로이터통신 Tue Jul 30, 2013 2:48pm IST
http://in.reuters.com/article/2013/07/30/novartis-gilenya-idINL6N0G02A52013073

* Patient took Novartis’ Gilenya MS pill

* Developed progressive viral disease

* First incidence in 71,000 patients

* Gilenya facing competition from Biogen’s Tecfidera

ZURICH, July 30 (Reuters) – A patient taking Novartis’ multiple sclerosis pill Gilenya developed a rare and potentially fatal viral disease, the Swiss drugmaker said on Tuesday, an unexpected setback as it faces growing competition from new oral treatments.

Gilenya is one of Novartis’ big new drug hopes, growing 66 percent in the second quarter to $468 million. But the drug faces competition from new medicines such as Biogen Idec’s Tecfidera.

Novartis said it had been informed of a case of progressive multifocal leukoencephalopathy (PML) in a patient who had been taking Gilenya for MS for seven months.

It said it was working with the reporting physician to understand all possible contributing factors, including those beyond treatment, given several atypical features of the case.

“The course of the underlying neurological disease was rapid with some atypical findings for MS on the MRI scans of the brain and spinal cord, as well as some unusual clinical features,” Novartis said in a statement.

Novartis said all previously reported cases of PML among the approximately 71,000 patients treated with Gilenya thus far had been attributed to prior treatment with Biogen Idec’s Tysabri, which bears a known risk of PML.

Deutsche bank analyst Tim Race said the case may provoke some concerns about Gilenya’s future growth potential. But he noted the incidence of reported PML cases for Gilenya has so far been extremely low.

“By the time there was a similar level of patient experience with Tysabri there had been 298 cases reported. Thus, even if the risk proves to be real it is likely to be of a very different order of magnitude,” Race said in a note.

Shares in Novartis were trading down 0.8 percent at 66.10 Swiss francs by 0904 GMT, compared to a 0.4 percent weaker European healthcare sector.

=============

노바티스 ‘길레니아’ 복용자, PML 발생 보고
치명적 바이러스 질환.. 발생 원인 조사 중

데일리팜 2013-07-31 08:05:57
http://www.dailypharm.com/Users/News/NewsView.html?ID=173758
노바티스는 다발성 경화증 치료제인 ‘길레니아(Gilenya)’를 복용한 환자에서 드물고 잠재적으로 치명적인 바이러스 질환이 발생했다고 30일 밝혔다.

길레니아는 노바티스가 기대하는 약물 중 하나. 그러나 바이오겐의 ‘텍피데라(Tecfidera)’와 경쟁으로 영향이 있을 것으로 전망된다.

노바티스는 7개월간 길레니아를 복용한 환자에서 진행성 다소성 백질뇌염(progressive multifocal leukoencephalopathy, PML)이 발생했다고 말했다.

현재 노바티스는 치료제를 포함해 질병의 발생 원인이 될 수 있는 모든 인자에 대해 조사를 벌이고 있는 중이라고 말했다.

지금까지 노바티스는 길레니아로 치료를 받던 7만1000명 중 PML이 발생이 보고된 경우는 PML 위험성이 있는 ‘티사브리(Tysabri)’로 이전에 치료를 받았기 때문이라고 설명해왔다.

분석가들은 길레니아의 부작용에 대한 우려가 입증될 경우 길레니아의 성장세가 정체될 수 있다며 우려를 나타냈다.

====================

July 19, 2013 Shelley Wood
http://www.theheart.org/article/1561843.do?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+Theheartorg+%28theheart.org%29

Kyoto, Japan - The past week has seen a number of new twists in the tale of a prominent Japanese cardiologist accused of fabricating and manipulating data and images for cardiology research later published in a range of cardiology journals.

Last year, the American Heart Association (AHA) issued a notice of concern about five papers appearing in three AHA-published journals—Circulation, Circulation Research, andHypertension—between 2001 and 2004, as reported by heartwire.

Dr Hiroaki Matsubara

Concerns about Dr Hiroaki Matsubara ultimately spread to the Kyoto Heart Study, the >3000 patient, postmarketing study Matsubara presented to some fanfare at the European Society of Cardiology 2009 Congress and subsequently published in the European Heart Journal(EHJ). The EHJ later retracted that article, a move the AHA opted to follow this May after concluding its review of the studies published in a number of the association’s journals. Matsubara resigned from his post at Kyoto Prefectural University earlier this year.

Last Friday, Japan’s minister of health, Norihisa Tamura, as well as university officials at Kyoto Prefectural University announced that the Kyoto Heart Study data were “very likely” fabricated, according to AFP. “Incomplete” patient data were used in the study, which concluded the blood-pressure drug could also reduce other cardiovascular end points via mechanisms unrelated to blood-pressure lowering. Had “complete patient records” been used, the study would have reached “a different conclusion,” the university concluded.

Finally, it has also emerged that two Novartis employees were involved in the conduct and analysis of the Kyoto Heart Study and a second investigator-initiated trial, the Jikei Heart study, although their participation was not acknowledged in publications and presentations of the data. Those employees are no longer with Novartis.

Novartis has issued a statement saying that it had launched a third-party investigation into allegations of conflict of interest (COI) relating to the two Novartis employees back in April.

“At the time these Japanese valsartan [investigator-initiated trials] IITs started between 2001 and 2004, there were no specific guidelines for COI in IITs,” the statement reads. “The former employees and their managers misunderstood the appropriate level of involvement in IITs of employees of a pharmaceutical company. However, there are now COI guidelines for in place across the industry, which are followed by all Novartis Pharma Japan employees.”

In June, after its investigation concluded, the company implemented “preventive and corrective measures . . . to address the causes identified in the third-party investigation, demonstrating our social and ethical accountability,” the statement notes.

According to AFP, Novartis has also stressed that the university “was not able to conclude that there was intentional wrongdoing” and that it remains possible that the “inconsistencies” may have been unintentional.

The retractions, Matsubara’s resignation, the Novartis announcement, and other details have been followed in detail on blog sites Retraction Watch and Cardiobrief, as well as onPharmaTimes.

========

Shelley Wood Managing Editor | shelley@theheart.org
Follow @shelleywood2 on Twitter

Shelley Wood joined theheart.org as a medical journalist in 2000. Born and bred in Vancouver, BC, Shelley did her bachelor’s degree at McGill University in Montreal, QC and the University of Cape Town, South Africa, and then completed her graduate degree in journalism at the University of British Columbia, specializing in health reporting. In January 2009, she took over as managing editor for heartwire.

Shelley was awarded the National Institute for Health Care Management (NIHCM) Print Journalism Award in 2009 for her series, The Myxo ring mix-up. In 2010, she led theheart.org team to win the Online News Association Online Journalism Award in the category of Specialty Site Journalism (Independent). She lives in the Okanagan Valley – between the Coastal and Rocky Mountain ranges – in Kelowna, BC.

==================

노바티스 직원, 디오반 효능 조작 관여 탄로
코메디닷컴 2013.07.30 10:57 수정 2013.07.31 16:56
http://www.kormedi.com/news/article/1207334_2892.html

최근 글로벌 제약사 노바티스 직원이 일본의 저명한 심장병 전문의 마쓰바라 히로아키 교수의 임상 데이터 조작 사건에 연루된 것으로 알려지면서 파장이 커지고 있다고 의학정보사이트 ‘The Heart Org’는 지난 19일 보도했다.

미국심장학회(AHA, American Heart Association)는 지난 2001년부터 2004년까지 학회가 발행하는 3개 저널(Circulation, Circulation Research, Hypertension)에 실린 마쓰바라 교수의 논문(5편)이 임상 데이터와 이미지의 조작과 관련이 있다며 우려를 표명해 왔다.

유럽심장학회지(EHJ)는 마쓰바라 교수가 유럽심장학회(2009년) 회의에서 발표하고 이 저널에 게재한 고혈압 치료제 디오반(성분명: 발사르탄)의 ‘시판 후 연구’ 등의 논문을 이미 철회한 바 있다. 이어 AHA도 논란 끝에 여러 저널에 실린 마쓰바라 교수의 논문들을 지난 5월에 취소키로 결정했다.

마쓰바라 교수의 연구결과에 대한 이같은 우려는 일본 내에서도 증폭되고 있다. AFP통신에 따르면 지난 26일 교토 부립의과대학(KPUM)측과 일본 후생노동성이 마쓰바라 교수의 ‘교토 심장 연구(Kyoto Heart Study)’ 자료가 조작됐을 가능성이 매우 높다고 발표했다.

이 연구는 불완전한 환자 자료를 인용해 혈압약인 ‘디오반’이 혈압강하와 관련 없는 기전으로 다른 심혈관 질환에서 효과를 보였다고 발표한 바 있다. KPUM은 “이 논문이 온전한 환자 자료를 사용했다면 다른 결론을 내렸을 것”이라고 밝혔다.

대학 측은 또 데이터에 문제가 있었던 만큼 디오반이 다른 혈압약에 비해 뇌졸중, 협심증 등을 줄이는 효과가 있다는 연구진의 결론에는 오류가 있을 가능성이 크다고 밝혔다.

더욱 논란이 일고 있는 것은 2명의 노바티스 직원이 ‘교토 심장 연구’와 연구자 주도 임상시험(이하 IIT)인 ‘지케이 심장 연구(Jikei Heart Study)’의 실행과 분석에 관여했다는 사실이 드러난 것이다. 이들은 그럼에도 논문 출판과 발표에 연구 참여자로 공식 참여하지 않아 논란의 소지를 제공했다. 이들 직원은 현재 노바티스를 퇴사한 상태이다.

노바티스는 이번 논란과 관련해 제3의 기관에 의해 지난 4월부터 조사에 착수했다는 성명서를 발표하기도 했다.

노바티스는 “지난 2001년부터 2004년 사이 일본에서 디오반(성분명:발사르탄) IIT가 시작될 무렵, IIT의 이해충돌(COI) 관련해 구체적인 가이드라인이 존재하지 않았다”고 밝히며 “제약회사의 직원들이 어느 선까지 IIT에 관여하는 게 적절한가에 대한 이해가 부족했다”고 전했다. 이어 “현재는 업계 전반에 걸쳐 COI 가이드라인이 자리를 잡았으며, 모든 노바티스의 일본 직원들은 이를 잘 따르고 있다”고 말했다.

===================

日, 의대서 혈압강하제 임상 데이터 조작 파문

도쿄|서의동 특파원 phil21@kyunghyang.com

경향신문 2013-07-31 11:35:04ㅣ
http://news.khan.co.kr/kh_news/khan_art_view.html?artid=201307311135041&code=970203

스위스 제약사 노바티스의 일본법인이 취급하는 고혈압 치료제 디오반에 대해 일본의 의과대학이 실시한 임상연구 데이터가 인위적으로 조작된 것으로 드러났다.

도쿄 지케이카이(滋惠會)의대 조사위원회는 30일 이 대학 연구팀이 실행한 혈압강하제 디오반(성분 발사르탄) 임상 연구 논문에서 “노바티스 전 직원의 관여 등을 통해 데이터가 인위적으로 조작된 사실이 인정돼 논문을 철회키로 했다”고 발표했다. 지케이카이 의대조사에 따르면 대학이 보유하고 있는 671인분의 데이터와 최종통계를 비교한 결과 86건에서 혈압치가 다른 것으로 나타났다. 다만, 조작은 통계해석의 단계에서 벌어진 것으로 보여 “대학의 연구자가 간여한 것이 아니라 노바티스의 전 사원이 조작했다”고 대학측은 판단했다.

지케이카이 대학의 임상연구는 고혈압 환자 3081명을 대상으로 실시돼 디오반이 뇌졸중과 협심증을 예방하는 데 효과가 높다는 논문을 2007년 이 대학 연구진이 영국 의학지에 발표하기도 했으나 대학측은 데이터 조작이 밝혀짐에 따라 논문을 철회하기로 했다.

일본에서 디오반 임상연구는 지케이카이 의대, 교토(京都)부립 의과대학, 나고야(名古屋)대, 지바(千葉)대 등 5개 대학에서 실시됐으며 지케이카이 의대와 교토부립 의대의 연구 논문을 노바티스측이 홍보에 사용해 왔다. 디오반은 세계 판매량 1위의 혈압강하제다.

앞서 교토부립 의대도 지난 11일 이 대학의 마쓰바라 히로아키(松原弘明) 전 교수가 실시한 디오반 임상 연구에서 데이터 조작이 이뤄진 것으로 드러나 파문을 일으켰다. 노바스티측은 교토부립 의대 연구에 자사 직원을 참가시키고 연구진에 1억엔 규모의 기부금을 제공한 것으로 알려졌다.

================

Retraction Watch

2009 대유행 인플루엔자 바이러스에 대한 임상적 측면에서 세계보건기구 자문단의 집필위원회(the Writing Committee of the World Health Organization (WHO) Consultation on Clinical Aspects of Pandemic (H1N1) 2009 Influenza)가 [뉴잉글랜드저널오브메디신]에 기고한 “2009 신종플루 바이러스 감염의 임상적 측면”이라는 리뷰 아티클입니다.

WHO에 대한 비판적 견해가 거의 반영되지 않은 글이고, 타미플루 독점판매권을 가지고 있는 로슈 및 릴렌자 판매사인 글락소스미스클라인, 그리고 백신 제조사인 백스터, 노바티스, 글락소스미스클라인 등으로부터 연구비, 강연료, 자문료 등의 명목으로 재정적 지원을 받은 바 있는 일부 전문가들이 집필위원회에 포함되어 있다는 점도 고려해서 리뷰 아티클을 읽어야 할 것 같습니다.

Volume 362:1708-1719 May 6, 2010 Number 18 Next 출처 : http://content.nejm.org/cgi/content/full/362/18/1708

During the spring of 2009, a novel influenza A (H1N1) virus of swine origin caused human infection and acute respiratory illness in Mexico.^1,2 After initially spreading among persons in the United States and Canada,^3,4 the virus spread globally, resulting in the first influenza pandemic since 1968 with circulation outside the usual influenza season in the Northern Hemisphere (see the Supplementary Appendix, available with the full text of this article at NEJM.org). As of March 2010, almost all countries had reported cases, and more than 17,700 deaths among laboratory-confirmed cases had been reported to the World Health Organization (WHO).⁵ The number of laboratory-confirmed cases significantly underestimates the pandemic’s impact. In the United States, an estimated 59 million illnesses, 265,000 hospitalizations, and 12,000 deaths had been caused by the 2009 H1N1 virus as of mid-February 2010.⁶ This article reviews virologic, epidemiologic, and clinical data on 2009 H1N1 virus infections and summarizes key issues for clinicians worldwide.

Viral Characteristics

Pandemic 2009 H1N1 virus derives six genes from triple-reassortant North American swine virus lineages and two genes (encoding neuraminidase and matrix proteins) from Eurasian swine virus lineages.⁴ Although the 2009 H1N1 virus is antigenically distinct from other human and swine influenza A (H1N1) viruses,⁴ strains of this virus have been antigenically homogeneous, and the A/California/7/2009 strain that was selected for pandemic influenza vaccines worldwide is antigenically similar to nearly all isolates that have been examined to date.⁷ Multiple genetic groups have been recognized, including one recently predominant lineage,⁸ but any possible clinical importance of different lineages remains uncertain. Reassortment has not occurred with human influenza viruses to date. The level of pulmonary replication of the 2009 H1N1 virus has been higher than that of seasonal influenza A (H1N1) viruses in experimentally infected animals,^9,10,11 but the 2009 pandemic strain generally lacks mutations that are associated with increased pathogenicity in other influenza viruses (Table 1 in the Supplementary Appendix).

Epidemiology

Infection, Illness, and Disease Burden

Most illnesses caused by the 2009 H1N1 virus have been acute and self-limited, with the highest attack rates reported among children and young adults. The relative sparing of adults older than 60 years of age^3,12,13 is presumably due to the exposure of persons in this age group to antigenically related influenza viruses earlier in life, resulting in the development of cross-protective antibodies (Table 2 in the Supplementary Appendix).^10,14

Rates of illness from 2009 H1N1 virus infection have varied, but during one outbreak in New Zealand, the attack rate of illness was estimated at 7.5%, and the attack rate of overall infection was estimated at 11%.¹⁵ An estimated one third of infections in one boarding school were subclinical.¹⁶ After the peak of a second wave of infection in Pittsburgh, the seroprevalence of hemagglutination-inhibition antibody suggested that about 21% of all persons and 45% of those between the ages of 10 and 19 years had become infected.¹⁷

The overall case fatality rate has been less than 0.5%, and the wide range of estimates (0.0004 to 1.47%) reflects uncertainty regarding case ascertainment and the number of infections.^18,19,20 The case fatality rate for symptomatic illness was estimated to be 0.048% in the United States²¹ and 0.026% in the United Kingdom.¹³ In contrast to seasonal influenza, most of the serious illnesses caused by the pandemic virus have occurred among children and nonelderly adults, and approximately 90% of deaths have occurred in those under 65 years of age.

Rates of hospitalization and death have varied widely according to country.²² Hospitalization rates have been highest for children under the age of 5 years,²² especially those under the age of 1 year, and lowest for persons 65 years of age or older.²³ In the United States, among patients who were hospitalized with pandemic influenza, 32 to 45% were under the age of 18 years.^23,24 Approximately 9 to 31% of hospitalized patients have been admitted to an intensive care unit (ICU), where 14 to 46% of patients have died.^{23,24,25,26,27} The overall case fatality rate among hospitalized patients appears to have been highest among those 50 years of age or older and lowest among children.^1,13,23,27

Transmission and Outbreaks

The mechanisms of person-to-person transmission of the 2009 H1N1 virus appear to be similar to those of seasonal influenza, but the relative contributions of small-particle aerosols, large droplets, and fomites are uncertain. Rates of secondary outbreaks of illness vary according to the setting and the exposed population, but estimates range from 4 to 28%. Household transmission is highest among children and lowest among adults over 50 years of age.^28,29 In the United Kingdom and the United States, the rates of secondary outbreaks in households were 7% and 13%, respectively, with children at increased risk for infection by a factor of two to four.^16,28 Many outbreaks have occurred in schools, day-care facilities, camps, and hospitals.^16,30,31 Estimates of the basic reproduction number (the mean number of secondary cases of infection transmitted by a single primary case in a susceptible population) generally range from 1.3 to 1.7 according to the setting, which are similar to or slightly higher than the estimates for seasonal influenza,^20,32,33 but may be as high as 3.0 to 3.6 in outbreaks in crowded schools.³¹

Risk Groups and Risk Factors for Severe Disease

Approximately one quarter to one half of patients with 2009 H1N1 virus infection who were hospitalized or died had no reported coexisting medical conditions.^{13,23,26,27,34} Underlying conditions that are associated with complications from seasonal influenza also are risk factors for complications from 2009 H1N1 virus infection (Table 1). Pregnant women (especially those in the second or third trimester), women who are less than 2 weeks post partum, and patients with immunosuppression or neurologic disorders have also been overrepresented among those with severe 2009 H1N1 virus infection.^23,24,26,35 Although pregnant women represent only 1 to 2% of the population, among patients with 2009 H1N1 virus infection, they have accounted for up to 7 to 10% of hospitalized patients,^22,23,24 6 to 9% of ICU patients,^26,27 and 6 to 10% of patients who died.^23,35 There appears to be a particularly increased risk of death among infected women during the third trimester,³⁶ especially among those who have coinfection with the human immunodeficiency virus (HIV).³⁷

View this table: [in this window] [in a new window]   Table 1. Risk Factors for Complications of or Severe Illness with 2009 H1N1 Virus Infection.

 
Among patients with severe or fatal cases of 2009 H1N1 virus infection, severe obesity (body-mass index [the weight in kilograms divided by the square of the height in meters], 35) or morbid obesity (body-mass index, 40) has been reported at rates that are higher by a factor of 5 to 15 than the rate in the general population.^23,26,27,38 In addition to obesity-associated risks, such as cardiovascular disease and diabetes, possible adverse immunologic effects and management problems related to obesity may be contributory.

In certain disadvantaged groups, including indigenous populations of North America and the Australasia–Pacific region, rates of severe 2009 H1N1 virus infection have been increased by a factor of five to seven.^23,26,27 Factors that may contribute to this trend include crowding; an increased prevalence of underlying medical disorders, alcoholism, and smoking²⁷; delayed seeking of or access to care; and possibly unidentified genetic factors. Aboriginal status, the presence of coexisting conditions, and delayed receipt of antiviral therapy were independently associated with severe disease in one Canadian study.³⁹

Pathogenesis

Viral Replication

Studies of hemagglutinin-receptor binding indicate that the 2009 H1N1 virus is well adapted to mammalian hosts and binds to both 2,6-linked cellular receptors (as do seasonal influenza viruses) and 2,3-linked receptors,⁴⁰ which are present in the conjunctivae, distal airways, and alveolar pneumocytes. The 2009 H1N1 virus shows increased ex vivo replication in human bronchial epithelium at 33°C, as compared with a seasonal influenza virus,⁴¹ and is also characterized by increased replication and pathological changes in the lungs of nonhuman primates and increased replication in ex vivo human lung tissues.¹⁰ Such observations may help explain the ability of the virus to cause severe viral pneumonitis in humans.

In uncomplicated illness, nasopharyngeal viral RNA loads peak on the day of onset of symptoms and decline gradually afterward.⁴² However, viral replication may be more prolonged than in seasonal influenza, and on day 8 of uncomplicated illness in adults and teenagers, nasopharyngeal swabs have yielded viral RNA in 74% of patients and infectious virus in 13% of patients.^30,43 Infectious virus has been recovered from children up to 6 days after the resolution of fever.

Nasopharyngeal viral loads are increased in patients with severe pneumonia and decline slowly in critically ill patients.⁴⁴ Among intubated patients, viral RNA has been detected at higher levels and for longer periods in the lower respiratory tract than in the upper respiratory tract.⁴⁵ Viral RNA may be detected in secretions from the lower respiratory tract up to 28 days after the onset of severe pneumonia⁴⁶ and longer in patients with immunosuppression. Viral RNA and (infrequently) infectious virus have been detected in the stool of patients, and viral RNA has been detected infrequently in blood or urine of patients,^44,45 although one small study reported the frequent detection of viral RNA in blood, regardless of the severity of the illness.⁴⁷

Immune Responses

The patterns of innate and adaptive immune responses in patients with 2009 H1N1 virus infection are incompletely characterized. Seasonal and pandemic 2009 H1N1 viruses induce similar proinflammatory mediator responses in human cells in vitro⁴¹ but do not activate effective innate antiviral responses in human dendritic cells and macrophages.⁴⁸ Increased plasma levels of interleukin-15, interleukin-12p70, interleukin-8, and especially interleukin-6 may be markers of critical illness.^45,47 High systemic levels of interferon- and mediators involved in the development of type 1 and type 17 helper T-cell responses have been reported in hospitalized patients.⁴⁷ As compared with patients with less severe illness, patients who died or who had the acute respiratory distress syndrome (ARDS) had increased plasma levels of interleukin-6, interleukin-10, and interleukin-15 throughout the illness and of granulocyte colony-stimulating factor, interleukin-1, interleukin-8, interferon-inducible protein 10, and tumor necrosis factor during the late phase of illness.⁴⁴ Levels of serum hemagglutination-inhibition and neutralizing antibodies rise promptly after infection in immunocompetent persons,¹⁴ but symptomatic reinfections have been reported.⁴⁹

Pathological Features

In fatal cases of H1N1 virus infection, the most consistent histopathological findings are varying degrees of diffuse alveolar damage with hyaline membranes and septal edema, tracheitis, and necrotizing bronchiolitis^50,51,52 (Figure 1). Other early changes include pulmonary vascular congestion and, in some cases, alveolar hemorrhage. In addition to infecting cells in upper respiratory and tracheobronchial epithelium and mucosal glands, the 2009 H1N1 virus targets alveolar lining cells (type I and II pneumocytes)⁵⁰ (Figure 2). Viral antigens have been readily detectable in about two thirds of patients who died within 10 days after the onset of illness and may be detectable for more than 10 days.⁵⁰ Other autopsy findings include hemophagocytosis, pulmonary thromboemboli and hemorrhage, and myocarditis.⁴⁴ Bronchopneumonia with evidence of bacterial coinfection has been found in 26 to 38% of fatal cases.^50,51,52

View larger version (106K): [in this window] [in a new window]   Figure 1. Lung-Tissue Specimen Obtained at Autopsy from a 13-Year-Old Boy after a 7-Day Clinical Course of 2009 H1N1 Virus Infection. The specimen shows diffuse alveolar damage with hyaline membrane formation (arrows) and hemorrhage (hematoxylin and eosin). The patient, who had cerebral palsy, received oseltamivir for 2 days before he died. No evidence of bacterial coinfection was present. (Courtesy of Dr. Sherif R. Zaki, CDC.)

 

View larger version (102K): [in this window] [in a new window]   Figure 2. Immunostaining of Influenza Viral Antigens in Lung-Tissue Specimen Obtained at Autopsy from a 55-Year-Old Woman after a 7-Day Clinical Course of 2009 H1N1 Virus Infection. The specimen shows viral antigens (red color) in the nuclei of alveolar-lining cells (arrows), including type I and type II pneumocytes. Many infected cells have detached and are seen in alveolar spaces. Evidence of Streptococcus pneumoniae coinfection was also present in the patient, who had Down’s syndrome and hepatitis B infection (mouse anti-influenza nucleoprotein monoclonal antibody with naphthol fast-red substrate and hematoxylin counterstain). (Courtesy of Dr. Sherif R. Zaki, CDC.)

 
Clinical Features

Incubation Period

The incubation period appears to be approximately 1.5 to 3 days, which is similar to that of seasonal influenza.^{18,28,31,32,53} In a minority of patients, the period may extend to 7 days.

Clinical Presentation

Infection with the 2009 H1N1 virus causes a broad spectrum of clinical syndromes, ranging from afebrile upper respiratory illness to fulminant viral pneumonia. Mild illness without fever has been reported in 8 to 32% of infected persons.⁵³ Most patients presenting for care have typical influenza-like illness with fever and cough, symptoms that are sometimes accompanied by sore throat and rhinorrhea (Table 2).^{2,24,34,53,54,55,56} Systemic symptoms are frequent. Gastrointestinal symptoms (including nausea, vomiting, and diarrhea) occur more commonly than in seasonal influenza, especially in adults.^3,57 Dyspnea, tachypnea in children, chest pain, hemoptysis or purulent sputum, prolonged or recurrent fever, altered mental status, manifestations of dehydration, and reappearance of lower respiratory tract symptoms after improvement are signs of progression to more severe disease or complications.^{2,25,26,27,58}

View this table: [in this window] [in a new window]   Table 2. Symptom Profiles in Groups of Patients with Suspected or Confirmed Pandemic 2009 H1N1 Virus Infection Worldwide.

 
The principal clinical syndrome leading to hospitalization and intensive care is diffuse viral pneumonitis associated with severe hypoxemia, ARDS, and sometimes shock and renal failure.^26,27 This syndrome has accounted for approximately 49 to 72% of ICU admissions for 2009 H1N1 virus infection.^26,27 Rapid progression is common, typically starting on day 4 to 5 after the onset of illness, and intubation is often necessary within 24 hours after admission. Currently available prognostic algorithms for community-acquired pneumonia, such as CURB-65 (a measure of confusion, urea nitrogen, respiratory rate, and blood pressure and an age of 65 years or older), may not apply.⁵⁸ Radiographic findings commonly include diffuse mixed interstitial and alveolar infiltrates, although lobar and multilobar distributions occur, particularly in patients with bacterial coinfection. Chest computed tomography has shown multiple areas of ground-glass opacities, air bronchograms, and alveolar consolidation, particularly in the lower lobes.²⁴ Small pleural effusions occur, but an increased volume suggests volume overload or possibly empyema. Pulmonary thromboemboli have occurred in some critically ill patients with ARDS.

Other important syndromes include severe, prolonged exacerbation of chronic obstructive pulmonary disease (COPD) or asthma (in about 14 to 15% of patients), bacterial coinfections, and decompensation of serious coexisting conditions (Table 1).^23,26,27 Among hospitalized patients with 2009 H1N1 infection, a history of asthma has been reported in 24 to 50% of children and adults, and COPD in 36% of adults.^23,24 Bacterial pneumonia, usually caused by Staphylococcus aureus (often methicillin-resistant), Streptococcus pneumoniae, S. pyogenes, and sometimes other bacteria, has been suspected or diagnosed in 20 to 24% of ICU patients and has been found in 26 to 38% of patients who died, often in association with a short clinical course.^26,27,50,52 Death from 2009 H1N1 virus and bacterial coinfection has occurred within 2 to 3 days in some cases. Sporadic cases of neurologic manifestations (confusion, seizures, unconsciousness, acute or postinfectious encephalopathy, quadriparesis, and encephalitis)⁵⁹ and myocarditis have been reported, including some fulminant cases.

Laboratory findings at presentation in patients with severe disease typically include normal or low-normal leukocyte counts with lymphocytopenia and elevations in levels of serum aminotransferases, lactate dehydrogenase, creatine kinase, and creatinine.^2,25,27 Myositis and rhabdomyolysis have occurred in severe cases. A poor prognosis is associated with increased levels of creatine kinase, creatinine, and perhaps lactate dehydrogenase, as well as with the presence of thrombocytopenia and metabolic acidosis (Table 3 in the Supplementary Appendix).²

Special Populations

Young children with 2009 H1N1 virus infection may have marked irritability, severe lethargy, poor oral intake, dehydration resulting in shock, and seizures.^56,60 Other complications include invasive bacterial coinfections, encephalopathy or encephalitis (sometimes necrotizing), and diabetic ketoacidosis.^59,61 Bronchiolitis in infants and croup in young children may require hospitalization but do not usually necessitate ICU care. Suspected transplacental transmission of the 2009 H1N1 virus has been reported,⁶² and respiratory transmission from a symptomatic mother to a newborn can occur during the postpartum period. Newborn infants may also have apnea, tachypnea, cyanosis, and lethargy. Pregnant women are at increased risk for severe illness, spontaneous abortion, preterm labor and birth, and fetal distress.^35,36,57

Afebrile or atypical presentations have occurred in pregnant women, patients with immunosuppression, those undergoing hemodialysis, and other risk groups (Table 1). Patients with severe immunosuppression are at increased risk for protracted viral replication and pneumonia.^63,64

Diagnosis

Clinical Factors

Clinical suspicion and the accuracy of diagnosis vary substantially, depending on whether the case occurs sporadically or during a recognized outbreak, when a typical presentation of influenza-like illness is likely to represent 2009 H1N1 virus infection. However, the wide clinical spectrum of 2009 H1N1 virus infection and its features that overlap with those of other common infections have sometimes led to the misdiagnosis of other potentially treatable infections (e.g., legionellosis, meningococcemia, leptospirosis, dengue, and malaria).⁵⁸ Coinfection with dengue or certain respiratory viruses (parainfluenza virus and respiratory syncytial virus) and detection of S. pneumoniae have been reported in some patients with severe 2009 H1N1 virus infection.⁶⁵ Coinfection with other respiratory viruses, including seasonal influenza virus, has also been reported.^34,65

Virologic Factors

Viral RNA detection by conventional or real-time reverse-transcriptase–polymerase-chain-reaction (RT-PCR) assay remains the best method for the initial diagnosis of 2009 H1N1 virus infection.⁵⁸ Nasopharyngeal aspirates or swabs taken early after the onset of symptoms are suitable samples, but endotracheal or bronchoscopic aspirates have higher yields in patients with lower respiratory tract illness.^46,58,66 One study showed that among patients with detectable H1N1 viral RNA in bronchoscopic samples, 19% had negative upper respiratory tract samples.⁶⁶ Negative lower respiratory tract samples have been noted in 10% or more of patients with severe 2009 H1N1 virus infection. Consequently, negative results in single respiratory specimens do not rule out 2009 H1N1 virus infection, and repeated collection of multiple respiratory specimen types is recommended when clinical suspicion is high.

Commercially available rapid influenza antigen assays have poor clinical sensitivity (11 to 70%) for the detection of 2009 H1N1 virus in respiratory specimens and cannot differentiate among influenza A subtypes (Table 4 in the Supplementary Appendix). Consequently, negative test results should not be used to make decisions with respect to treatment or infection control. Direct or indirect immunofluorescence tests are less sensitive than RT-PCR.⁶⁶

The 2009 H1N1 virus replicates in various cell types,⁶⁷ but isolation usually takes several days. Serologic assays (microneutralization and hemagglutination inhibition) that detect increases in antibody levels in paired serum samples provide a retrospective diagnosis; single high titers in serum samples from convalescent patients may be indicative of recent infection,¹⁴ but routine testing of a single specimen to detect recent infection is not recommended.

Clinical Management

Antiviral Therapy

The currently circulating 2009 H1N1 virus is susceptible to the neuraminidase inhibitors oseltamivir (Tamiflu) and zanamivir (Relenza) but is almost always resistant to amantadine and rimantadine.^3,10 Therapy with a neuraminidase inhibitor is especially important for patients with underlying risk factors, including pregnancy,⁶⁸ and those with severe or progressive clinical illness (Table 3).⁶⁹ Standard doses of oseltamivir or inhaled zanamivir can be used for the treatment of mild illness, unless viral resistance to oseltamivir has been documented or is suspected (e.g., because of chemoprophylaxis failure), in which case zanamivir is preferred.

View this table: [in this window] [in a new window]   Table 3. Antiviral Therapy in Specific Subgroups of Patients.

 
Early therapy with oseltamivir in patients with 2009 H1N1 virus infection may reduce the duration of hospitalization⁷⁰ and the risk of progression to severe disease requiring ICU admission or resulting in death.^24,35,36 In one study involving 45 patients with 2009 H1N1 virus who had cancer or had undergone hematopoietic stem-cell transplantation, 18% had pneumonia and 37% were hospitalized; all patients received oseltamivir, and no deaths were reported.⁷¹ Oseltamivir-treated patients with HIV infection who were receiving highly active antiretroviral therapy had a clinical course similar to that in immunocompetent persons.⁷² Deaths have occurred despite early therapy,⁷³ but the administration of oseltamivir even after an interval of more than 48 hours since the onset of illness has been associated with reduced rates of death among hospitalized patients infected with the 2009 H1N1 virus,²⁵ seasonal influenza virus, or H5N1 virus. Decisions regarding antiviral treatment should not await laboratory confirmation, and patients presenting with progressive illness more than 48 hours after the onset of illness should be treated empirically with oseltamivir as soon as possible. Patients with progressive or severe illness who have a negative initial test result for 2009 H1N1 virus should continue to receive therapy unless an alternative diagnosis is established.

In uncomplicated illness, the early use of oseltamivir is usually associated with prompt clearance of infectious 2009 H1N1 virus from the upper respiratory tract.⁵³ However, infectious virus has commonly been detected after the resolution of fever and has sometimes been detected after the completion of therapy,³⁰ and viral RNA of uncertain clinical significance may be detectable for up to 12 days after the onset of illness.⁷⁴ In one study, the independent risk factors for prolonged viral RNA detection were an age of less than 14 years, male sex, and an interval of more than 48 hours between the onset of illness and the start of oseltamivir treatment.⁵³

In severely ill patients, viral RNA may be detectable in endotracheal aspirates for several weeks after the initiation of oseltamivir therapy.^45,46 An increased dose of the drug (e.g., 150 mg twice daily in adults) and particularly an increased duration of therapy (e.g., a total of 10 days) with avoidance of treatment interruptions are reasonable in patients with pneumonia or evidence of clinical progression.⁶⁹ Doses of up to 450 mg twice daily have been administered successfully in healthy adults, and controlled studies of higher-dose regimens are in progress. Higher weight-adjusted doses are also required in infants and young children to provide drug exposure similar to that in adults.^69,75 Bioavailability in critically ill patients receiving oseltamivir by nasogastric tube appears to be similar to that in patients with uncomplicated illness.⁷⁶ The tolerability and efficacy of inhaled zanamivir have not been adequately studied in patients with severe influenza. However, the failure of inhaled zanamivir therapy to clear virus in patients with pneumonia has been reported.⁶³ Some seriously ill patients treated with inhaled zanamivir have had respiratory distress, and nebulized delivery of extemporaneously prepared solutions of zanamivir powder with its lactose carrier has been associated with lethal ventilator dysfunction.⁷⁷

Oseltamivir Resistance

A His275Tyr mutation in viral neuraminidase confers high-level resistance to oseltamivir but not to zanamivir.^3,78 Most oseltamivir-resistant 2009 H1N1 viruses have been sporadic isolates from treated patients, particularly those with immunosuppression who received prolonged oseltamivir therapy^63,64 or those in whom postexposure oseltamivir chemoprophylaxis failed.⁷⁸ However, oseltamivir-resistant isolates have been found in patients without known exposure to oseltamivir and in limited clusters of cases associated with person-to-person transmission in otherwise healthy patients and those with immunosuppression.^78,79 Although in most cases oseltamivir-resistant variants have caused mild, self-limited illness, they have been associated with pneumonia in children and with severe, sometimes fatal illness in patients with immunosuppression.^64,78,80

Intravenous Neuraminidase Inhibitors

Intravenous administration of zanamivir or peramivir provides rapid drug delivery at high levels (Table 5 in the Supplementary Appendix). The efficacy of intravenous peramivir appeared to be similar to that of oseltamivir in one study of adults hospitalized with seasonal influenza,⁸¹ but peramivir is less active by a factor of at least 80 for oseltamivir-resistant viruses carrying the His275Tyr mutation than for oseltamivir-susceptible viruses. Intravenous zanamivir (if available) is the preferred option for hospitalized patients with suspected or documented oseltamivir-resistant 2009 H1N1 virus infection.^63,64,80 Both drugs are available on a compassionate-use basis for treating seriously ill patients, and peramivir was recently authorized for emergency use in hospitalized patients in the United States⁸¹ and licensed for use in Japan.

General principles of clinical management and prevention are summarized in WHO⁵⁸ and country-specific guidelines and are reviewed in the Supplementary Appendix.

Future Directions

A large amount of information about the natural history and clinical management of 2009 H1N1 virus infection has been obtained in a remarkably short period of time, but considerable gaps remain. The uncertain evolution of this virus among humans and potentially other species highlights the need for continued virologic surveillance for antigenic changes, viral reassortment, antiviral resistance, and altered virulence. Improvements in the global capacity for detection of influenza viruses by molecular analysis, such as RT-PCR assay, and by viral isolation are needed. A simple, inexpensive, highly accurate rapid influenza diagnostic test that is easily deployable worldwide has yet to be developed. The burden and character of disease in low-resource settings are still incompletely understood,⁸² especially with respect to disadvantaged populations, including marginalized, refugee, and aboriginal populations. Poverty, homelessness, illiteracy, recent immigration, language barriers, and cultural factors may impede access to care, with the potential for more serious outcomes of influenza. Thus, public health efforts reduce risk factors and to identify at-risk populations for the purpose of providing immunization and early care, including the use of antiviral drugs, should focus on social as well as clinical factors. Both experience with previous pandemics and recent modeling efforts indicate that the age bias observed for outbreaks of 2009 H1N1 virus infection may shift in coming months toward older persons, with implications for the allocation of public health resources.⁸³

Major gaps exist in our understanding of viral transmission, pathogenesis of disease, genetic and other host factors related to susceptibility^84,85 or disease severity, and optimal management of severe illness. The development of new antiviral regimens with improved effectiveness, combinations with targeted adjunctive therapies (i.e., immunodulators and neutralizing antibodies or immunotherapy), and improved management of influenza-associated ARDS are priorities, along with better prevention, recognition, and treatment of invasive bacterial coinfections. Available findings highlight the importance of early use of antiviral drugs and antibiotics in the treatment of serious cases and of the potential value of influenza-specific and pneumococcal vaccines for prevention. Both the gaps in knowledge and the experience to date underline the urgent need for better international collaboration in clinical research, particularly in the case of diseases with pandemic potential, for which rapid detection, investigation, and characterization of clinical syndromes are prerequisites for improved mitigation of their public health consequences.

Dr. Kumar reports receiving grant support (to the University of Manitoba) from Roche for studies of oseltamivir; and Dr. Nicholson, receiving travel expenses and lecture and consulting fees from Baxter, Novartis, and GlaxoSmithKline. No other potential conflict of interest relevant to this article was reported.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

The opinions expressed in this article are those of the members of the Writing Committee and do not necessarily reflect those of the institutions or organizations with which they are affiliated.

We thank Rebecca Harris of the WHO, Geneva, for her assistance in the preparation of the manuscript and our colleagues who shared unpublished information during the WHO Consultation on Clinical Aspects of Pandemic (H1N1) 2009 Influenza, October 14–16, 2009, in Washington, D.C., and subsequently.

^* The members of the Writing Committee of the World Health Organization (WHO) Consultation on Clinical Aspects of Pandemic (H1N1) 2009 Influenza, who are listed in the Appendix, assume responsibility for the content of the article.

Address reprint requests to Dr. Frederick G. Hayden at P.O. Box 800473, University of Virginia Health System, Charlottesville, VA 22908, or at fgh@virginia.edu

.

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Appendix

The members of the Writing Committee are as follows: Edgar Bautista, M.D., National Institute of Respiratory Diseases, Mexico City; Tawee Chotpitayasunondh, M.D., Queen Sirikit National Institute of Child Health, Bangkok, Thailand; Zhancheng Gao, M.D., Ph.D., Peking University People’s Hospital, Beijing; Scott A. Harper, M.D., M.P.H., Michael Shaw, Ph.D., Timothy M. Uyeki, M.D., M.P.H., M.P.P. (coeditor), and Sherif R. Zaki, M.D., Ph.D., Centers for Disease Control and Prevention, Atlanta; Frederick G. Hayden, M.D. (editor), University of Virginia, Charlottesville, and Wellcome Trust, London; David S. Hui, M.D., Chinese University of Hong Kong, Hong Kong; Joel D. Kettner, M.D., University of Manitoba and Manitoba Health, and Anand Kumar, M.D., University of Manitoba — both in Winnipeg, Canada; Matthew Lim, M.D., Nahoko Shindo, M.D., Ph.D., and Charles Penn, Ph.D., World Health Organization, Geneva; and Karl G. Nicholson, M.D., University of Leicester, Leicester, United Kingdom.

Fortunately, the prospects for developing an effective vaccine to prevent infection with the current H1N1 virus are excellent, and the world’s pharmaceutical companies are working diligently at this task. In contemplating equal access to such a vaccine, it is important to consider three key issues: manufacturing capacity, cost, and delivery.

Only a few countries in the world have plants for manufacturing influenza vaccine, and three companies — GlaxoSmithKline, Sanofi-Aventis, and Novartis — account for most of the world’s manufacturing capacity. The number of doses of vaccine against H1N1 influenza that could be produced with the existing capacity is very large, but the sobering truth is that even if production were switched over completely from seasonal influenza vaccine to pandemic influenza vaccine, there would not be nearly enough for everyone in the world. The size of the gap in potential supply depends greatly on the dose that is required, and it may be possible to reduce the necessary dose by as much as 75% with the use of an adjuvant. The challenging problem is that much, if not most, of the manufacturing capacity is already spoken for through purchasing contracts held by many of the world’s wealthy countries.

The second issue is cost. Despite the enormous technological investment required to create a vaccine, the traditional cost of seasonal influenza vaccines even in wealthy countries is quite low. For the pandemic H1N1 influenza vaccine, the major manufacturers have indicated a willingness to offer tiered pricing, with affordable prices for poor countries. Going even further, Sanofi-Aventis has committed to donating 100 million doses of its vaccine to a stockpile for poor countries, and GlaxoSmithKline has committed to donating 50 million doses. Nevertheless, financial commitments from wealthy countries will be needed to help poorer countries purchase vaccines — cost should not be a barrier to access.

Finally, the scope of access to vaccines will in part be determined by the infrastructure required to deliver them to all citizens in mass campaigns. Ironically, poor countries may have an advantage on this front, since many have recent experience with mass campaigns involving vaccines against polio, measles, and hepatitis B; delivery may therefore be less of a challenge for them, provided that the vaccines reach them in a timely fashion. By contrast, in many wealthier countries, such campaigns have not been undertaken for some time. Getting the vaccine to large numbers of young adults, in particular, may be a formidable task for which preparations must surely be made as soon as possible.

Our limited capacity for producing potentially lifesaving vaccines presents a pressing moral challenge. I believe wholeheartedly that all lives have equal value (this is the basic principle motivating the Bill and Melinda Gates Foundation, where I work), and I believe that every stakeholder has a responsibility to ensure that the pandemic does not take a 1918-like toll on the world. We have therefore worked with partner stakeholders to develop a proposed set of principles to guide the global allocation of pandemic vaccine (see Principles to Guide Global Allocation of Pandemic Vaccine).

Rich countries have a responsibility to stand in line and receive their vaccine allotments alongside poor countries, even if they have paid for their vaccine before others could do so. It would be inexcusable to force poor countries to wait until the rich have been served under their existing contracts with vaccine manufacturers. Moreover, rich countries must also consider how they can provide contributions to offset the cost of vaccines for countries that cannot afford to pay for them. Countries that are home to influenza-vaccine manufacturing plants have a special responsibility to avoid nationalizing those facilities in an effort to reserve their output for their own citizens before others. And all countries must prepare now for the rapid delivery of the vaccines as soon as they become available.

Manufacturers have a responsibility to apply their full capabilities to creating the greatest possible quantity of vaccine doses. Despite contractual obligations to supply many wealthy countries with their vaccines, manufacturers must resist the temptation to commit all their capacity to those who can pay the most. This is not a time to adhere to the “first come, first served” model of business, since we may be facing a health crisis of global proportions in which all people and countries are equally at risk. To ensure fairness, full adherence to a tiered pricing scheme in which the cost to the purchaser is proportionate to its ability to pay is essential. The generous donations made by Sanofi-Aventis and GlaxoSmithKline set an example that all manufacturers should emulate. In return for their responsible actions, it would be reasonable for manufacturers to be indemnified against liability from potential adverse reactions to their vaccines.

Regulatory agencies have an important responsibility in this impending crisis because they stand between the manufacturers of pandemic influenza vaccines and the people who will benefit from them. It is critically important that regulators apply their usual rigorous standards in approving the new vaccines — but also that they do so in a timely fashion. A special task facing them is the rapid review and consideration of the safety and efficacy of adjuvants, whose use could greatly reduce the required dose of vaccine and thereby expand the number of doses that could be manufactured.

The WHO has provided strong leadership as the world has contemplated the prospect of an influenza pandemic. We are counting on the organization to guide us, wisely and fairly, through the complex challenges that lie ahead.

The prospect of a worsening global influenza pandemic is real and will not go away anytime soon. I cannot imagine standing by and watching if, at the time of crisis, the rich live and the poor die. It will take collective commitment and action by all of us to prevent this from happening.

Principles to Guide Global Allocation of Pandemic Vaccine.

1. The global community should take steps to protect all populations, including those without resources to protect themselves.

2. Vaccination should be considered in the context of comprehensive pandemic preparedness and response efforts in all nations.

3. Developed countries and vaccine manufacturers should urgently agree upon a mechanism to ensure access to vaccine by developing countries.

4. Influenza vaccine manufacturers should identify strategies such as tiered pricing and donations to make pandemic vaccine more accessible to developing nations.

5. Pandemic vaccines allocated to developing nations should become available in the same time frame as vaccines for developed nations.

6. The global community should obtain data to help establish a consensus on the safety and efficacy of adjuvants, and efforts should be made to ensure the fullest use of this and other dose-sparing strategies.

7. All countries obtaining pandemic vaccine should ensure that mechanisms are in place to provide the vaccine to their populations, to ensure that this scarce resource is not wasted, and donors should be prepared to provide resources and technical assistance to help countries bolster these mechanisms.

8. The World Health Organization is uniquely positioned to lead the global response to a pandemic virus and should support governments and industry in their efforts to implement these principles.

* From the Pneumonia and Flu Web site of the Bill and Melinda Gates Foundation (www.gatesfoundation.org/topics/Pages/pneumonia-flu.aspx).

Dr. Yamada reports holding equity in GlaxoSmithKline. No other potential conflict of interest relevant to this article was reported.

Source Information

From the Global Health Program, Bill and Melinda Gates Foundation, Seattle.

This article (10.1056/NEJMp0906972) was published on August 12, 2009, at NEJM.org.