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Critically ill patients have considerable oxidative stress. Glutamine and antioxidant supplementation may offer therapeutic benefit, although current data are conflicting.
In this blinded 2-by-2 factorial trial, we randomly assigned 1223 critically ill adults in 40 intensive care units (ICUs) in Canada, the United States, and Europe who had multiorgan failure and were receiving mechanical ventilation to receive supplements of glutamine, antioxidants, both, or placebo. Supplements were started within 24 hours after admission to the ICU and were provided both intravenously and enterally. The primary outcome was 28-day mortality. Because of the interim-analysis plan, a P value of less than 0.044 at the final analysis was considered to indicate statistical significance.
There was a trend toward increased mortality at 28 days among patients who received glutamine as compared with those who did not receive glutamine (32.4% vs. 27.2%; adjusted odds ratio, 1.28; 95% confidence interval [CI], 1.00 to 1.64; P=0.05). In-hospital mortality and mortality at 6 months were significantly higher among those who received glutamine than among those who did not. Glutamine had no effect on rates of organ failure or infectious complications. Antioxidants had no effect on 28-day mortality (30.8%, vs. 28.8% with no antioxidants; adjusted odds ratio, 1.09; 95% CI, 0.86 to 1.40; P=0.48) or any other secondary end point. There were no differences among the groups with respect to serious adverse events (P=0.83).
Early provision of glutamine or antioxidants did not improve clinical outcomes, and glutamine was associated with an increase in mortality among critically ill patients with multiorgan failure. (Funded by the Canadian Institutes of Health Research; ClinicalTrials.gov number, NCT00133978.) Sporadic human infections with avian influenza A viruses, which usually occur after recent exposure to poultry, have caused a wide spectrum of illness, ranging from conjunctivitis and upper respiratory tract disease to pneumonia and multiorgan failure. Low pathogenic avian influenza A (H7N2, H7N3, H9N2, or H10N7)1-4 virus infections have caused lower respiratory tract illness that is mild (conjunctivitis or uncomplicated influenza-like illness) to moderate in severity. Most human infections with highly pathogenic avian influenza (HPAI) A (H7) viruses have resulted in conjunctivitis (H7N3) or uncomplicated influenza illness, but one case of fatal acute respiratory distress syndrome (ARDS) was reported in a patient with H7N7 virus infection during an outbreak in the Netherlands.1,5In contrast, the cumulative case fatality rate since 2003 for reported cases of HPAI H5N1 virus infection is approximately 60%. 6-8 The transmission of H7 viruses to mammals has been reported only rarely9 in Asia. Human infections with N9 subtype viruses had not been documented anywhere in the world. In February and March 2013, three patients were hospitalized with severe lower respiratory tract disease of unknown cause. We report the identification of a novel avian-origin reassortant influenza A (H7N9) virus associated with these infections.
Surveillance, Reporting, and Data Collection
and the Anhui CDC. available with the full text of this article at NEJM. according to the manufacturer's recommendations. Phylogenetic trees were constructed by means of the neighbor-joining method with the use of MEGA software. RNA Extraction and Real-Time RT-PCR RNA was extracted from throat-swab samples with the use of the QIAamp Viral RNA Mini Kit (Qiagen). Isolation of the Virus Throat-swab specimens obtained from all three patients were maintained in a viral-transport medium. history of seasonal influenza vaccination. H5N1. including demographic characteristics. chest radiographic findings. We performed multiple sequence alignments with the ClustalW program using MEGA software. clinical complications. A confirmed case of human infection with avian-origin influenza A (H7N9) virus was defined as evidence of pneumonia with H7N9 viral RNA or isolation of H7N9 virus from respiratory specimens at the CNIC. 2013. clinical signs and symptoms. or other animals. recent visits to a live animal market. the Shanghai Centers for Disease Control and Prevention (CDC). to estimate the viral gene relationship with selected influenza A virus strains obtained from GenBank. with the use of Qiagen OneStep RT-PCR Kit. or B). Genome Sequencing and Phylogenetic Analysis A total of 198 primer sets were used to amplify the full genome for sequencing. We performed the sequencing using an ABI 3730xl automatic DNA analyzer (Life Technologies) and the ABI BigDye Terminator v3. Specific real-time reverse-transcriptase–polymerase-chainreaction (RT-PCR) assays for seasonal influenza viruses (H1. underlying medical conditions.org).Throat-swab specimens obtained from three adult Chinese patients (two from Shanghai City and one from Anhui Province) who were hospitalized with severe bilateral pneumonia.05. H3. 2013 (accession numbers are provided in Table S1 in theSupplementary Appendix. The specimens were propagated in the allantoic sac and amniotic cavity of 9-to-11-day-old specific pathogenfree embryonated chicken eggs for 48 to 72 hours at 35°C. the samples were sent to the Chinese National Influenza Center (CNIC) on March 25. antiviral treatment. Full genome sequences of the viruses from these patients were deposited in the Global Initiative on Sharing Avian Influenza Data (GISAID) database on March 29. High fever and dyspnea developed 1 . RESULTS Patients Patient 1 was an 87-year-old man with chronic obstructive pulmonary disease (COPD) and hypertension who reported a cough and sputum production at the onset of illness. recent exposures to swine. leukopenia. version 5. and outcomes. including diagnostic testing for influenza and other respiratory viruses. and novel coronavirus were used. and lymphocytopenia were sent to Shanghai Public Health Clinical Center. After preliminary detection of respiratory pathogens. version 5. Real-time RT-PCR assays with selfdesigned specific primer and probe sets for detecting H1 to H16 and N1 to N9 subtypes were then performed to verify the viral subtypes.1 cycle sequencing kit (Life Technologies). severe acute respiratory syndrome coronavirus (SARS-CoV). PCR products were purified from agarose gel with the use of the QIAquick Gel Extraction Kit (Qiagen). poultry. A standardized surveillance reporting form was used to collect epidemiologic and clinical data. according to the manufacturer's instructions. respectively. laboratory testing results.05.
respectively. Patient 3 was a 35-year-old woman who lived in Anhui Province. hepatitis B virus infection. Epidemiologic. Patient 2 was a 27-year-old man with a history of hepatitis B virus infection with positive hepatitis B surface antigen who presented to the hospital with high fever and cough. H5N1. The demographic and epidemiologic characteristics of the three patients are summarized in Table 1TABLE 1 Demographic. subtype ZJ12). She had a history of depression. She had visited a chicken market 1 week before the onset of symptoms. Patient 3 also had high fever and cough at the onset of the illness. He had no known history of exposure to live birds during the 2 weeks before the onset of symptoms. the HA gene from the H7N9 viruses in our three patients was highly divergent from that in the KO14 virus.. This patient was a butcher who worked at a market where there were transactions involving live birds. The gene encoding hemagglutinin (HA) shared the highest identity with A/duck/Zhejiang/12/2011 (H7N3. He sold pork but had not butchered bird meat before the onset of illness. and 3. viral isolation. H3 or B).week after the onset of illness. and Clinical Outcomes of Three Patients Infected with Avian-Origin Influenza A (H7N9) Virus. by means of real-time RT-PCR.. All six internal genes shared the highest similarity with A/brambling/Beijing/16/2012-like viruses (H9N2) (Figure 1). Phylogenetic analysis of all genes of the isolates showed that each gene was of avian origin (Figure 1FIGURE 1 Phylogenetic Trees of Genes of H7N9 Influenza A Viruses. and were admitted to the Fifth People's Hospital. and Virologic Characteristics and Complications. SARS-CoV. The gene encoding neuraminidase (NA) protein was most closely related to A/wild bird/Korea/A14/2011 (H7N9. to be positive for H7N9 and negative for seasonal influenza viruses (H1. and full genome sequencing. Original clinical samples obtained from all three patients were confirmed. Treatment. Both Patient 1 and Patient 2 lived in Min-hang District. Complete sequences of the three H7N9 influenza viruses showed that they were 97. and A/Anhui/1/2013 (H7N9) were isolated from Patients 1.7 to 100% identical in all eight gene segments (see Table S1 in theSupplementary Appendix). however. Determination of Causative Pathogens We confirmed. and Figure S1 in theSupplementary Appendix). subtype KO14). Shanghai. and obesity. Influenza viruses A/Shanghai/1/2013 (H7N9). A/Shanghai/2/2013 (H7N9). by means of real-time RT-PCR. that all three patients were infected with a novel avian-origin influenza A (H7N9) virus. Phylogenetic results indicated that it was a triple reassortant H7N9 virus (Figure . 2. and HCoV-Erasmus Medical Center (EMC).
Clinical Features and Outcomes of the Patients The clinical characteristics of the patients are shown in Table S3 in theSupplementary Appendix. such as Q226L in HA and R292K in NA. and intravenous immunoglobulin were administered in all three patients. creatine kinase. diagnostic tests for the novel reassortant H7N9 viruses have been developed. the HA cleavage site possesses only a single amino acid R (arginine). To date. On the basis of these data. The M2 protein contained the S31N substitution. All the patients had ARDS. Substitution Q226L at the 210-loop in the HA gene was found in both the A/Anhui/1/2013 and A/Shanghai/2/2013 viruses but not in the A/Shanghai/1/2013 virus (Table 2TABLE 2 Molecular Analysis of Three of the 2013 H7N9 Viruses.int/influenza/gisrs_laboratory/a_h7n9/en/). Elevated levels of aspartate aminotransferase.). Carbapenem-resistant Acinetobacter baumannii was cultured from lower respiratory tract specimens obtained from two of the patients after the initiation of mechanical ventilation.2FIGURE 2 Hypothetical Host and Lineage Origins of the Gene Segments of the Novel Reassortant Human Influenza A (H7N9) Viruses. The white-cell count was normal or slightly decreased. The specific sequences are available on the website of the World Health Organization (www. Antiviral therapy was initiated 6 to 7 days after the onset of illness (Table 1). which differed from those in A/Anhui/1/2013 and A/Shanghai/2/2013. Fever and cough were the most common symptoms. A T160A mutation was identified at the 150-loop (H3 numbering) in the HA gene of all three viruses. In all three viruses. The amino acids in A/Shanghai/1/2013. glucocorticoids.). He died from refractory hypoxemia 13 days after the onset of illness.). Other mutations — 89V and E627K in PB2 and 42S in NS1 — were also identified (Table 2). Sequencing analysis indicates that all five viruses are highly similar to both A/Shanghai/2/2013 and A/Anhui/1/2013. are shown in Table S2 in theSupplementary Appendix. Patient 3 had septic shock and acute renal damage. Some variability is observed. indicating resistance to amantadine. Several complications of the illness were observed. indicating low pathogenic effects in poultry. Bilateral ground-glass opacities and consolidation were detected on chest radiography (Figure 3FIGURE 3 Chest Radiographs. and lactate dehydrogenase were observed in all the patients. five additional H7N9 viruses have been isolated from five patients. Patient 1 declined admission to the intensive care unit (ICU) and intubation.who. Five amino acids were deleted in the stalk region of NA residue 69 to 73. Patient 2 was admitted to the ICU and intubated 48 hours after . Combination antibiotic therapy.
17 Q226L in the HA protein. Currently.19 Moreover. the phylogenetic trees showed that A/Shanghai/1/2013 is phylogenetically distinct from A/Anhui/1/2013 and A/Shanghai/2/2013 across all gene segments.10.5 All three cases of H7N9 infection reported here were virulent. DISCUSSION We have identified a novel reassortant influenza A (H7N9) virus that is associated with severe human infection. Currently.5. Human H7 influenza infections are generally mild. which is normally more common in pediatric patients with influenza.admission owing to progressive dyspnea.21 and it has been suggested that this deletion may be associated with adaptation and transmission in domestic poultry. Thus. and two had a history of direct contact with poultry. and extracorporeal membrane oxygenation was initiated. The HA gene was similar to that of an H7N3 virus (ZJ12) from a nearby region (Zhejiang Province) in China. Encephalopathy. causing conjunctivitis or modest respiratory symptoms. He died from refractory hypoxemia after 4 days in the ICU. whereas most avian viruses bind to α2. In addition. as well as H5 subtypes. and ultimately resulted in death.14. swine. ARDS and septic shock developed in Patient 3 on day 6 after the onset of illness. She died on April 9. However. All the patients had preexisting medical conditions. there are no data to suggest that this reassortment occurred in a mammalian host. Two patients presented with rhabdomyolysis. making it difficult to resolve this question. The effects of these mutations require further study. the lack of a glycosylation site on the 150loop might decrease the affinity to α-2.1.15 Human influenza viruses preferentially bind to α2. which suggests that there have been at least two introductions into humans (Figure 1. The affinity of the influenza virus to different sialyl-sugar structures is an important determinant of range and pathogenicity in the viral host. which was first reported in H7 field viruses. and the similarity of the human viruses to avian viruses may be stronger support for direct avian transmission of this virus. 22. A similar deletion in the H5N1 avian virus has been shown to be responsible for the change in viral tropism to the respiratory tract20 or to enhance viral replication. Although human infections with avian-origin H7 avian influenza viruses have been observed before.3 sialyl glycan. as reported previously. and Figure S1 in the Supplementary Appendix).13 was observed in two patients.16. and humans is limited in China and nearby countries. A deletion of five amino acids in the viral NA stalk has been observed in the novel reassortant H7N9 viruses. only 25 H7N9 viruses are available in GenBank. and Figure S1 in the Supplementary Appendix).3 avian-like receptors.6 human-like receptors. but only the NA gene was closely related to that from another H7N9 virus (KO14).6 sialyl glycan. it has been reported that H7N9 viruses similar to those isolated from the three patients described here have been . which has rarely been reported in patients infected with H1N1 or H5N112 influenza viruses. although a fatal case was reported before this H7N9 outbreak.2. the human H7N9 viruses are the product of reassortment of viruses that are of avian-origin only. All the internal gene segments were closely related to those from avian H9N2 viruses. She was admitted to the ICU.11 infection of humans with an N9 subtype influenza virus has not been reported previously.18. with the patients' conditions deteriorating rapidly with the development of severe pneumonia and ARDS.23Since April 4. A laboratory-produced Q226L mutation at the 210-loop of HA has been shown to change the receptor binding of avian origin to a human-type receptor binding and might increase the ability of the virus to be transmitted by air. was expected to bind strongly to α-2. influenza surveillance of birds. The H7N9 viruses we identified in the three patients were of avian origin. particularly a virus isolated from a brambling in Beijing (BJ16) (Figure 1.
The difference between the two Shanghai viruses and the similarity between the Shanghai/2 and Anhui/1 viruses argue against human-to-human transmission in these cases. and no close contacts of the patients have tested positive for these viruses. METHODS Case Definitions The case definitions of suspected and confirmed human infection with H7N9 virus were based on the H5N1 case definitions. we summarize the preliminary findings of case investigations and follow-up monitoring of close contacts of persons with confirmed cases of H7N9 virus infection who have been identified to date. This is an ongoing investigation. as recommended by the World Health Organization (WHO) in 2006 (Section S1 in the Supplementary Appendix. indicating that the novel H7N9 viruses might currently be circulating in poultry. and increased surveillance and analyses of these viruses are needed. Moreover. We are concerned by the sudden emergence of these infections and the potential threat to the human population. therefore. respiratory failure. and fatal outcomes. but the pathogenesis in humans remains unknown. However. An understanding of the source and mode of transmission of these infections.2 The laboratory test assays for H7N9 virus that we performed have been described previously (Section S2 in the Supplementary Appendix). Other possible virulence molecular markers are shown in Table 2. and it is not known whether the current candidate H7 vaccine viruses. of which three are North American viruses and the other three are avian viruses from 2000 in the Netherlands. and appropriate counter measures are urgently required.3 Identification of Cases . The potential virulence mutations are described on the basis of previous studies in animals. characterized by high fever and severe respiratory symptoms. the E627K substitution in the PB2 gene has been associated with increased virulence in mice and was reported to be associated with improved replication of avian influenza viruses in mammals.org). limited human-to-human transmission was observed in the H7 outbreak in the Netherlands in 200310. may pose a serious human health risk. Heightened protective measures should be taken when dealing with these viruses.isolated from pigeons and chickens. In this report.25 A combination of these substitutions may contribute to the human infection and severe disease. The influenza H7N9 A/Anhui/1/2013 strain has been proposed to be one of the candidate vaccine strains since it grows to a very high titer in eggs. Currently there is no vaccine available for these novel viruses.1We analyzed available data from field investigations to characterize the descriptive epidemiology of laboratory-confirmed cases of avian influenza A (H7N9) virus infection in humans reported to the Chinese Center for Disease Control and Prevention (China CDC) as of April 17. acute respiratory distress syndrome (ARDS). 2013. further surveillance. Severe avian influenza A (H7N9) infections.24. the pandemic potential of these novel avian-origin viruses should not be underestimated. may be effective. available with the full text of this article at NEJM. Supported he first identified cases of human infection with a novel influenza A (H7N9) virus occurred in eastern China during February and March 2013 and were characterized by rapidly progressive pneumonia.
and patterns of exposures to poultry or other animals such as swine and wild birds. Statistical Analysis We used descriptive statistics to summarize the epidemiologic characteristics and H7N9 testing results for persons with suspected cases of H7N9 virus infection. hospitalization. once we identified the close contacts. which were shipped to the National Influenza Center of the China CDC in Beijing for H7N9 laboratory testing. as well as environmental exposures. visits to clinical facilities. Identification and Follow-up of Close Contacts We defined close contacts of patients with confirmed H7N9 virus infection as described previously for H5N1 field investigations7 (Section S3 in the Supplementary Appendix).Suspected cases of H7N9 virus infection were identified through the Chinese surveillance system for pneumonia of unexplained origin. for those with confirmed cases.5 Persons with suspected cases of H7N9 virus infection with mild or moderate illness were identified from the Chinese sentinel surveillance system for influenza-like illness. and health care workers who provided medical care for the case patients. Data Collection It was determined by the National Health and Family Planning Commission that the collection of data from H7N9 case patients and their close contacts was part of a continuing public health investigation of an outbreak and was exempt from institutional review board assessment.6 Once each suspected case of H7N9 virus infection was identified. the local CDCs. All epidemiologic information that was collected during the field investigations. and for close contacts of those with confirmed cases. Data on demographic characteristics and exposure were collected for close contacts. Antiviral chemoprophylaxis was not provided to close contacts. including exposure history. was cross-validated. and clinical outcomes. which was established in 2004. We collected information on the dates of illness onset. Epidemiologic data were collected through interviews and field observations and were reported to the China CDC. frequency. timelines of events. enhanced surveillance was implemented for suspected cases of H7N9 virus infection among persons with mild or moderate illness. including prefecture and provincial CDCs. conducted the initial field investigations and obtained respiratory specimens. we monitored them daily for 7 days for symptoms of illness and collected throat swabs from contacts in whom symptoms developed to test for the presence of the H7N9 virus. times. The methods we used for estimating the incubation period have been described previously.8 RESULTS Epidemiologic Characteristics of Confirmed Cases . contacts. 2013. including the dates. Data were collected through a review of medical records and interviews with relatives. and identification of close contacts. since we were unable to interview any critically ill H7N9 case patients. Households and places that were known to have been visited by the case patients in the 2 weeks before the onset of illness were investigated to assess exposures to poultry and swine. Oseltamivir treatment was recommended for close contacts in whom symptoms developed (Section 3 in the Supplementary Appendix).4 Beginning on April 3. Paired serum samples were obtained from patients with suspected H7N9 virus infection who did not have respiratory specimens available for H7N9 serologic testing. A field investigation team comprising staff members of the China CDC and or local CDC conducted field investigations of the confirmed cases of H7N9 virus infection. which has been described previously. Investigators interviewed the relatives of each patient with a confirmed case of H7N9 virus infection to determine exposure histories during the 2 weeks before the onset of the illness.
Among 82 confirmed cases of H7N9 virus infection. 4 with clinically mild cases had been discharged from the hospital. 2 to 89). and 60 patients with confirmed cases and 1 with a suspected case remained critically ill. Viral culture of 73 respiratory specimens that were confirmed as positive by means of real-time reverse-transcriptase–polymerase-chain-reaction (RTPCR) assays and diagnostic testing of specimens from suspected cases are ongoing. Most confirmed cases occurred in males (73%). and 54 of 71 patients with available data (76%) had underlying medical conditions (Table 1TABLE 1 Epidemiologic Characteristics of 82 Patients with Confirmed H7N9 Virus Infection in China. 2013. . 2013. and Figure 2FIGURE 2 Geographic Distribution of 82 Confirmed and 2 Suspected Cases of H7N9 Virus Infection in China. 2 (2%) by means of serologic testing. Among 46 of 54 case patients with sufficient data for a more specific classification of underlying conditions.2%) were confirmed to be infected with the H7N9 virus. and 1 transported live poultry. isolation precautions were instituted for 33 (65%) in an intensive care unit (ICU) because of severe lower respiratory tract disease. both of whom had clinically mild upper respiratory illness (see Figure S1 in the Supplementary Appendixfor the age distribution). 2013. 7 (9%) were confirmed by means of virus isolation. as of April 17. Among the 51 patients with confirmed cases for whom data were available. Henan (2 confirmed cases) and Beijing (1 confirmed case). Jiangsu (20 confirmed cases and 1 suspected case). Of 5551 respiratory specimens obtained from outpatients with an influenza-like illness through the sentinel surveillance system for influenza-like illness. and 81 patients (12. and 2 (2%) were in children younger than 5 years of age. respiratory specimens from 664 hospitalized patients with pneumonia of unexplained origin were tested. 84% of the case patients were urban residents. cases were identified in the following provinces: Shanghai (31 confirmed cases and 1 suspected case). a total of 17 patients with confirmed H7N9 virus infection (21%) and 1 patient with suspected infection had died of acute respiratory distress syndrome (ARDS) or multiorgan failure.). As of April 17. and 1 pediatric patient had not been admitted to the hospital. 40 (87%) were considered to be at increased risk for influenza complications owing to age (<5 years or ≥65 years) or prevalence of certain underlying medical conditions. According to Province in China. As of April 17. Anhui (3 confirmed cases).9 Four of the patients with confirmed cases (5%) worked as poultry workers: 3 slaughtered poultry at a live poultry market. and 73 (89%) by means of nucleic acid detection. 1 (0.02%) tested positive for the H7N9 virus.). The median age of patients with confirmed H7N9 virus infection was 63 years (range. Zhejiang (25 confirmed cases). 38 cases (46%) occurred in persons 65 years of age or older.From March 25 through April 17. a total of 82 laboratory-confirmed cases of H7N9 virus infection and 2 suspected cases had been identified (Figure 1FIGURE 1 Date of Onset of Illness in First 82 Patients with Confirmed H7N9 Virus Infection. A total of 81 of 82 patients with confirmed H7N9 virus infection (99%) were hospitalized.
and prepared. 1 to 10) (Table S1 in the Supplementary Appendix). 59 (77%) reported a history of recent exposure to animals. close. the exposures occurred either while they were working at or visiting a live animal market. including eating together.Data on recent exposure to animals were available for 77 of the 82 patients with confirmed H7N9 virus infection.e. his brother (confirmed case 1) and his father (confirmed case 2) had prolonged. providing care. and Section S4 in the Supplementary Appendix). geese. none brought live poultry into their home. Family Clusters As of April 17. Diarrhea developed in the father. and dogs. cooked. including eating together. Information on a history of exposure to live animals is unclear for 5 patients with confirmed H7N9 virus infection. his daughter (confirmed case) had prolonged. quail. had not brought live poultry into the home or visited a live poultry market or had any direct or indirect contact with poultry or pigs). The estimated median incubation period in 23 patients with confirmed cases for whom detailed data on animal and environmental exposures was available was 6 days (range. three family clusters had been identified in two provinces. After the father (suspected case) became ill. Another family cluster was identified that included one person with confirmed H7N9 virus infection and one person with a suspected case (Figure 2. and the index patient's brother (confirmed case 1) lived with his wife nearby. purchased a chicken. Detailed exposure and timeline information are available for two family clusters that were identified early (Figure 3FIGURE 3 Timeline of Pertinent Exposures and Dates of Illness Onset in Two Family Clusters of Cases of H7N9 Virus Infection in China. cats. and Section S4 in the Supplementary Appendix).. and accompanying him to seek medical care before his hospitalization (Section S4 in the Supplementary Appendix). observed the slaughtering process. The first family cluster comprised two persons with confirmed H7N9 virus infection and one with a suspected infection. Of these. 12 (20%) to ducks. She also provided unprotected bedside hospital care for her father during the period from March 11 through March 15. unprotected contact with him. The index case patient and his father (confirmed case 2) lived in the same house. since the investigations are still ongoing. After the index case patient (suspected case 1) became ill. The daughter did not raise poultry or animals at home and had not had any exposures to animals (i. and none had direct contact with sick or dead poultry. and ate the chicken within 2 weeks before the onset of his illness. (Table 1): 45 (76%) to chickens. The index case patient had visited a live poultry market. None of the three members of the cluster raised poultry or other animals. wild birds. the investigation of one cluster in Shanghai is still ongoing. The father had visited a live poultry market 7 days before the onset of his illness. and 4 (7%) to swine. pet birds. and accompanying him to seek medical care before his hospital admission. brought the freshly killed chicken home. and the daughter washed her father's diarrhea-soiled underwear on March 18 while wearing gloves. Other animals that these 59 patients reported having been exposed to included pigeons.. Medical Care Timelines . providing care. unprotected contact with him. close.
the median time from the onset of illness to the first medical visit was 1 day. To date. 0 to 7) after the onset of illness were negative for the H7N9 virus. and 17 patients died a median of 11 days after the onset of illness. the mortality is 21%. 2013. but since many of patients with confirmed H7N9 virus infection remain critically ill.10. Anhui (100). 41 (64%) received oseltamivir treatment beginning a median of 6 days after the onset of illness. All the throat swabs collected from these 19 ill contacts a median of 1 day (range.11. 134 (20%) were family member or relatives.14 Only one fatal case of H7 virus infection has been reported previously. Among the 678 close contacts of 33 patients with confirmed cases for whom demographic information was available. median age of patients with confirmed cases. Among 64 of the patients with available data on oseltamivir administration. respiratory symptoms developed during the 7-day surveillance period in 19 (1. Human infections with influenza A (H7) viruses have been reported sporadically and are usually associated with exposures to poultry. a total of 1251 of the 1689 contacts had been followed for up for 7 days.13. 422 (62%) were health care workers. as assessed by means of realtime RT-PCR. indicates that the infection affected persons in a wide age spectrum and caused severe lower respiratory tract illness. Jiangsu (448). Zhejiang (676).10-12 Previous human cases of H7 virus infection have been characterized by mild illness (conjunctivitis or uncomplicated influenza) or moderate illness (lower respiratory tract disease) that results in hospitalization. 1 patient who shared a room with a confirmed case patient. and 122 (18%) were social contacts. DISCUSSION An epidemiologic study of 82 confirmed cases of H7N9 virus infection in China among persons with illness onset during the period from February through April 17. that case occurred in an adult with a highly pathogenic avian influenza A (H7N7) virus infection. and patients were hospitalized a median of 4.5%): 2 household members. suggesting that the . 63 years) or the prevalence of certain underlying medical conditions. we suspect that the mortality may increase.5 days after the onset of illness (Table 2TABLE 2 Clinical Characteristics and Medical Care Timelines for 82 Patients with Confirmed H7N9 Virus Infection in China. and Beijing (2). among these close contacts (not including those in the family clusters). ARDS developed during the course of hospitalization in 19 of 40 patients with confirmed H7N9 virus infection for whom data were available (48%) after a median of 8 days. and 15 health care workers (Section S5 in the Supplementary Appendix). As of April 17. patients with confirmed H7N9 virus infection were epidemiologically unrelated and were identified in six areas of China. Close Contacts As of April 17.15 Many of the confirmed H7N9 case patients had critical and fatal illness.). Most of the patients with confirmed H7N9 virus infection were considered to be at increased risk for complications from influenza owing to age (<5 years or ≥65 years. Henan (28). 1 medical intern. data were available for 1689 close contacts of the 82 patients with confirmed cases in Shanghai (435 contacts). Except for one family cluster with 2 confirmed cases.Among the 81 patients with confirmed H7N9 virus infection for whom data were available (99% of the 82 patients with confirmed cases).
7. contact. Since this H7N9 virus appears to have emerged recently to infect humans. Although the source of the H7N9 virus infection in patients with confirmed cases who had exposure to animals cannot be verified without extensive H7N9 testing of animals. including during visits to live animal markets. because specimens were not available for H7N9 testing from patients with suspected cases. implementation of control measures at live poultry markets. and droplet precautions by health care personnel in hospitals. such as a ban on the selling of live poultry in market stalls or even market closure.19 However. expanded testing of outpatients with influenza-like illness has identified some mild cases of illness with H7N9 virus infection. and market disinfection — measures that have been taken to control the spread of H5N1 virus — may be considered in order to help control potential zoonotic transmission of H7N9 virus. active monitoring of close contacts. and since April 3. Until the source of H7N9 virus infection is known.21 Paired serum samples are being obtained during the acute and convalescent stages of illness from contacts of case patients for further assessment of the potential for secondary human-to-human H7N9 virus transmission. and persons of any age may be susceptible to infection. national guidelines recommend that antiviral treatment with oseltamivir should be administered as soon as possible in patients with suspected or confirmed cases of H7N9 virus infection. where avian influenza A viruses can be maintained and amplified. population immunity is expected to be low. additional studies are needed. has been identified as a risk factor for H5N1 virus infection in Hong Kong 17 and urban China. visiting a live poultry market. the actual risk is currently unknown. but 77% of cases with available data occurred in patients who had exposure to live animals such as poultry or swine.18. Follow-up prospective investigations of close contacts of patients with confirmed H7N9 virus infection have not conclusively established human-to-human H7N9 transmission of the virus from one confirmed case to another to date. No animal outbreaks were identified in the areas with confirmed H7N9 cases. such as prompt isolation of the patient. This raises the possibility of zoonotic H7N9 virus transmission from healthy-appearing swine or poultry to humans through direct or close contact or through exposure to environments that are contaminated with infected swine or poultry. .16However.H7N9 virus is more virulent in humans than are other H7 viruses.20. poultry culling. Enhanced surveillance for less severe illness with H7N9 virus infection will help to determine the clinical spectrum of the illness and the total number of cases of H7N9 symptomatic illness and to inform an understanding of the true case fatality proportion. one patient with a suspected case died before a specimen could be obtained. unprotected contact with a symptomatic patient with suspected H7N9 virus infection remains a possibility. and H7N9 testing of the other patient with a suspected case is still ongoing. in two family clusters. we suspect that it is likely to be infected poultry. prolonged. including the identification of asymptomatic infections. limited human-to-human transmission of H7N9 virus after close. In addition. and implementation of standard. and the Chinese national guidelines recommend implementing control measures. early surveillance for H7N9 cases was focused on case finding for severe lower respiratory tract illness. Similar family clusters of H5N1 cases that occurred after common poultry exposures or limited human-to-human transmission have been identified. case–control studies are needed to identify risk factors for H7N9 virus infection. However. Although the risk of humanto-human transmission of H7N9 virus appears to be low. The H7N9 case fatality proportion to date is lower than that for reported cases of H5N1 virus infection. For example.
intensity. Information on exposures is useful for estimating the incubation period after possible exposure to animals or live-animal markets and for evaluating the risk factors for H7N9 virus infection. Fourth. Third. Follow-up investigations of contacts of patients with confirmed H7N9 virus infection suggest that the risk of secondary H7N9 virus transmission. Retrospective observational studies of influenza A (H1N1)pdm09 and H5N1 virus infections suggest that early oseltamivir treatment probably has the greatest clinical benefit but that starting treatment up to 5 days after the onset of illness may still reduce the risk of critical illness and death. a novel influenza A (H7N9) virus has caused severe and fatal illness in persons in six different areas of China to date. and duration of exposures. probably owing to delayed suspicion of influenza. more time is needed to allow for a humoral immune response in serum obtained during the convalescent period and to allow time for serologic testing to be performed. complete follow-up data were not available for some of the close contacts. Patients with confirmed cases received oseltamivir antiviral treatment a median of 6 days after the onset of illness (median before April 3. is low at this time. and 60 case patients remain hospitalized. Early clinical suspicion of H7N9 virus infection and early administration of oseltamivir may help to reduce the severity of the disease. the corresponding median times among patients with H5N1 virus infection were 7 days and 7. Some clinically mild cases have been identified since the surveillance was widened. limited nonsustained human-to-human H7N9 virus transmission could not be ruled out and may have occurred among blood-related family members. However. and the median time from the onset of illness to the development of ARDS among the 19 case patients with ARDS (out of 40 patients for whom data on ARDS were available) was 8 days. 2013. This will help ensure standard data collection. In summary. 9 days).22The median duration from the onset of illness to death among the 17 persons with confirmed cases who died was 11 days. Clinical outcomes in the 82 patients with confirmed H7N9 virus infection are reported as of April 17. frequency.The median time from the onset of illness to hospitalization among the 81 of 82 patients with confirmed H7N9 virus infection for whom data on hospitalization were available was 4. in two family clusters that include persons with confirmed H7N9 virus infection and persons with epidemiologically linked suspected cases. the China CDC has issued a guideline and protocol for field investigations of case patients and close contacts and since April 1 has provided training for personnel at all 31 provincial CDCs. As of April 17. specimens were not available for H7N9 testing from some patients with suspected cases. Our study had several limitations. we did not collect detailed information from all patients on exposures.23-27 Preliminary data suggest that the H7N9 viruses isolated from humans and analyzed to date are resistant to adamantane antiviral agents and are susceptible to neuraminidase inhibitors. Enhanced surveillance for severe and mild human . Second. First. we did not have a standard protocol and questionnaire to collect information from all contacts of the first 82 patients with confirmed cases. and given the fact that it is early in the investigation. The initial findings suggest that H7N9 virus infection can cause critical illness and fatal disease and may affect persons in a wider age range than the H5N1 virus has in China to date (Figure S1 in the Supplementary Appendix). such as the times. Paired serum samples have not been obtained from some of the contacts. However. including to health care personnel.5 days.5 days. The initial epidemiologic findings suggest that most confirmed H7N9 cases were epidemiologically unrelated. no serologic testing results are available at this time. suggesting that there is a wide clinical spectrum of H7N9 virus infection. 2013. we may not have identified all the close contacts of case patients and were not able to conduct active follow-up of all contacts.
(Funded by the National Institutes of Health. we examined genotypespecific expression of 17q21 genes in unstimulated and HRV-stimulated peripheral-blood mononuclear cells (PBMCs). we tested five aspects of cortisol metabolism: daily levels of corticotropin and cortisol. Our aim was to determine the effects of these two factors on the risk of asthma in the Childhood Origins of Asthma (COAST) and the Copenhagen Prospective Study on Asthma in Childhood (COPSAC) birth cohorts. CONCLUSIONS Variants at the 17q21 locus were associated with asthma in children who had had HRV wheezing illnesses and with expression of two genes at this locus. although the relative increase was not associated with the 17q21 genotypes. plasma clearance of 100 mg . although the increase with exposure to HRV was not genotype-specific. and production during infusion of deuterium-labeled steroid hormones as tracers. Case–control studies to identify risk factors and continued investigations of case patients and their contacts are indicated. metabolism. METHODS In a total of 158 patients in the intensive care unit and 64 matched controls. Moreover. The expression levels of both genes increased in response to HRV stimulation. low corticotropin levels have also been reported in critically ill patients. Finally. BACKGROUND Both genetic variation at the 17q21 locus and virus-induced respiratory wheezing illnesses are associated with the development of asthma. which has been attributed to stress-induced activation of the hypothalamic–pituitary–adrenal axis. Data from investigations of potential animal and environmental sources are urgently needed to inform public health control measures.illness with H7N9 virus infection is needed to determine the clinical spectrum of the infection and the total number of symptomatic H7N9 infections. which may be due to reduced cortisol metabolism. resulting in a significant interaction effect with respect to the risk of asthma. but not with RSV wheezing illnesses.) BACKGROUND Critical illness is often accompanied by hypercortisolemia. The associations of 17q21 variants with asthma were restricted to children who had had HRV wheezing illnesses. The expression of these genes was associated with 17q21 variants in both conditions. RESULTS The 17q21 variants were associated with HRV wheezing illnesses in early life. However. METHODS We tested genotypes at the 17q21 locus for associations with asthma and with human rhinovirus (HRV) and respiratory syncytial virus (RSV) wheezing illnesses and tested for interactions between 17q21 genotypes and HRV and RSV wheezing illnesses with respect to the risk of asthma. plasma cortisol clearance. the expression levels ofORMDL3 and of GSDMB were significantly increased in HRV-stimulated PBMCs. as compared with unstimulated PBMCs.
Clinical Pearls . Entamoeba histolytica. long arrow) and a tumor in the hilus of the right lung (Panel B. arrow). Six organisms (giardia. All these factors accounted for an increase by a factor of 3. tracer kinetics.02). A specimen of the metacarpal lesion obtained through needle aspiration was negative for bacteria. as compared with controls (P<0.867 returned travelers over a 9-year period (from 1996 to 2005). The final diagnosis was lung adenocarcinoma with osseous lesions of the hand and ribs. short arrow). Laboratory tests revealed a C-reactive protein level of 123 mg per liter and a leukocyte count of 34×109 per liter.004 for all comparisons). to assess major cortisol-metabolizing enzymes. CONCLUSIONS During critical illness. and assessment of liverbiopsy samples (P≤0. related to suppressed expression and activity of cortisolmetabolizing enzymes. and Current Controlled Trials numbers. 31% bacterial. redness. Impaired cortisol clearance also correlated with a lower cortisol response to corticotropin stimulation. and a chest radiograph showed a solid mass of the thoracic wall expanding into the subpleural space (Panel B. Cortisol production was 83% higher in the patients (P=0. (Funded by the Belgian Fund for Scientific Research and others. He also reported having a cough. as suggested by urinary steroid ratios. contributed to hypercortisolemia and hence corticotropin suppression.gov numbers.001). A radiograph of the hand showed osteolysis of the first metacarpal (Panel A. weight loss. and tenderness over the first right metacarpal and a mass (10 cm in diameter) fixed to the thorax. The diagnostic and therapeutic implications for critically ill patients are unknown. campylobacter. The patient received palliative care.03 for both comparisons). and levels of messenger RNA and protein in liver and adipose tissue. NCT00512122 andNCT00115479. and salmonella species) accounted for 70% of the gastrointestinal burden. and 3% viral.of hydrocortisone. In a recent study that analyzed data from the GeoSentinel Surveillance Network (which consists of 42 specialized travel or tropical-medicine sites located around the world) on 25. Reduced cortisol metabolism was associated with reduced inactivation of cortisol in the liver and kidney. and a history of heavy smoking. of the 2902 clinically significant pathogens that were isolated. levels of urinary cortisol metabolites. reduced cortisol breakdown. Physical examination revealed swelling. whereas corticotropin levels were lower (P<0. shigella. approximately 65% were parasitic. strongyloides. ClinicalTrials. There was a reduction of more than 50% in cortisol clearance during tracer infusion and after the administration of 100 mg of hydrocortisone in the patients (P≤0.5 in plasma cortisol levels in the patients. RESULTS Total and free circulating cortisol levels were consistently higher in the patients than in controls. A 59-year-old man presented with a 6-week history of pain in the thumb.001 for both comparisons).
person-to-person transmission is possible. postinfectious fatigue. it is easy to confuse E. where they mature into adult egg-laying female worms. histolytica with the identically appearing and much more common nonpathogenic parasite E. Only 1% of clinical cases of amebiasis involve the liver. with microscopy. the cyst emerges in the terminal ileum as an active trophozoite. Morning Report Questions Q: What are the manifestations of strongyloides infection? A: Strongyloides stercoralis (threadworm) is the most dominant species causing infection in humans. the disease can cause growth and cognitive impairment as a result of iron and micronutrient deficiencies.. toxic megacolon. and enter respiratory pathways. typical clinical course. causing amebiasis. rectovaginal fistulas. The clinical manifestations range from mild intestinal problems that resolve spontaneously to complex symptoms that last up to several weeks. Disease of the right colon is common and is associated with the following serious complications: strictures. abdominal pain. such as protein-losing enteropathy. After it has been ingested. chronic diarrhea. . bowel obstruction. and methods to diagnose amebiasis? E. However. perforation. dispar.What are the clinical manifestations of Giardia lamblia infection? Giardia lamblia (also called Giardia intestinalis or Giardia duodenalis) is highly contagious (ingestion of as few as 10 to 25 cysts may cause disease). and some trophozoites enter the portal circulation and disperse to the liver and other soft organs. and finally reach the small intestine. abdominal pain. histolytica and E. are swallowed. reach the lungs via the blood circulation. moshkovskii are pathogenic in humans. Microscopic examination of the stool is no longer performed for amebiasis because of its low sensitivity and specificity. Female worms embed in the submucosa of the duodenum. and weight loss. The parasite is acquired through the ingestion of food or water contaminated with fecal cysts. Several stool antigen assays specific for E. Invasion may take days to years after the initial infection and is characterized by fever. nausea. However. 90% of cases are asymptomatic and self-limiting. with persons becoming infected through the ingestion of cysts in contaminated food or water. From there. In children. Symptomatic disease occurs when trophozoites invade the mucosa and submucosa. peritonitis. and bloody dark-brown diarrhea.What is the natural history. which migrates to the colon where it colonizes the mucus layer. histolytica are commercially available to make an accurate diagnosis of intestinal or hepatic amebiasis on the basis of the Gal/GalNAc lectin. . Third-stage filariform larvae penetrate the skin (usually the foot) of the human host. they migrate upward through the trachea. and death.
although a rash may appear as much as a week later. can present with fever. and the first-stage rhabditiform larvae either are passed out in the feces and develop into infective third-stage larvae or remain in the gastrointestinal tract of the human host and start a new infection cycle (autoinfection). A skin reaction may develop within a few hours after infection in migrants or tourists infected for the first time. larva currens. and weight loss. which can result in bladder cancer. Case 14-2013: A 70-Year-Old Woman with Vaginal Bleeding.nejm. and human contact with water inhabited by the intermediate host snails. strongyloidiasis can cause a hyperinfection syndrome owing to the reproductive capacity of the parasite inside the host. this reaction leads to fibrosis and calcification of the bladder and ureters. In immunocompromised persons. strongyloides should be considered in the differential diagnosis. the symptoms include erythematous pruritus. a T-cell-mediated granulomatous reaction to schistosome eggs leads to fibrosis and chronic disease of the human liver. A maculopapular eruption consisting of discrete erythematous. japonicum. In travelers presenting with eosinophilia or elevated IgE levels. resulting in the development of severe hepatosplenic schistosomiasis. In cases of disseminated disease. fatigue. the hyperinfection syndrome can be associated with a mortality rate of close to 90%. hematuria (S. hematobium. Schistosome larvae (cercariae) emerge from the snails and penetrate human skin. mansoni and S. diarrhea (with or without blood). a specific freshwater snail as intermediate host. mansoni. The three most important species in humans are Schistosoma hematobium.org/action/doSecureKeyLogin?uuid=7676846&dateTime=2013051 80000&key=0rSCw5hWJYFuQ6MwpDd%2FHHb9duCvOf9ptOHi%2FlfDIO0%3D&uri=/doi/full/ . nonproductive cough. (https://www. Schistosome transmission requires the contamination of water by egg-containing feces or urine. which usually begins with the deposition of schistosome eggs into host tissues. hematobium). myalgia. in cases of S. In cases of infection with S. malaise. TEACHING TOPIC Vaginal Bleeding CASE RECORDS OF THE MASSACHUSETTS GENERAL HOSPITAL. For a subset of patients with disease. Patients with acute schistosomiasis.where they produce dozens of eggs per day. japonicum. Autoinfection can result in persistent infection for decades. or Katayama fever. These hatch in the gut lumen. and S. abdominal pain. Q: What is the natural history and clinical presentation of schistosomiasis? A: Schistosomiasis is a common chronic helminth disease caused by intravascular parasitic schistosoma trematode worms. S. raised lesions that vary in size from 1 to 3 cm may arise at the site of percutaneous penetration by the cercariae. diarrhea. More than 50% of patients with a chronic infection are asymptomatic. thereby instigating infection. skin eruptions. and right-upper-quadrant pain.
an enlarged uterus. the tumor has a heterologous component (most commonly rhabdomyosarcoma or chondrosarcoma). There is no transition between the two components. high operative risk. Because metastasis is common. although in up to 50% of cases.10. Tumor stage is the most important prognostic factor in these tumors.What is the typical presentation of carcinosarcoma of the uterus? Postmenopausal vaginal bleeding is the most common manifestation of carcinosarcoma. standard treatment is a radical total abdominal hysterectomy and bilateral salpingo-oophorectomy with lymphadenectomy. Morning Report Questions Q: What features affect the overall prognosis of patients with carcinosarcoma? A: Diagnostic features of malignant mixed mullerian tumor (carcinosarcoma) include the finding of a biphasic malignant tumor that is composed of high-grade carcinoma (most commonly endometrioid or serous) and sarcoma and is typically homologous (arising from mesenchymal tissue normally found in the uterus). Patients with carcinosarcoma also frequently present with the classic triad of painful postmenopausal bleeding. although histologic features also affect .when there is a desire to preserve fertility.1056/NEJMcpc1209276?query=BUL) R. In contrast. Endometrial cancers have several potential patterns of spread: direct invasion and expansion of the primary tumor. Ten percent of premenopausal women with abnormal bleeding have a malignant tumor. and intraperitoneal dissemination. preoperative combination positron-emission tomography and computed tomography (PET-CT) and a meticulous exploratory laparotomy are standard practice. and unresectable disease. 75% of women over 70 years of age with postmenopausal bleeding have cancer. lymphatic invasion. . Penson and Others CME Exam The underlying cause of abnormal vaginal bleeding is age-dependent.Under what circumstances is surgery not the primary treatment for uterine cancer? In only a few circumstances is surgery not the primary treatment for uterine cancer -. The initial spread is to regional lymph nodes. and prolapsed tumor visible at the cervical os.T. The goals of surgical treatment are excision of all disease with at least a 1-cm margin and staging of the tumor. and the risk rises with age in postmenopausal women. Clinical Pearls . therefore. hematogenous spread.
outcome. 3. more bleeding events of WHO grade 2. or 4. . .J. or 4 occurred in the no-prophylaxis group than in the prophylaxis group. 3. More patients in the no-prophylaxis group had bleeding events of WHO grade 3 or 4. "A No-Prophylaxis . The results of our study support the need for the continued use of prophylaxis . or 4 and a decreased time to the first bleeding event of WHO grade 2. myometrial and lymphovascular invasion are also associated with a poor prognosis. but this difference was not significant. The finding of serous or clear-cell carcinoma is associated with a more aggressive course. even though they are typically present in patients with carcinosarcoma. . Virtually all these bleeding episodes were WHO grade 2. Sarcomatous components adversely affect the overall prognosis of patients with stage I tumors (5-year survival is 30% among patients with heterologous elements as compared with 80% among patients with homologous elements). Hormonal therapy is of no use. 3. only 7 of the 600 patients in the study had a bleeding event of WHO grade 3 or 4. with a significant increase in the number of days with bleeding events of WHO grade 2. since estrogen and progesterone receptors do not control tumor growth. Radiation therapy has been shown to reduce the rates of local recurrence in the pelvis but does not increase the survival benefit among patients with carcinosarcoma." S. QUOTE OF THE WEEK "In our study. Original Article. Q: What are the treatment options for carcinosarcoma? A: Carcinosarcoma is thought to require multiple methods of treatment. Stanworth and Others. Adjuvant chemotherapy has not been shown to have an effect on recurrence rates or progression-free or overall survival among patients with carcinosarcoma.
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