Clinical Care of Two Patients with Ebola Virus Disease in the United States PDF

The n e w e ng l a n d j o u r na l of m e dic i n e brief report Clinical Care...

The n e w e ng l a n d j o u r na l of m e dic i n e brief report Clinical Care of Two Patients with Ebola Virus Disease in the United States G. Marshall Lyon, M.D., M.M.Sc., Aneesh K. Mehta, M.D., Jay B. Varkey, M.D., Kent Brantly, M.D., Lance Plyler, M.D., Anita K. McElroy, M.D., Ph.D., Colleen S. Kraft, M.D., Jonathan S. Towner, Ph.D., Christina Spiropoulou, Ph.D., Ute Ströher, Ph.D., Timothy M. Uyeki, M.D., M.P.H., M.P.P., and Bruce S. Ribner, M.D., M.P.H., for the Emory Serious Communicable Diseases Unit* Sum m a r y West Africa is currently experiencing the largest outbreak of Ebola virus disease (EVD) in history. Two patients with EVD were transferred from Liberia to our hos- pital in the United States for ongoing care. Malaria had also been diagnosed in one patient, who was treated for it early in the course of EVD. The two patients had substantial intravascular volume depletion and marked electrolyte abnormalities. We undertook aggressive supportive measures of hydration (typically, 3 to 5 liters of intravenous fluids per day early in the course of care) and electrolyte correction. As the patients’ condition improved clinically, there was a concomitant decline in the amount of virus detected in plasma. T From the Departments of Medicine he largest outbreak of EVD in history began in December 2013 in (G.M.L., A.K. Mehta, J.B.V., C.S.K., B.S.R.), Guinea, a country in West Africa.1 By late March, Liberia had reported seven Pathology (C.S.K.), and Pediatrics (A.K. McElroy), Division of Infectious Diseas- cases. By the end of May, the epidemic had spread to Sierra Leone. As of es, Emory University School of Medicine, November 5, 2014, a total of 13,042 cases of EVD (including 4818 deaths) had been and the Centers for Disease Control and reported in six countries in West Africa (Guinea, Sierra Leone, Liberia, Mali, Nige- Prevention (A.K. McElroy, J.S.T., C.S., U.S., T.M.U.) — both in Atlanta; and Samaritan’s ria, and Senegal), the United States, and Spain.2 Purse, Boone, NC (K.B., L.P.). Address re- EVD causes a nonspecific febrile illness associated with myalgia, with progres- print requests to Dr. Lyon at 101 Woodruff sion to gastrointestinal symptoms (abdominal pain, nausea, vomiting, and diar- Cir., WMB 2101, Atlanta, GA 30322, or at [email protected]. rhea). In the second week of illness, hemorrhagic symptoms and sepsis may de- velop.3-5 Mortality from EVD historically has ranged from 40 to 88%.3,4,6-8 The Drs. Lyon and Mehta contributed equally current outbreak is attributed to Zaire ebolavirus (EBOV). The aggregated case fatal- to this article. ity rate associated with EBOV is 78%, which is higher than that for other Ebola * A complete list of investigators in the virus species.4,8,9 Here, we review the clinical course of two American health care Emory Serious Communicable Diseas- workers who contracted EVD in Liberia and were transferred to Emory University es Unit is provided in the Supplemen- tary Appendix, available at NEJM.org. Hospital for continued management. This article was published on November 12, 2014, at NEJM.org. C A SE R EP OR T S N Engl J Med 2014;371:2402-9. Patient 1 DOI: 10.1056/NEJMoa1409838 The first patient was a 33-year-old physician who had been working in Liberia since Copyright © 2014 Massachusetts Medical Society. October 2013, during which time he had remained healthy while taking daily com- bination therapy with atovaquone and proguanil as prophylaxis against malaria. In April 2014, he and his team established an EVD care unit in Monrovia, and patients with confirmed EVD began arriving at this facility on June 11, 2014. On July 23, 2014, he awoke feeling febrile and fatigued; his oral temperature was 37.8°C. He 2402 n engl j med 371;25 nejm.org december 18, 2014 The New England Journal of Medicine Downloaded from nejm.org on September 8, 2024. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.  brief report reported his symptoms to colleagues and re- since his oxygen saturation by pulse oximetry mained at home. Results on two rapid diagnostic (SpO2) was 91 to 93% while he was breathing tests for malaria (Standard Diagnostics) were ambient air. There was clinical evidence of hypo- negative. He started empirical malaria treatment volemia (orthostasis and resting tachycardia) with artemether and lumefantrine. Later that despite 3+ pitting edema to the waist. He had no day, his oral temperature was 38.6°C, and nausea signs of bleeding but had a persistent petechial developed. He was tested for malaria by means of rash. He had decreased breath sounds and dull- a rapid diagnostic test and for yellow fever, Lassa ness on percussion in the right lower thorax, fever, and EBOV by means of semiquantitative findings that were consistent with a small pleu- real-time reverse-transcriptase–polymerase-chain- ral effusion, although no chest radiography was reaction (RT-PCR) assays, all of which were per- performed to confirm this finding. There was formed at the Liberian National Reference Labo- mild tenderness on palpation in the right upper ratory. The results for all the tests were negative. quadrant of the abdomen, but the liver span was As his fevers continued, intravenous lactated normal. Laboratory examinations were performed Ringer’s solution and empirical antibiotics were in the SCDU with the use of point-of-care instru- administered. On day 4 of the illness, repeat mentation. Figure 1 shows the changes in perti- blood testing for malaria, yellow fever, Lassa nent laboratory values over the duration of the fever, and EBOV showed positive results for hospital stay. EBOV. On day 6, a petechial rash developed on A point-of-care measurement showed an in- his arms and chest, his fever spiked at 40.3°C, ternational normalized ratio of 1.3. The patient’s and he had increasing malaise. Abdominal pain kidney function was normal throughout hospi- and profuse diarrhea also developed. The rash talization. A plasma specimen that was collected progressed to a maculopapular rash covering his on admission to the hospital tested positive for body from legs to face. He also had an episode EBOV on semiquantitative RT-PCR assay at the of melena and received 1 unit of whole blood. Centers for Disease Control and Prevention (CDC). On day 7, he had hematemesis and received an- The lowest platelet count (51,000 per cubic milli- other unit of whole blood. Later the same day, he meter) occurred on day 14 of the illness. Imme- received 1 unit of convalescent whole blood from diately after admission, the patient underwent a patient who had recovered from EBOV. How- intravenous volume resuscitation, which was ini- ever, his condition continued to worsen. For tially performed with normal saline, with fluids fever and myalgia, he received 1 g of acetamin- changed later to 5% dextrose and half-normal ophen every 6 hours. He hydrated orally with saline with potassium chloride. Tang and Gatorade, despite persistent anorex- After initial fluid resuscitation, frequent pre- ia. On day 9, he received an intravenous dose mature ventricular contractions at up to 6 episodes of ZMapp, an experimental cocktail of three per minute developed. The patient was found to EBOV glycoprotein-specific monoclonal antibod- have hypokalemia (potassium level, 3.0 mmol per ies (Mapp Biopharmaceutical and LeafBio). The liter; lower limit of the normal range, 3.6 mmol medical team caring for him reported improve- per liter). He received 80 to 100 mmol of oral or ments in his vital signs and alertness within intravenous potassium chloride per day for the 8 hours after the infusion of the monoclonal first 5 days of hospitalization. He continued to antibody cocktail. In addition, the extent of the have diarrhea, with a total output of 2 to 4 liters rash decreased, and the patient reported that his per day. The goals of his care were to balance energy level had increased to the point that he fluid input and output and to correct electrolyte was able to walk. disturbances. In order to replace fluid losses On day 10, he was transferred to the Serious from diarrhea, he required 2 to 5 liters of intra- Communicable Diseases Unit (SCDU) at Emory venous fluids per day (plus oral intake) until University Hospital in Atlanta. On arrival at the day 17. In addition, his dietary intake was sup- hospital on day 11, he was febrile (temperature, plemented with oral protein drinks and a multi- 38.9°C) and had tachycardia (≥120 beats per vitamin. minute), but the blood pressure was stable, with The patient received additional infusions of the mean arterial pressures of 67 to 103 mm Hg. antibody cocktail on days 12 and 15 of the illness, He required oxygen supplementation at a rate of without adverse effects. On day 15 of the illness, 2 liters per minute during the first 48 hours, he became afebrile. Between days 14 and 17, n engl j med 371;25 nejm.org december 18, 2014 2403 The New England Journal of Medicine Downloaded from nejm.org on September 8, 2024. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.  2404 A Patient 1 B Patient 2 ZMapp ZMapp Sodium Calcium 12 145 12 ZMapp Corrected Calcium calcium 10 140 10 Corrected Calcium ULN 8 135 calcium 8 and LLN 6 130 Calcium ULN 6 Potassium and LLN Potassium 4 125 Potassium 4 ULN and LLN Albumin Calcium (mg/dl), Calcium (mg/dl), 2 120 2 Albumin Albumin (g/dl), and Albumin (g/dl), and Sodium (mmol/liter) Albumin ULN Potassium (mmol/liter) Potassium (mmol/liter) 0 115 0 Albumin ULN and LLN and LLN 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 The 300 800 120 900 ALP ALP 700 800 250 ALP ULN 100 ALP ULN 600 700 200 500 ALT 80 600 ALT AST 500 AST 150 400 60 AST/ALT ULN 400 AST/ALT ULN 100 300 40 300 n engl j med 371;25 ALP (U/liter) ALP (U/liter) 200 200 50 100 20 100 ALT and AST (U/liter) ALT and AST (U/liter) 0 0 0 0 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 nejm.org Platelet transfusion 20 700,000 White-cell 16 400,000 White-cell n e w e ng l a n d j o u r na l 18 600,000 count 14 350,000 count The New England Journal of Medicine 16 of 500,000 Hemoglobin 12 300,000 Hemoglobin 14 12 Platelet 10 250,000 Platelet 400,000 count count 10 8 200,000 8 300,000 6 150,000 6 200,000 4 100,000 december 18, 2014 4 2 100,000 2 50,000 and Hemoglobin (g/dl) and Hemoglobin (g/dl) m e dic i n e Downloaded from nejm.org on September 8, 2024. For personal use only. White Cells (×10−3/mm3) White Cells (×10−3/mm3) Platelet Count (per mm3) Platelet Count (per mm3) 0 0 0 0 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 15 16 17 18 19 20 21 22 23 24 25 26 27 Day of Illness Day of Illness Figure 1. Laboratory Values over the Course of Ebola Virus Disease (EVD) in Patients 1 and 2. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved. Shown are the changes in laboratory values during hospitalization in Patient 1 (Panel A) and Patient 2 (Panel B) after transfer to Emory University Hospital from Liberia. In both panels, the vertical dashed lines point to the days on which the patients received an experimental antibody cocktail called ZMapp. For the two patients, values are provided for pertinent elec- trolytes (top graphs), liver enzymes (middle graphs), and blood counts, including white-cell counts, hemoglobin levels, and platelet counts (bottom graphs). The administration of a platelet transfusion in Patient 2 is indicated by the dashed line in the bottom graph of Panel B. To convert the values for calcium to millimoles per liter, multiply by 0.250. ALP denotes alkaline phosphatase, ALT alanine aminotransferase, AST aspartate aminotransferase, LLN lower limit of the normal range, and ULN upper limit of the normal range.  brief report the frequency and volume of stools decreased; was afebrile and remained without fever through- stools were formed on day 17, and intravenous out hospitalization. She had intermittent tachy- fluids were stopped. On day 29, he was removed cardia, at up to 104 beats per minute, but with from isolation after two consecutive plasma mean arterial pressures (on cuff readings) that specimens that were collected at least 24 hours were maintained at 87 to 119 mm Hg. She had apart tested negative for EBOV on semiquanti- intermittent tachypnea, with up to 25 breaths tative RT-PCR assay. He was discharged the per minute, although the SpO2 was maintained following day. at more than 92%, with oxygen supplementation of 1 to 3 liters per minute by nasal cannula. The Patient 2 laboratory examinations showed both hypokale- The second patient was a 59-year-old female mis- mia and hypoalbuminemia. (All laboratory data sionary who had been working in Liberia at the are provided in Fig. 1.) same facility as Patient 1. She assisted health The patient’s kidney function remained nor- care workers with donning and doffing personal mal throughout her hospitalization. A rapid protective equipment and performing decontam- malaria test (BinaxNOW Malaria, Alere) was ination. On July 22, 2014, she noted the onset of negative. A plasma specimen that was collected fever, fatigue, and malaise. A blood smear for on day 15 tested positive for EBOV on semiquan- malaria was positive, and she was prescribed titative RT-PCR assay at the CDC. The patient artemether–lumefantrine for 4 days. However, received intravenous rehydration with normal she continued to be febrile, with a peak tempera- saline, which was subsequently changed to 5% ture of 39.4°C. Empirical ceftriaxone was started, dextrose and half-normal saline, with 40 mmol but a truncal rash developed. Oral azithromycin of potassium chloride and oral potassium sup- was substituted but caused hand swelling; her plementation. Over the course of the first 2 days treatment was successfully changed to oral levo- at our hospital, she required 2 to 3 liters of in- floxacin. A serum sample that was obtained on travenous fluids in addition to oral fluids and day 5 of the illness yielded a positive result for 60 to 80 mmol of potassium chloride per day. EBOV on RT-PCR assay. On day 9, asthenia that The steady increase in alkaline phosphatase levels required assistance with walking developed, as was attributed to hypocalcemia (Fig. 1). How- well as diarrhea without nausea or vomiting. De- ever, we could not fractionate the alkaline phos- spite anorexia, the patient continued to drink phatase to confirm bone as the source. The pa- fluids, including oral rehydration solution. On tient had thrombocytopenia on arrival but did day 10, she received an infusion of the experi- not require the transfusion of 1 unit of platelets mental ZMapp antibody cocktail. She had some (O negative) until day 17. On day 16, the patient subjective improvement in energy within 8 hours received a third dose of the experimental ZMapp after the infusion, and her appetite improved on antibody cocktail. She had a few loose stools day 11 such that she could eat solid food, but she between days 12 and 20 but no diarrhea. Periph- remained fatigued and weak. On day 12, she was eral neuropathy developed in both feet, which noted to have some minor bleeding from her responded to gabapentin. After 20 days of ill- nose and venipuncture sites; the hemoglobin ness, her anorexia and asthenia improved. She level was 11.5 g per deciliter, and she received 1 was discharged from the hospital on day 29, unit of whole blood. She received a second infu- after two consecutive plasma specimens that sion of the antibody cocktail without adverse ef- were collected at least 24 hours apart were nega- fects on day 13. tive for EBOV on semiquantitative RT-PCR assay. On day 14, the patient was medically evacu- At the time of discharge, she was able to walk ated from Liberia to Emory University Hospital without assistance. and arrived on day 15. During transport, intra- venous access could not be obtained owing to Clinical Follow-up anasarca. On admission to the SCDU, she had The two patients received ZMapp under emer- evidence of hypovolemia (initial central venous gency investigational new drug approvals from pressure, 3 cm of water, after the placement of the Food and Drug Administration; both provid- a central venous catheter in the right internal ed written informed consent, originally in Libe- jugular vein) despite 3+ pitting anasarca. She ria and again on arrival in the United States. The n engl j med 371;25 nejm.org december 18, 2014 2405 The New England Journal of Medicine Downloaded from nejm.org on September 8, 2024. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.  The n e w e ng l a n d j o u r na l of m e dic i n e A Patient 1 ZMapp ZMapp dose no. 2 dose no. 3 7000 0 6000 5 10 EBOV Antibody Titer 5000 15 RT-PCR Ct 4000 20 3000 25 IgM IgG 2000 NP IgG 30 Viral load 1000 35 in blood Viral load 0 40 in urine 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 Day of Illness 39 Temperature 38 (ºC) 37 Diarrhea B Patient 2 ZMapp dose no. 3 7000 32 6000 33 34 EBOV Antibody Titer 5000 35 RT-PCR Ct 4000 36 3000 37 IgM IgG 2000 NP IgG 38 Viral load 1000 39 in blood Viral load 0 40 in urine 15 16 17 18 19 20 21 22 23 24 25 26 27 Day of Illness 39 Temperature 38 (ºC) 37 Diarrhea Figure 2. Association between EBOV-Specific Antibodies, Viral Load, and EVD Symptoms. Shown is the association between the development of specific antibodies against Zaire ebolavirus (EBOV), the re- duction in the viral load in blood and urine, and EVD-related symptoms in Patient 1 (Panel A) and Patient 2 (Panel B). The reverse-transcriptase–polymerase-chain-reaction (RT-PCR) assay targets the nucleoprotein (NP) sequences of EBOV, and the results for viral load are shown as cycle threshold (Ct) values (i.e., the number of cycles at which the fluorescence in the assay exceeds the threshold). The Ct value is inversely related to the viral load. IgM and IgG titers on enzyme-linked immunosorbent assay (ELISA) against an EBOV lysate are shown. However, the titers may include antibodies from both the monoclonal antibody cocktail (ZMapp) that was administered and endogenous EBOV-specific antibodies. To evaluate the kinetics of the host-specific antibodies, an ELISA was developed to detect antibodies against the EBOV NP antigen, which would not be contained in the monoclonal antibody cocktail. These data indicate that the production of EBOV-specific antibodies is associated with a reduction in the viral load in the blood and urine, and the reduction in the viral load is associated with the resolution of EVD-related symptoms. 2406 n engl j med 371;25 nejm.org december 18, 2014 The New England Journal of Medicine Downloaded from nejm.org on September 8, 2024. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.  brief report two patients had a decline in the plasma EBOV pothesize that a subgroup of patients may die viral load (with a corresponding increase in cycle from complications of hypovolemia and concomi- threshold values on semiquantitative RT-PCR as- tant electrolyte derangement, primarily hypoka- say) during hospitalization. EBOV was isolated lemia. Patient 1 had some ventricular ectopy, so from a blood specimen that was collected from we suspect that electrolyte abnormalities and Patient 1 on the first day of hospitalization (ill- volume shifts could cause cardiac arrhythmias ness day 11). EBOV nucleic acid was detectable in and sudden death from cardiac causes in some plasma and urine for nearly 4 weeks after the patients. onset of illness. The two patients had detectable Our experience with these two patients builds IgM and IgG antibodies after the second week of on published data involving patients with EVD. illness. Figure 2 shows the results of semiquanti- Rollin et al.13 reported that the development of tative RT-PCR assays for EBOV and immunoglob- liver failure (as shown by an elevated level of as- ulin responses in the two patients. In general, partate aminotransferase but not of alanine ami- there was a correlation between increasing anti- notransferase) or renal failure was associated body levels and decreasing cycle threshold values with an increased risk of death.13 One of our pa- on RT-PCR assay. tients had substantial liver injury but with good Patient 1 and Patient 2 each had a follow-up hepatic synthetic function and good kidney evaluation 4 weeks after discharge. Both pa- function maintained. Rollin et al. reported that tients reported a continued increase in strength hypoalbuminemia, hypocalcemia, and elevated and stamina. Patient 2 reported resolution of amylase d-dimer levels were all associated with peripheral neuropathy, and she was given in- increased mortality among patients with EVD structions on tapering gabapentin. caused by Sudan ebolavirus (SUDV).13 However, the two patients in our study had hypoalbuminemia Discussion and elevated alkaline phosphatase levels, which should be predictive of an increased risk of Two patients with EVD who were treated at Emory death.13 In addition, their serum calcium levels University Hospital had hypovolemia, hypokale- were near the levels that were found by Rollin mia, hypocalcemia, and hypoalbuminemia. Pa- et al. to be associated with increased mortality.13 tient 1 also had hyponatremia. Both patients had In our patients, aggressive volume and elec- thrombocytopenia without evidence of coagulop- trolyte replacement with a special focus on re- athy. With aggressive fluid and electrolyte replace- placing potassium and calcium appeared to be ment, the condition of both patients improved. of value. Although we believe that aggressive The clinical benefit of the experimental mono- hydration is important, the vascular leak syn- clonal antibody therapy in these patients is un- drome can lead to substantial pooling of fluid in known. The two patients were observed to have the third space, including pleural effusions. This subjective and objective improvement shortly af- finding suggests the need for adjustment of ter receiving the first dose of the antibody cock- fluid replacement on the basis of the patient’s tail, but this improvement occurred in the con- respiratory status. Although the oral rehydration text of receiving other care as well. Studies in solution recommended by the World Health Or- animals have shown a survival benefit for ZMapp ganization contains some potassium,14 most even when treatment was initiated after the onset intravenous fluids that are recommended for of symptoms.10 However, there are currently no rehydration do not have substantial levels of data on the safety or efficacy of ZMapp in hu- potassium, calcium, or magnesium.14 Rehydra- mans. Clinical improvement in these patients tion with commercial sports drinks may in- could have resulted from a direct effect of the an- crease the risk of hypokalemia.15 Thus, our tibodies, from improvement in fluid status findings suggest that it may be prudent to sup- through increased oncotic pressure, or from other plement oral rehydration with oral potassium, unidentified factors. Controlled clinical trials are calcium, and magnesium, especially in patients needed to assess the efficacy of ZMapp for EVD. with large-volume diarrhea. Although it is likely that most deaths from Measurement of viral loads and testing for EVD are caused by multiorgan dysfunction and antibody responses to EBOV were performed septic shock or disseminated intravascular coagu- only after the two patients arrived in the United lation and bleeding complications,7,11,12 we hy- States, and both patients had evidence of EBOV- n engl j med 371;25 nejm.org december 18, 2014 2407 The New England Journal of Medicine Downloaded from nejm.org on September 8, 2024. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.  The n e w e ng l a n d j o u r na l of m e dic i n e specific IgM and IgG antibody levels at that time vival in SUDV-infected patients.21 Therefore, the (Fig. 2). In a previous study, EBOV IgM and IgG ability to fractionate and administer blood prod- antibodies were detectable at 8 to 10 days after ucts safely may be beneficial to patients in this the onset of illness, with the IgM antibody epidemic. peak at 18 days.16 SUDV IgG is detectable for Our limited experience with two patients up to 12 years.16,17 In both of our patients, plasma cannot be extrapolated to all patients with EVD. EBOV loads decreased over time, in correlation However, intensive care nursing, aggressive oral with the resolution of clinical illness and labora- and intravenous rehydration, electrolyte supple- tory abnormalities. Nevertheless, EBOV RNA mentation, and transfusion of blood products continued to be detectable until the fourth week appeared to be critical for a positive outcome in of illness. It is unclear whether this represents our patients with EVD. persistence of infectious virus or simply detect- The views expressed in this article are those of the authors and do not necessarily represent the official position of the CDC. able RNA. Supported by the CDC. Both of our patients received whole-blood Disclosure forms provided by the authors are available with transfusions in Liberia, including (in the case of the full text of this article at NEJM.org. We thank Nancy Writebol and her family and the family of Patient 1) blood from an EVD survivor. Although Kent Brantly; Drs. John Fankhauser and Deborah Eisenhut and convalescent serum from Ebola survivors has the teams at SIM, Samaritan’s Purse, and the ELWA hospital; been administered previously, no inferences Drs. Debra Birnkrant and Robert Kosko and the staff at the Divi- sion of Antiviral Products at the Food and Drug Administration; with respect to its benefits are possible without Drs. Miles Brennan and Jeanne Novak and their team at CBR a controlled clinical trial.18,19 Patients with EVD International; Drs. David Kuhar and Paul Meechan and the staff and coagulopathy benefit from infusion of fresh- at the Division of Healthcare Quality Promotion and the Envi- ronment, Safety, and Health Compliance Office at the CDC; Dr. frozen plasma and platelets.20,21 Some experts Stuart Nichol, Shelley Campbell, Aridth Gibbons, and Deborah recommend the early use of platelet transfu- Cannon at the Viral Special Pathogens Branch of the CDC; Dr. sions, since platelets produce the majority of the Gary Kobinger of the National Microbiology Laboratory of the Public Health Agency of Canada; and Drs. Rachel Friedman, soluble CD40 ligand that is present in the Mark Mulligan, Monica Farley, and the staff at the Division of blood.21 Such use has been correlated with sur- Infectious Diseases at Emory University. References 1. Global alert and response: Ebola virus 7. 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Philadelphia: Churchill Living- hemorrhagic fevers. In: Mandell GL, Ben- Guarner J. Ebola hemorrhagic fever in stone, 2010:2777-85. nett JE, Dolin R, eds. Mandell, Douglas, 2014: the tale of an evolving epidemic. 15. Rao SSC, Summers RW, Rao GRS, et and Bennett’s principles and practices of Ann Intern Med 2014 August 19 (Epub al. Oral rehydration for viral gastroenteri- infectious diseases. 7th ed. Philadelphia: ahead of print). tis in adults: a randomized, controlled Churchill Livingstone, 2010:2259-63. 10. Qiu X, Wong G, Audet J, et al. Rever- trial of 3 solutions. JPEN J Parenter En- 4. Kortepeter MG, Bausch DG, Bray M. sion of advanced Ebola virus disease in teral Nutr 2006;30:433-9. Basic clinical and laboratory features of nonhuman primates with ZMapp. Nature 16. Ksiazek TG, Rollin PE, Williams AJ, et filoviral hemorrhagic fever. J Infect Dis 2014;514:47-53. al. Clinical virology of Ebola hemorrhagic 2011;204:Suppl 3:S810-S816. 11. Okware SI, Omaswa FG, Zaramba S, fever (EHF): virus, virus antigen, and IgG 5. Feldmann H, Sanchez A, Geisbert TW. et al. An outbreak of Ebola in Uganda. and IgM antibody findings among EHF Filoviridae: Marburg and Ebola viruses. Trop Med Int Health 2002;7:1068-75. patients in Kikwit, Democratic Republic In: Knipe DM, Howley PM, eds. Fields vi- 12. Bwaka MA, Bonnet MJ, Calain P, et al. of the Congo, 1995. J Infect Dis 1999; rology. 6th ed. Philadelphia: Lippincott Ebola hemorrhagic fever in Kikwit, Dem- 179:Suppl 1:S177-S187. Williams & Wilkins, 2013:923-56. ocratic Republic of the Congo: clinical 17. Sobarzo A, Ochayon DE, Lutwama JJ, 6. Ebola haemorrhagic fever in Zaire, observations in 103 patients. J Infect Dis et al. Persistent immune responses after 1976. Bull World Health Organ 1978;56: 1999;179:Suppl 1:S1-S7. Ebola virus infection. N Engl J Med 271-93. 13. Rollin PE, Bausch DG, Sanchez A. 2013;369:492-3. 2408 n engl j med 371;25 nejm.org december 18, 2014 The New England Journal of Medicine Downloaded from nejm.org on September 8, 2024. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.  brief report 18. Mupapa K, Massamba M, Kibadi K, et neva: World Health Organization, 2014 monocytes/macrophages is a key event. al. Treatment of Ebola hemorrhagic fever (http://www.who.int/bloodproducts/brn/ J Infect Dis 2003;188:1618-29. with blood transfusions from convales- brn_positionpaperconvplasmafiloviruses 21. McElroy AK, Erickson BR, Flietstra cent patients. J Infect Dis 1999;179:Suppl _finalweb14august2014.pdf). TD, et al. Ebola hemorrhagic fever: novel 1:S18-S23. 20. Geisbert TW, Young HA, Jahrling PB, biomarker correlates of clinical outcome. 19. WHO Blood Regulators Network. Davis KJ, Kagan E, Hensley LE. Mecha- J Infect Dis 2014;210:558-66. Position paper on collection and use of nisms underlying coagulation abnormal- Copyright © 2014 Massachusetts Medical Society. convalescent plasma or serum as an ele- ities in Ebola hemorrhagic fever: over­ ment in filovirus outbreak response. Ge- expression of tissue factor in primate n engl j med 371;25 nejm.org december 18, 2014 2409 The New England Journal of Medicine Downloaded from nejm.org on September 8, 2024. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.