases, 4 definitive). Clinical complications occurred in 52.1% of the cases, and mortality was 26% (13.9% attributed to pneumonia). CONCLUSIONS: Non-ICU HAP is an important cause of hospital morbidity, observed most frequently in medical wards and elderly patients with severe underlying diseases. In this setting, S pneumoniae and Legionella sp should be considered in addition to other nosocomial pathogens; urinary antigen detection is useful in determining the prevalence of these microorganisms.
Microbiological investigations on a nosocomial case of Legionella pneumophila pneumonia associated with water birth and review of neonatal cases
Franzin L, Cabodi D, Scolfaro C, Gioannini P.
Infectious Diseases Unit and Department of Pediatric Science, University of Turin, Turin, Italy.
Infez Med. 2004 Mar;12(1):69-75.
ABSTRACT: A case of Legionella pneumophila 1 pneumonia, confirmed by positive serology and urinary antigen, occurred in a 7-day old neonate after water birth in hospital. As respiratory samples were not available for culture, further microbiological investigations were performed in neonate and environment, in order to recognize the source of infection. The hospital water supply was contaminated by L. pneumophila 1 strains (300-2000 cfu/L) of two monoclonal subtypes of Pontiac subgroup. L. spiritensis (10-225 cfu/L) was isolated from cold tap water of the patient's home. PCR from tap and humidifiers water of the patient's home was positive for Legionella spp, but not for L. pneumophila. Because L. pneumophila 1, responsible of child infection, was only isolated from the hospital pool water for waterbirthing, we conclude that the infant acquired the nosocomial legionellosis by prolonged delivery in contaminated water, perhaps by aspiration. Infection control measures for waterbirthing are highly recommended. A review of neonatal case of legionellosis is also presented. As this rare infection may have a high fatality rate if unrecognized, pediatricians shoud be aware of the possibility of the legionellosis in newborns.
Recurrent cytomegalovirus disease, visceral leishmaniosis, and Legionella pneumonia after liver transplantation: a case report
Halkic N, Ksontini R, Scholl B, Blanc C, Kovacsovics T, Meylan P, Muheim C, Gillet M, Mosimann F.
Departments of Surgery, Anesthesiology, the Division of Hematology, and the Institute of Microbiology, Lausanne University Hospital (CHUV), Lausanne, Switzerland. firstname.lastname@example.org
Can J Anaesth. 2004 Jan;51(1):84-7.
Abstract: PURPOSE: Recurrent cytomegalovirus (CMV) disease is a frequent complication of liver transplantation. Visceral leishmaniosis in a transplant recipient is, on the other hand, extremely rare and only two cases of kala-azar have been described after liver transplantation. Immunosuppressed patients are known to be at risk of Legionella infection and the relationship between infection with this organism and hospital water supplies has been well described. These three diseases carry a high mortality rate. Our report examines the potential relationship between these complications. CLINICAL FEATURES: We describe the case of a liver transplant recipient who presented the three complications successively and survived. After reviewing the literature, we explore hypotheses linking these infections and discuss treatment strategies. CONCLUSIONS: In the patient described, infection with leishmania probably occurred months prior to the clinical presentation, a delay that matches the incubation period of kala-azar. The simultaneous onset of leishmaniosis and of a high CMV viremia may have been a coincidence. However, CMV infection has been shown to be an independent predictor of invasive fungal infection in liver transplant recipients. CMV does indeed have a suppressive effect on the humoral and cellular immune response in vitro as well as in vivo. The clinical manifestations of leishmaniosis may, therefore, have been precipitated in this patient by the additive immunosuppressive effect of antirejection drugs and CMV.
A 7-year study of severe hospital-acquired pneumonia requiring ICU admission
Valles J, Mesalles E, Mariscal D, Del Mar Fernandez M, Pena R, Jimenez JL, Rello J.
Critical Care Center, Hospital Sabadell, Institut Universitari Parc Tauli-Universitat Autonoma de Barcelona, Parc Tauli s/n, 08208, Barcelona, Spain.
Intensive Care Med. 2003 Nov;29(11):1981-8.
ABSTRACT: OBJECTIVE: To examine the characteristics, prognostic factors, and outcome of patients with severe hospital-acquired pneumonia admitted to the ICU. DESIGN AND SETTING: Prospective observational clinical study in two medical-surgical ICUs with 16 and 20 beds PATIENTS AND PARTICIPANTS: During a 7-year period all hospitalized patients requiring admission to either ICU for hospital-acquired pneumonia were followed up. MEASUREMENTS AND RESULTS: We diagnosed 96 episodes of severe hospital-acquired pneumonia, and in 67 cases a causal diagnosis was made. Most episodes were late-onset pneumonia. Gram-negative micro-organisms were isolated in 51% of episodes diagnosed, and Pseudomonas aeruginosa was the most frequent pathogen isolated (24%). Clearly significant variations happened between hospitals, particularly affecting the incidence of Aspergillus spp. and Legionella pneumophila. Forty-nine patients developed septic shock (51%). Fifty-one patients died (53%). Aspergillosis and pneumonia due to P. aeruginosa were associated with the highest mortality. Septic shock (OR: 14.27) and chronic obstructive pulmonary disease (OR: 6.11) were independently associated with a poor prognosis. CONCLUSIONS: Patients with severe hospital-acquired pneumonia admitted to the ICU present high mortality. The presence of septic shock and chronic obstructive pulmonary disease in conjunction with specific microorganisms are associated with a poor prognosis. Local epidemiological data combined with a patient-based approach may allow a more accurate therapy decision making.
Established and emerging waterborne nosocomial infections
Merlani GM, Francioli P.
Department of Infectious Diseases, Vaudois University Hospital, Lausanne, Switzerland.
Curr Opin Infect Dis. 2003 Aug;16(4):343-7.
ABSTRACT: PURPOSE OF REVIEW: To assess the recent advances in the field of waterborne nosocomial infections. RECENT FINDINGS: In the last year, many publications have confirmed the importance of well known nosocomial waterborne pathogens such as Legionella spp. or other Gram-negative bacteria, especially non-fermentative bacilli. There have also been numerous reports of outbreaks or pseudo-outbreaks caused by Mycobacteria spp. The most intriguing information relates to the possibility that some fungi causing nosocomial infections may originate from the hospital water distribution system. SUMMARY: Despite progress in understanding the pathogenesis of nosocomial waterborne infections, outbreaks, pseudo-outbreaks and sporadic infections still occur. Targeted quality control of hospital water, updated procedures for the appropriate use of sterile and non-sterile water, coupled with surveillance constitute the cornerstones of prevention of these infections.
A nosocomial outbreak of Legionella pneumophila caused by contaminated transesophageal echocardiography probes
Levy PY, Teysseire N, Etienne J, Raoult D.
Unite Des Rickettsies, CNRS UMR 6020, Faculte de Medecine, Universite de la Mediterranee, Marseille, France.
Infect Control Hosp Epidemiol. 2003 Aug;24(8):619-22.
ABSTRACT: A case-control study of three cases of Legionella pneumophila pneumonia identified transesophageal echocardiography (TEE) as a risk factor. Patient isolates and environmental strains from water used for rinsing TEE probes were identical by pulsed-field gel electrophoresis. This is the first report of endoscopy as a potential source of legionellosis.
Epidemiological monitoring of Legionellosis: a case-control study in an
University General Hospital
Laurenti P, Quaranta G, Branca G, Tumbarello M, Capoluongo E, Orsini M, Spica VR.
Università Cattolica del Sacro Cuore, Roma.
Ig Sanita Pubbl. 2003 Jul-Aug;59(4):203-14.
ABSTRACT: The authors report the early results of a case-control study carried out about the risk of Legionellosis. During the first year, they have tested urine samples from patients with unknown pneumonia, using a legionella-sensitive test for the detection of its antigen. Out of 171 samples, 9 have turned out to be positive (5.3%). Lifestyles, predisposing factors, possible sources of infection and stressful events were investigated.
A case of nosocomial Legionella pneumophila pneumonia
Torii K, Iinuma Y, Ichikawa M, Kato K, Koide M, Baba H, Suzuki R, Ohta M.
Department of Bacteriology, Graduate School of Medicine, University of Nagoya, Nagoya 466-8550, Japan. email@example.com
Jpn J Infect Dis. 2003 Jun;56(3):101-2.
ABSTRACT: We report a case of Legionella pneumophila pneumonia in a patient with interstitial lung disease. Intensive environmental investigations revealed that a system of all-day-running bathwater was the source of infection. In this case, the concentration of L. pneumophila in the hospital bathwater was low. We therefore emphasize that even a low concentration of L. pneumophila in environmental water can cause serious infections to immunocompromised patients in a hospital.
Case records of the
. Weekly clinicopathological exercises. Case 14-2003. A 73-year-old woman with pneumonia and progressive respiratory failure Massachusetts General Hospital
Waxman AB, Shepard JA, Mark EJ.
Pulmonary and Critical Care Unit,
, Massachusetts General Hospital Boston, USA.
N Engl J Med. 2003 May 8; 348(19): 1902-12