Pharmacogenomics: Hope and Hype Physicians and researchers have expressed great optimism and confidence in pharmacogenetics merging into medical practice. As the science progresses, it may become feasible that, rather than treating a patient with therapies that may not work for them – or could be toxic – doctors armed with pharmacogenetic know-how will tailor treatments. This approach h
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Development of a standard treatment protocol for severe acute Loletta K-Y So, Arthur C W Lau, Loretta Y C Yam, Thomas M T Cheung, Edwin Poon, Raymond W H Yung, K Y Yuen A series of 31 patients with probable SARS, diagnosed from We launched the initial protocol on March 12, 2003, WHO criteria, were treated according to a treatment protocol consisting of combination treatment with a broad-spectrum consisting of antibacterials and a combination of ribavirin antiviral and an immunomodulating agent. Antibacterials and methylprednisolone. Through experience with the first were instituted before exclusion of recognised pathogens.
11 patients, we were able to finalise standard dose regimens, Acute viral infection may produce damage to host cells by including pulsed methylprednisolone. One patient recovered on cytolysis or immunopathological damage. In the early stage, antibacterial treatment alone, 17 showed rapid and sustained cytolysis is accompanied by viral amplification, such that responses, and 13 achieved improvement with step-up orpulsed methylprednisolone. Four patients required short Standard treatment protocol for SARS (suspected periods of non-invasive ventilation. No patient required intubation or mechanical ventilation. There was no mortality ortreatment morbidity in this series.
Antibacterial treatment● Start levofloxacin 500 mg once daily intravenously or Severe acute respiratory syndrome (SARS) is an emerging ● Or clarithromycin 500 mg twice daily orally plus co- infectious disease associated with a novel coronavirus1 and amoxiclav (amoxicillin and clavulanic acid) 375 mg three causing worldwide outbreaks. In two large series, the times daily orally if patient <18 years, pregnant, or clinical, laboratory, radiological, and microbiological findings have been analysed.1,2 Treatment strategies remain diverse and experimental without uniform effectiveness. We Add combination treatment with ribavirin and describe, from our continuing prospective study, the development of a standard treatment protocol and its ● Extensive or bilateral chest radiographic involvement ● Or persistent chest radiographic involvement and Between March 9, and March 29, 2003, 31 clinically compatible SARS patients were admitted to Pamela Youde ● Or clinical, chest radiographic, or laboratory findings Nethersole Eastern Hospital, Hong Kong, among whom 16 could be traced to an index case admitted on ● Or oxygen saturation <95% in room air March 2 and who died on March 16. Our case definitionswere: fever 38ЊC or higher at presentation or in the previous Standard corticosteroid regimen for 21 days 2 days, with or without chills or rigor; influenza-like ● Methylprednisolone 1 mg/kg every 8 h (3 mg/kg daily) symptoms; new radiological infiltrates compatible with pneumonia; and contact history. Exclusions were pre- ● Then methylprednisolone 1 mg/kg every 12 h (2 mg/kg existing infective lung disorders, aspiration, or hospital- acquired bacterial pneumonia. All cases fulfilled the WHO ● Then prednisolone 0·5 mg/kg twice daily (1 mg/kg daily) criteria for probable SARS cases current at that time.3 Laboratory investigations included haematological ● Then prednisolone 0·5 mg/kg daily orally for 3 days (complete blood counts with differentials and clotting ● Then prednisolone 0·25 mg/kg daily orally for 3 days profile), biochemical (electrolytes, liver and renal function, creatine kinase, lactate dehydrogenase), and microbiological Ribavirin regimen for 10–14 days tests to exclude other causative pathogens (bacterial cultures ● Ribavirin 400 mg every 8 h (1200 mg daily) intravenously of blood, sputum, and urine, serologies by for at least 3 days (or until condition becomes stable) microagglutination for mycoplasma and legionella, ● Then ribavirin 1200 mg twice daily (2400 mg daily) orally serologies by direct immunofluorescence for chlamydia,influenza, parainfluenza, and respiratory syncytial and adenoviruses, nasopharyngeal aspirates for viral cell ● Give pulsed methylprednisolone if clinical condition, chest cultures, and direct sputum smear for Pneumocystis carinii by radiograph, or oxygen saturation worsens (at least two of silver stain). All chest radiographs were semiquantified by separating each lung into six sections (upper, middle, and ● Give as methylprednisolone 500 mg twice daily lower zones and medial and lateral divisions) and scoring intravenously for 2 days, then back to standard them on a four-point scale: 0 clear, 1 subtle haziness or mild infiltrates, 2 ground-glass appearance or prominent infiltrates, and 3 confluent or dense opacities. Three ● Consider non-invasive ventilation or mechanical ventilation respirologists scored chest radiographs independently, with if oxygen saturation <96% while on >6 L per min oxygen or consensus decided between themselves in case of if patient complains of increasing shortness of breath THE LANCET • Vol 361 • May 10, 2003 • www.thelancet.com For personal use. Only reproduce with permission from The Lancet Publishing Group.
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 Patterns of disease progression and response to different corticosteroid doses in three patientsA=rapid and sustained response to ribavirin and methylprednisolone 3 mg/kg daily. B=extensive disease requiring early pulsed methylprednisolone toachieve response. C=early step down of methylprednisolone dose resulted in rebound of SARS; the patient responded later to pulsed methylprednisolone.
antivirals may be important in treatment. In the later stage, conditioning) was increased to 10–12 changes per h. Two when adaptive immune response is mounted, viral clearance exhaust ventilation fans were installed in each cubicle to can be accompanied by severe inflammatory damage, achieve negative-pressure airflow. Closed-system suction was especially with high viral burden.4 An immunomodulating used for mechanical ventilators, the tubes of which were fitted agent, such as a corticosteroid, could reduce tissue with high-efficiency particulate air or similar filters. All damage. As an antiviral we chose ribavirin for its potency health-care workers wore surgical or N-95 masks, protective against DNA and RNA viruses, and methylprednisolone to eye-wear, full-face shields, caps, gowns with full sleeve coverage, surgical gloves, and shoe covers. Advanced barriers, Dose and weaning schedules of methylprednisolone were such as the Air-Mate HEPA Powered Air Purifying modified according to our experiences in treating the first 11 Respirator System (3M, MN, USA) or T4 Personal patients and the index case. The index case’s fatal outcome Protection System (Stryker Instruments, MI, USA) were suggested that late administration of combination treatment stocked in case high-risk procedures, such as endotracheal was probably ineffective. Patients with heavier bodyweights intubation, were required. Staff washed hands with antiseptic worsened despite intravenous 30 mg methylprednisolone rubs after every contact with patients or contaminated objects every 12 h. Correction for bodyweight to 1 mg/kg daily and after taking off protective garments. Direct contact of resulted in lowering of fever and radiographic improvement in eyes, nose, or mouth with hands before sanitisation was 1–2 days, but in most patients fever worsened again thereafter.
discouraged. Environmental or equipment surfaces were We therefore increased the initial methylprednisolone dose to cleaned daily and immediately after use with domestic bleach 3 mg/kg daily, but several severe cases continued to worsen (1000 ppm hypochlorite solution) for non-metallic items and and required pulsed methylprednisolone. Finally, since step- down of methylprednisolone dose in 2–3 days resulted in We treated 31 Chinese residents (11 men) with a mean rebound of SARS in some patients, each dose level was age of 39·6 years (SD 13·3). Four (13%) patients were continued for 5 days. We finalised our treatment protocol on smokers and one had comorbidities (diabetes mellitus, hypertension, coronary artery disease). Clinical and We also implemented stringent infection control measures laboratory features for 12 were described in earlier reports.1,5 to keep to a minimum droplet spread and possible contact Overall, presenting symptoms included pyrexia (90%), with patients’ secretions, fluids, or excreta. Patients with chills or rigor (71%), malaise (65%), anorexia (65%), suspected or probable SARS and convalescent cases were put cough (52%), myalgia (42%), headache (42%), dyspnoea into isolation cubicles, each accommodating four to six (29%), and diarrhoea (23%). Mean temperature was patients, and visits were not allowed. Air change (central air 38·5ЊC (0·8), pulse 97·5 beats per min (11·1), respiratory THE LANCET • Vol 361 • May 10, 2003 • www.thelancet.com For personal use. Only reproduce with permission from The Lancet Publishing Group.
rate 19·7 breaths per min (2·0), and oxygen saturation Tsang KW, Ho PL, Ooi GC, et al. A cluster of cases of severe acute 94·9% (2·4). Common presenting laboratory findings were respiratory syndrome in Hong Kong. http://content.nejm.org/cgi/ lymphopenia (0·91ϫ109/L [0·29]) in 58%, reprint/NEJMoa030666v1.pdf (accessed April 22, 2003).
thrombocytopenia (165ϫ109/L ) in 39%, and raised Departments of Medicine and Microbiology, Pamela Youde lactate dehydrogenase (242 IU/L ) in 68%. All patients Nethersole Eastern Hospital, Hong Kong, Special Administrative had chest-radiograph abnormalities on admission (71% Region, China (L K-Y So MRCP, A C W Lau MRCP, L Y C Yam FRCP, bilateral), with 19%, 74%, 97% in upper, middle, lower T M T Cheung MRCP, E Poon MRCP, R W H Yung FRCPath); Department zones, respectively, features of subtle haziness in 36%, of Microbiology, Queen Mary Hospital, University of Hong Kong, ground glass appearance in 57%, and dense opacities in 7%.
Total mean chest radiography scores were 8·9 (5·9).
Correspondence to: Dr Loletta Kit-Ying So, Department of Medicine, We followed up patients for a mean of 18·9 days (4·1). 30 3 Lok Man Road, Chaiwan, Hong Kong, Special Administrative of 31 patients required combination treatment at a mean of 1·7 (1·5) days after admission and 5·5 (2·7) days after symptom onset. One patient, who was seropositive for thenovel coronavirus and viral RNA in nasopharyngeal aspiratesrecovered on levofloxacin alone. Rapid (within 1–2 days)and sustained response to the combination treatment was Acquired mutations in GATA1 in
evident in 17 patients (figure). In the remaining 13, tworequired step-up of methylprednisolone dose and 11 received pulsed methylprednisolone for severe disease(figure) or rebound after rapid step-down of methylprednisolone dose (figure). 16 patients requiredoxygen and four required short periods (2–5 days) of non- Jürgen Groet, Suzanne McElwaine, Monica Spinelli, invasive ventilation at 8–10 cm H O expiratory pressure. No Andrea Rinaldi, Ingo Burtscher, Claire Mulligan, Afua Mensah, Simona Cavani, Franca Dagna-Bricarelli, Giuseppe Basso, patient required intubation nor mechanical ventilation, and no death has occurred since we started using the treatmentprotocol. We attribute the death of our index case to late Transient myeloid disorder is a unique self-regressing neoplasia diagnosis and treatment that did not conform to our specific to Down’s syndrome. The transcription factor GATA1 is needed for normal growth and maturation of erythroid cells and High dose corticosteroids produced no severe megakaryocytes. Mutations in GATA1 have been reported in
complications, although prophylactic antibiotics (piperacillin acute megakaryoblastic leukaemia in Down’s syndrome. We and tazobactam) had been given to seven patients who had aimed to investigate changes in GATA1 in patients with Down’s fever and raised white cell counts; all recovered and had syndrome and either transient myeloid disorder (n=10) or acute negative bacterial cultures. Ribavirin led to no megakaryoblastic leukaemia (n=6). We recorded mutations complications, despite its known adverse effects of eliminating exon 2 from GATA1 in all patients with transient myeloid disorder (age 0–24 days) and in all with acute In this emerging disease that frequently has rapid megakaryoblastic leukaemia (age 14–38 months). The range of deterioration, the inclusion of control patients was not mutations did not differ between patients with each disorder.
possible or ethical. Future controlled studies may be able Patients with transient myeloid disorder with mutations in to shed more light on the efficacy of our treatment GATA1 can regress spontaneously to complete remission, and
mutations do not necessarily predict later acutemegakaryoblastic leukaemia.
ContributorsL K-Y So and A C W Lau designed the study. The treatment protocol was developed by A C W Lau, L K-Y So, T M T Cheung, and L Y C Yam. Data collection was done by L K-Y So, A C W Lau, and Transient myeloid disorder is a self-regressing E Poon, and data analyses by A C W Lau and L K-Y So. L K-Y So and myeloproliferative disorder that arises mainly in babies with A C W Lau wrote the report, which was reviewed by all investigators. K Y Yuen and R W H Yung provided microbiological and infection Down’s syndrome during the first 4 weeks of life,1–3 affecting control advice, and L Y C Yam coordinated the whole study.
as many as 10% of all neonates with Down’s syndrome. Itcould therefore provide valuable insights into cellular mechanisms that could be exploited to control proliferation outside conventional therapeutic approaches.1,2 Wechsler and colleagues4 noted acquired mutations in the We thank S W Pang, F M F Cheung, and Lily Ma-Tung, Department of erythroid/megakaryocyte lineage-specific transcription factor Pathology, for providing diagnostic support for our index case; and GATA15 in genomic DNA samples from six of six patients Frankie Choi, Department of Nuclear Medicine, Pamela YoudeNethersole Eastern Hospital, for his scientific and technical with Down’s syndrome and acute megakaryoblastic contributions. We thank also all our medical and nursing colleagues who leukaemia, and in none of 92 controls. All mutations were have worked in the SARS wards of Pamela Youde Nethersole Eastern acquired (DNA from remission samples did not have the GATA1 changes) and all resulted in a premature translationtermination, eliminating the GATA1 activation domain Peiris JSM, Lai ST, Poon LLM, et al. Coronavirus as a possible cause of severe acute respiratory syndrome. Lancet 2003; 361: 1319–25.
Without examination of patients with transient myeloid Lee N, Hui D, Wu A, et al. A major outbreak of severe acute disorder, we cannot understand if the GATA1 dysfunction is respiratory syndrome in Hong Kong. http://content.nejm.org/cgi/reprint/NEJMoa030685v1.pdf (accessed April 22, 2003).
a primary permissive event or a second hit, important for WHO. Case definitions for surveillance of severe acute respiratory emergence of fully developed leukaemia. Thus, we aimed to syndrome (SARS). http://www.who.int/csr/sars/casedefinition/en investigate GATA1 mutations in tissue samples from patients with Down’s syndrome and transient myeloid disorder.
Cheung CY, Poon LL, Lau AS, et al. Induction of postinflammatory We analysed exon 2 of GATA1 by reverse transcription cytokines in human macrophages by influenza A (H5N1) viruses: amechanism for the unusual severity of human disease? Lancet 2002; PCR (RT-PCR), directly from RNA of presentation samples 360: 1831–37.
of patients. Samples were surplus or archived clinical THE LANCET • Vol 361 • May 10, 2003 • www.thelancet.com For personal use. Only reproduce with permission from The Lancet Publishing Group.
Crimes de perigo abstrato como meio para cepção de Estado Democrático de Direito, que veda oarbítrio estatal. Daí a importância de se definir o queseriam bens jurídicos, tendo em vista que, em regra,somente a lesão ou perigo de lesão a bens jurídicos é Lucimara Aparecida Silva Antunes de Oliveira* Tratando-se de crimes de perigo abstrato, a defini- Sumário : 1 Introdução. 2 Os