25th Anniversary of the Last Case of Naturally Acquired Smallpox FREE

MMWR. 2002;51:952

On October 26, 1977, the last case of naturally acquired smallpox occurred in the Merca District of Somalia. In May 1980, the World Health Assembly certified the world free of naturally occurring smallpox. The eradication of a disease was an unprecedented accomplishment. Eradication efforts for both paralytic poliomyelitis and dracunculiasis (i.e., guinea worm disease) are ongoing. Beyond the benefit to the world population's health and economy, smallpox eradication demonstrated the benefits of international commitment and cooperation toward a common cause in public health. Improvements made in international vaccination programs, global disease surveillance, and public health logistics systems that were results of the smallpox eradication program continue today.¹

Although smallpox was eradicated in 1977, the risk for importation of disease into the United States had greatly decreased before that time. As a result, the United States discontinued routine smallpox vaccinations for the general population in 1971, and the Advisory Committee on Immunization Practices recommended against routine vaccination of health-care workers in 1976. The last case of smallpox in the United States occurred in 1949. An MMWR report in 1997 commemorating the 20th anniversary of the eradication of smallpox noted that smallpox vaccine and its eradication of smallpox disease were on the list of things that need be done only once in the history of the world.¹

The U.S. public health system is preparing for the potential use of smallpox (variola) virus as a bioterrorism agent. Although preparedness efforts have been ongoing since at least 1999 and a strategic plan for preparedness and response against biologic and chemical terrorism was published in April 2000,² the terrorist attacks against the United States on September 11, 2001, prompted extensive review of policies and procedures about potential acts of bioterrorism, especially the intentional release of smallpox virus. To enhance preparedness, the U.S. Department of Health and Human Services has contracted for production of enough smallpox vaccine for the entire U.S. population if vaccination becomes necessary, developed a plan for responding to a smallpox attack (http://www.bt.cdc.gov/agent/smallpox/response-plan/index.asp), and is reviewing whether increased vaccination before an attack is warranted and how such a vaccination program would be implemented. A final U.S. policy on smallpox vaccination is pending. Additional information on smallpox is available at http://www.bt.cdc.gov/agent/smallpox/index.asp.

MMWR. 2002;51:989-993

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In June 2001, seven cases of yellow fever vaccine–associated viscerotropic disease (YEL-AVD) (previously called multiple organ system failure) in recipients of 17D-derived yellow fever vaccine (YEL) were reported to the Advisory Committee on Immunization Practices (ACIP).^1- 3 ACIP reviewed the cases, recommended enhanced surveillance for adverse events, and updated the ACIP statement on YEL.⁴ This report summarizes the preliminary surveillance findings, including two new suspected cases of YEL-AVD and four suspected cases of YEL-associated neurotropic disease (YEL-AND) (previously called postvaccinal encephalitis). Although YEL remains essential for travelers to areas in which yellow fever (YF) is endemic, these findings underscore the need for continued enhanced surveillance and timely clinical assessment of YEL-associated disease.

The Vaccine Adverse Event Reporting System (VAERS) receives reports of adverse events following licensed vaccine administration in the United States.⁵ Enhanced surveillance for YEL adverse events was initiated in June 2001 and includes soliciting reports from health-care providers at certified YF-vaccination clinics and reviewing all VAERS case reports of febrile illness associated temporally with YEL (i.e., illness onset ≤30 days following receipt of YEL). During June 20, 2001–August 31, 2002, a total of 117 reports of adverse events following YEL administration were reported compared with 104 reports during a comparable period in 2000-2001. Of the 117 reports, six cases of persons with severe adverse events consistent with YEL-AND or YEL-AVD were reported. All six patients were vaccinated in the United States with 17D-derived YEL, required hospitalization, and recovered without sequelae. The first case was reported initially as nonserious in May 2001 but was reclassified after the enhanced surveillance system was in place.

On April 27, 2001, a man aged 25 years received YEL and influenza and poliovirus vaccines in preparation for travel to North Africa, Israel, Turkey, and Ecuador. One day after vaccination, he had lymphadenopathy, headache, and malaise; 2 days later, he reported nausea, diarrhea, diaphoresis, and fever. Nine days after vaccination, he was hospitalized with a fulminant illness characterized by fever of 101.6°F (38.7°C) and acute hepatic and renal failure. The next day, he had hypotension and respiratory failure requiring resuscitation, vasopressors, dialysis, and mechanical ventilation. No bacterial pathogens were identified from urine, blood, or stool specimens. A toxicology screen was negative. After 24 days of hospitalization, he recovered and was discharged. No acute-phase serum or tissue samples for viral isolation or polymerase chain reaction (PCR) were obtained. Convalescent-phase serum samples collected 351 days after vaccination demonstrated a YF-neutralizing antibody titer of 1:640.

On March 28, 2002, a man aged 70 years received YEL in preparation for travel to Venezuela. He had fever, dyspnea, myalgia, and malaise 5 days after vaccination; 3 days later, he was hospitalized because of fever, thrombocytopenia, and elevated hepatocellular enzymes, bilirubin, and creatinine. He subsequently became hypotensive and was intubated for respiratory failure. Hyponatremia developed and dialysis was required for renal failure. Blood and urine cultures were negative for bacteria, fungi, and viruses. Serum collected on hospital days 21, 25, and 33 and pleural fluid collected on day 26 were negative by real-time, quantitative PCR (TaqMan®) with consensus flavivirus primers and viral culture. Serum collected on hospital day 26 had a neutralizing antibody titer of 1:1,280. After a 41-day hospitalization, he recovered and was discharged.

On September 17, 2001, a man aged 36 years received YEL in preparation for travel to Brazil. He had diaphoresis, fever of 102.2°F (39.0°C), rigors, and headache 13 days after vaccination; 16 days after vaccination, he lost consciousness and was hospitalized with severe headache and fever of 106.0°F (41.1°C). Examination of cerebrospinal fluid (CSF) revealed 406 white blood cells per mm³ (WBC/mm³) (predominantly lymphocytes) and elevated protein. Blood, urine, and CSF cultures were negative for bacteria, fungi, and viruses. YF-specific IgM-capture ELISA (MAC-ELISA) of CSF was strongly positive. CSF viral testing by TaqMan® and viral culture was negative. Additional MAC-ELISA results were negative for Eastern equine encephalitis, St. Louis encephalitis, West Nile encephalitis, and La Crosse encephalitis viruses. After a 5-day hospitalization, he recovered and was discharged.

On October 4, 2001, a man aged 71 years received YEL and typhoid and hepatitis A vaccines in preparation for travel to Guatemala. He had fever and malaise 6 days later; 13 days after vaccination, he became confused, had expressive aphasia, and was hospitalized with fever of 101.1°F (38.4°C). He had leukocytosis but normal hepatocellular enzymes. CSF had 137 WBC/mm³ and elevated protein. CSF YF-specific IgM testing by MAC-ELISA was positive; viral testing by TaqMan® and viral culture was negative. CSF was negative for herpes viruses, flaviviruses, and enteroviruses. After a 7-day hospitalization, he recovered and was discharged.

On February 7, 2002, a man aged 41 years received YEL and hepatitis A vaccine in preparation for travel to Venezuela. Six days after vaccination, he had low-grade fever, headache, and myalgia, which worsened over several days; 16 days after vaccination, he was hospitalized with fever of 104.0°F (40.0°C), headache, and rigors. CSF had 63 WBC/mm³ (predominantly mononuclear) and elevated protein. Hepatocellular enzymes were normal. Bacterial and fungal cultures of blood and CSF and CSF cryptococcal antigen were negative. CSF enteroviral testing and Leptospira serology were negative. CSF YF-specific IgM testing by MAC-ELISA was strongly positive; viral testing by TaqMan® and viral culture was negative. After 5 days, he recovered and was discharged.

On May 17, 2002, a boy aged 16 years received YEL in preparation for travel to South America; 23 days after vaccination, he had left-arm numbness, inability to speak, loss of right-side fine motor control, expressive aphasia, and severe dysarthria. Magnetic resonance imaging showed diffuse, bilateral, white-matter disease; CSF examination was normal. MAC-ELISA YF-specific IgM tests on CSF collected 26 days after vaccination were strongly positive; CSF tests by TaqMan® with consensus flavivirus primers and viral cell culture were negative. Tests for Rocky Mountain spotted fever, herpes simplex, multiple sclerosis, lupus, autoimmune diseases, and metabolic enzyme deficiencies were negative. Reverse-transcriptase PCR with primers for Colorado tick fever was negative; serum collected 4 months after illness onset did not contain neutralizing antibodies for that virus. No bacteria or fungi were cultured from CSF. The patient was afebrile throughout his illness and was discharged after a 3-day hospitalization.

S Levy, MD, Saint Agnes Medical Center, Fresno, California. K Mullane, DO, Loyola Univ Medical Center, Maywood, Illinois. M Miller, MD, Albany Medical College; S Siva, MD, Albany Medical Center Hospital, Albany, New York. D Barnes, MD, Southview Medical Group, Birmingham, Alabama. P Dhaliwal, MD, Brandon Regional Hospital, Brandon, Florida. SC Tiwari, MD, St. Dominic-Jackson Memorial Hospital, Jackson, Mississippi. KG Julian, MD, Hershey Medical Center, Hershey, Pennsylvania. Epidemiology and Surveillance Div, National Immunization Program; Div of Vector-Borne Infectious Diseases; Div of Global Migration and Quarantine, National Center for Infectious Diseases; EIS Officer, CDC.

This report documents two probable new cases of 17D-derived YEL-AVD and four probable new cases of 17D-derived YEL-AND in the United States. YEL-AND has long been recognized as a vaccine-associated adverse event, but incidence decreased substantially with implementation of the seed-lot standardization process in 1945. Since then, 27 cases of YEL-AND, including seven U.S. cases, have been reported worldwide.^1,6 YEL-AVD was recently recognized; since 1996, 12 cases of YEL-AVD, including six U.S. cases, have been reported worldwide.^1- 4

This report describes the first U.S. case of YEL-AVD in a person aged <50 years. Of the 12 cases reported worldwide, five were in persons aged <50 years. Similar to the YEL-AVD cases reported previously, onset of symptoms occurred 1-6 days after vaccination.¹ Two of the four persons with YEL-AND became ill 13-23 days after vaccination.

YF is a flavivirus that causes a febrile illness in humans that can progress to hepatic and renal failure and hemorrhage caused by platelet and clotting abnormalities. In primates and mice, YF also can cause meningo-encephalitis.⁶ YEL is a live virus preparation containing 17D vaccine strain made by serial passage of wild type YF virus to attenuate neurotropic and viscerotropic properties while preserving immunogenicity.⁴ Sequencing evidence suggests that YEL-AVD and YEL-AND might represent an aberrant host response to 17D vaccine strain rather than a reversion of vaccine virus to wild type.^1,3

The cases of neurologic disease had evidence that 17D-derived YEL was the likely cause of illness. The four patients had onset of illness soon after YEL was administered and had high levels of YF-specific IgM antibody in CSF; no other causes of neurologic disease were identified. However, viral isolation of YEL-associated virus in these patients was either negative or not performed because of inadequate samples. The presence of IgM antibody in CSF might be caused by serum antibody from recent vaccination crossing an inflamed blood-brain barrier; however, this is unlikely because of the large size of IgM. The two patients with visceral involvement also had illness associated temporally with YEL, had clinical features similar to other reported cases of YEL-AVD,^1- 3 and had extensive diagnostic testing, excluding other infectious and noninfectious etiologies. However, tissue samples were not available for testing because both patients survived despite multiple organ system failure.

Enhanced surveillance was useful in identifying additional suspect cases of YEL-AVD and YEL-AND. These findings indicate the need for continued enhanced surveillance, timely clinical assessment, and a refined risk estimate for severe adverse events following receipt of YEL. However, enhanced VAERS surveillance efforts alone might not detect all serious adverse events after receipt of YEL.⁷

Clinicians are encouraged to report promptly to VAERS any patients with symptoms suggestive of viscerotropic or neurotropic illness or any patients with fever of ≥101.3°F (≥38.5°C) for >24 hours and illness onset ≤30 days following receipt of YEL. VAERS report forms are available online at http://www.vaers.org or by telephone, 800-822-7967. Completed forms can be submitted online; by fax, 877-721-0366; or by mail, P.O. Box 1100, Rockville, MD 20849-1100. Supplemental clinical information and information about the availability of clinical, autopsy, or residual vaccine specimens may be requested. CDC will conduct virologic and immunohistochemical studies of these specimens. Additional information is available from CDC at http://www.cdc.gov/ncidod/dvbid/yellowfever/index.htm and http://www.cdc.gov/travel and by telephone, 970-221-6400 and 404-498-1600.

Because of the potential severity of YF infection, YF vaccination is recommended for persons aged ≥9 months traveling to countries where YF is endemic or epidemic. YF has caused recent deaths in unvaccinated U.S. and European travelers to endemic areas of sub-Saharan Africa and tropical South America.^8- 10 To mitigate the risk for YEL-associated disease, health-care providers should provide YEL only to persons planning to travel to areas reporting ongoing YF activity or with a history of endemic transmission.

MMWR. 2002;51:973-974

On October 28, this report was posted on the MMWR website (http://www.cdc.gov/mmwr).

CDC, the Food and Drug Administration (FDA), and the Health Resources and Services Administration (HRSA), in collaboration with blood collection agencies and state and local health departments, continue to investigate West Nile virus (WNV) infections in recipients of blood transfusions. During August 28–October 26, CDC received reports of 47 persons with possible transfusion-related WNV infection. Investigations showed that 14 of these persons either did not have WNV infection or did not acquire WNV infection through transfusion. The remaining 33 cases, reported from 17 states, occurred among persons who had confirmed or probable WNV infection and had received blood components in the month before illness onset. To date, evidence that WNV can be transmitted through blood transfusion has been found in six of the 33 cases; investigations are ongoing for the other 27 cases.

Among the six cases with evidence that WNV can be transmitted through blood transfusion, three have been previously summarized.^1- 2 Two patients developed confirmed West Nile virus meningoencephalitis (WNME) after receiving different blood components derived from the same blood donation, which was subsequently found to have evidence of WNV.² In follow-up testing, the donor associated with these components had WNV-specific IgM antibody.

On interview, this donor reported having a fever and a rash 2 and 5 days after donation, respectively. In a third case, WNV was isolated from an untransfused unit of fresh frozen plasma (FFP) derived from the suspected donation, indicating that the virus can survive in some blood components.¹ The donor of this unit sought medical care 4 days after donation for an illness of 1-2 weeks duration characterized by nasal congestion, sinus pain, headache, malaise, and fatigue and was treated for sinusitis. On follow-up, the donor tested positive for WNV-specific IgM antibody.

Investigations of three additional patients found evidence that these persons acquired WNV infection by transfusion. An adolescent with a hematologic malignancy who had been hospitalized continuously for 65 days developed WNME after receiving 93 blood components in the month before illness onset. Of 72 retention segments* available from these donations, one tested positive for WNV by kinetic quantitative polymerase chain reaction assay (Taqman®) and negative for WNV-specific IgM antibody. The donor of the unit associated with the Taqman®-positive retention segment reported fever, chills, headache, painful eyes, and generalized weakness beginning 2 days after donation in early September and subsequently developed WNV IgM antibody.

Two additional patients had WNME diagnosed after each had received a component derived from the same blood donation.

The first patient, a man aged 60 years with a malignancy, received 4 units of red blood cells during September 18-30 and subsequently developed encephalitis. Serum and cerebrospinal fluid samples tested positive for WNV-specific IgM antibody on October 8 and 16, respectively; the patient subsequently died.

One of four retention segments associated with the units the patient received tested positive for WNV by Taqman® and negative for WNV-specific IgM antibody. A unit of FFP associated with this Taqman®-positive donation had been administered on October 6 to the second patient, a woman aged 40 years with a malignancy; 3 days later, this patient had fever. Serum collected from the patient 1 day before transfusion was negative for WNV by Taqman® and WNV-specific IgM antibody. Serum collected from the patient 9 days after transfusion tested positive for WNV by reverse transcription polymerase chain reaction and negative for WNV-specific IgM antibody; serum collected 6 days later tested positive for WNV by Taqman® and positive for WNV-specific IgM antibody. The donor of the Taqman®-positive unit subsequently developed WNV IgM antibody. During follow-up interview, the donor reported having fever, chills, headache, eye pain, and myalgias 5 days before donation and a rash 4 days after donation in late August.

Cases of WNV infection in patients who have received blood transfusions within the month preceding illness onset should be reported to CDC through state and local public health authorities. Serum or tissue samples should be retained for later studies. In addition, cases of WNV infection occurring in persons who have illness onset within 2 weeks after blood donation should be reported. Prompt reporting of these cases will facilitate withdrawal of potentially infectious blood components.

FDA has issued a guidance document for deferral of donors with suspect or diagnosed WNV infection who have illness onset before or after donation.³ In addition, the document provides recommendations for retrieval and quarantine of blood and blood components in such donors. FDA, in collaboration with CDC, the National Institutes of Health, and HRSA, is sponsoring a workshop on development of donor-screening assays for WNV. Additional information on this workshop is available at http://www.fda.gov/cber/meetings/wnv110402.htm.

*Blood samples from tubing that had been attached to the original donor collection bag or from the packed red blood cell component prepared from the whole blood collection.