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Wednesday, May 20, 2009


A ProMED-mail post

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International Society for Infectious Diseases

Date: Tue 19 May 2009
Source: CDC. MMWR Morb Mortal Wkly Rep 2009; 58 (early release); 1-4 [edited]

Progressive vaccinia in a military smallpox vaccinee -- United States, 2009
Progressive vaccinia (PV), previously known as vaccinia necrosum,
vaccinia gangrenosum, or disseminated vaccinia, is a rare, often
fatal adverse event after vaccination with smallpox vaccine, which is
made from live vaccinia virus (1). During recent vaccination programs
potential cases of PV were investigated, but none met standard case
definitions (2). PV has not been confirmed to have occurred in the
United States since 1987 (3). On [2 Mar 2009], a US Navy Hospital
contacted the Poxvirus Program at CDC to report a possible case of PV
in a male military smallpox vaccinee. The service member had been
newly diagnosed with acute myelogenous leukemia M0 (AML M0). During
evaluation for a chemotherapy-induced neutropenic fever, he was found
to have an expanding and nonhealing painless vaccination site 6.5
weeks after receipt of smallpox vaccine. Clinical and laboratory
investigation confirmed that the vaccinee met the Brighton
Collaboration and CDC adverse event surveillance guideline case
definition for PV (4,5). This report summarizes the patient's
protracted clinical course and the military and civilian interagency
governmental, academic, and industry public health contributions to
his complex medical management. The quantities of investigational and
licensed therapeutics and diagnostics used were greater than
anticipated based on existing smallpox preparedness plans. To support
future public health needs adequately, the estimated national supply
of therapeutics and diagnostic resources required to care for
smallpox vaccine adverse events should be reevaluated.

Case description
On 13 Jan 2009, a healthy service member aged 20 years received a
primary smallpox vaccination (ACAM2000 [Acambis, Inc., Cambridge,
Massachusetts]) in accordance with the US Department of Defense
smallpox vaccination policy*; no other vaccinations were administered
that day. Twelve days later, the patient visited a local hospital
with fever and headache of one day's duration and was admitted for
workup of leukopenia after his white blood cell count was found to be
1400 cells/mm3. On [28 Jan 2009], after transfer to a US Navy
tertiary-care facility, he was diagnosed with AML M0. On [30 Jan and
13 Feb 2009], the patient underwent 2 successive rounds of induction
chemotherapy with cytarabine, idarubicin, and dexamethasone. Before
initial chemotherapy, the vaccination site pustule had a central
crust and measured approximately 1 cm [0.4 in] in diameter with
minimal surrounding erythema. During the patient's hospital stay from
the end of January to the beginning of March [2009], his vaccination
site dressing was changed daily.

On [2 Mar 2009], during the evaluation of neutropenic fever, the
failure of the patient's vaccination site to heal was described. An
annular lesion with a deep bulla, raised violaceous leading edge, and
a central crust that bled with pressure was noted. The size of the
lesion had progressed to approximately 4 x 4 cm [1.6 x 1.6 in] with
minimal surrounding erythema or induration. The patient described no
pain at the site, although he reported occasional pruritus. A swab of
the lesion and serum were sent to CDC for viral and serologic
analysis. Viral analysis of the swab by multiple real-time polymerase
chain reaction (PCR) assays for orthopoxvirus and vaccinia yielded
evidence of viral DNA; viral culture was positive for orthopoxvirus.
Serum showed equivocal to absent levels of anti-orthopoxvirus
immunoglobulin G (IgG) and immunoglobulin M (IgM) by enzyme-linked
immunosorbent assay. The results of the diagnostic testing combined
with the patient's medical history met the PV level 1 case definition
as defined by the Brighton Collaboration and the confirmed case
definition as described by CDC surveillance guidelines (4,5). The
criteria met by both case definitions were 1) a documented clinical
diagnosis of a disease that is known to be associated with
cell-mediated immunodeficiency (in this case AML M0), 2) the primary
vaccination site's failure to resolve (in this case more than 6 weeks
post vaccination), and 3) the laboratory confirmation of vaccinia
virus as the causative agent.

On [3 Mar 2009], imiquimod was applied directly to the lesion. Within
24 hours of confirmation of PV on [4 Mar 2009], the patient received
licensed Vaccinia Immune Globulin Intravenous (Human) (VIGIV)
(Cangene Corporation, Winnipeg, Canada). On [5 Mar and 6 Mar 2009],
oral and topical ST-246 (SIGA Technologies, Corvallis, Oregon) were
administered under an Emergency Investigational New Drug (E-IND)
application. The patient remained stable until the evening of [7 Mar
2009], when he became septic with _Pseudomonas aeruginosa_, likely
from a perirectal abscess. He required intubation, maximal
vasopressor support, multiple antibiotics, and stress dose
corticosteroids. He then developed multiorgan failure and began
continuous venovenous hemodialysis. During the next 12 days, the
patient slowly stabilized. As a consequence of the duration and
amount of vasopressor support, the patient required a bilateral
trans-tibial amputation because of dry gangrene of his feet.

During [6-19 Mar 2009] the patient received additional oral and
topical ST-246 and VIGIV; his ST-246 levels were noted to be lower
than those achieved both in healthy subjects in phase I clinical
trials and in successful treatment of nonhuman primates with systemic
orthopoxvirus disease. The lesion size remained unchanged, but the
central crust of the vaccination site sloughed off, followed by most
of the outer "ring" flattening, leaving a shallow ulcer with
healthy-appearing granulation tissue. During his steroid taper,
additional satellite lesions surrounding the vaccination site
appeared on [18 Mar 2009], and viral DNA was detected again in the
blood. These lesions became vesicular in nature, and on [26 Mar
2009], after a 2nd E-IND was issued, CMX001 (Chimerix, Inc., Research
Triangle Park, North Carolina), a lipid conjugate of cidofovir, was

From [24 Mar 2009] onward, the satellite and main vaccination site
lesions continued to crust, the scabs separated, and underlying
tissue epithelialized. Blood viral DNA levels cleared on [29 Mar
2009]. On [10 Apr 2009], the borders of lesions again appeared
raised; a shave biopsy grew methicillin-resistant _Staphylococcus
aureus_, which responded to antibiotic therapy. The patient received
intermittent granulocyte colony-stimulating factor, and his absolute
neutrophil and lymphocyte count increased over time. By [1 May 2009],
significant portions of the scabs/eschars had fallen off or were
removed manually, revealing healthy epidermis. Numerous therapeutics
with different biologic mechanisms were used to treat PV in this patient.

From [21 Feb 2009] onward, the patient had remained in contact
isolation, first for a _Clostridium difficile_ infection and then for
his progressive vaccinia infection. On [5 May 2009], contact
precautions were discontinued because of the lack of viable virus in
lesion specimens from the previous 4 weeks. No cases of contact
vaccinia were identified among this patient's health-care workers or
close contacts.

During [3 Mar-18 May 2009], nearly 200 clinical specimens (lesion and
satellite swabs/crusts, ethylenediaminetetraacetic acid [EDTA] blood,
bone marrow, and serum) were collected and submitted to CDC to
evaluate disease progression and guide therapeutic interventions.
After [23 Apr 2009], swabs from satellite lesions or the main
vaccination site showed significantly reduced or absent levels of
viral DNA, and no viable virus was detected after [2 Apr 2009].
Oropharyngeal sampling and bone marrow biopsies from early and late
March [2009], respectively, were negative for vaccinia virus.
Orthopoxvirus DNA was detected in EDTA blood at intermittent times
during the course of the patient's infection; however, no viable
virus was cultured from blood. As of [12 May 2009], the patient had
no demonstrable IgM response to orthopoxvirus; IgG levels appeared
fully reliant on VIGIV infusion.

During [3 Mar-18 May 2009], a total of 20 conference calls to discuss
patient status and treatment options were held between the Vaccine
Healthcare Centers Network, Military Vaccine Agency (MILVAX), Bureau
of Medicine and Surgery of the Navy, CDC, Food and Drug
Administration (FDA), National Institutes of Health (NIH), SIGA
Technologies, Chimerix, Inc., and academic and health-care
professionals. As of [18 May 2009], MILVAX provided 22 and the
Strategic National Stockpile (SNS) provided 254 vials of VIGIV used
in treatment of this case.

[Reported by: E Lederman, MD, H Groff, MD, T Warkentien, MD, A Reese,
MD, US Naval Medical Center. D Hruby, PhD, T Bolken, D Grosenbach,
PhD, S Yan, PhD, SIGA Technologies, Corvallis, Oregon. W Painter, MD,
L Trost, MD, B Lampert, MD, Chimerix, Inc., Research Triangle Park,
North Carolina. J Cohen, MD, National Institutes of Health; R Engler,
MD, Walter Reed Vaccine Healthcare Center; W Davidson, MPH, S Smith,
MS, K Wilkins, Z Braden, Y Li, PhD, I Damon, MD, Div of Viral and
Rickettsial Diseases, National Center for Zoonotic, Vector-Borne, and
Enteric Diseases, CDC]

MMWR editorial note
Although PV is a rare adverse event (one case per million during
routine vaccination during 1963-1968), its case fatality rate in
primary US vaccinees was 15 percent despite treatment with massive
amounts of VIG (intramuscular) (6). Extensive surgical debridement
was sometimes required, even necessitating disarticulation of the arm
to "debulk" the amount of infectious material (7). Before smallpox
vaccination, patients are screened for numerous contraindications
(8). At the time of his vaccination, the patient described in this
report did not have any obvious signs or symptoms that would meet any
exclusion criteria for vaccination. Training in use of, and careful
adherence to, screening tools can identify vaccine candidates at risk
for PV and other adverse events (2). Despite this, vaccinees with
occult immunodeficiencies might not be recognized, and therefore
appropriately deferring vaccination in these persons is not always possible.

Lack of inflammation at the expanding vaccination site is the
hallmark of PV. Any smallpox vaccinee who has an expanding,
nonhealing, painless vaccination site without inflammation for more
than 2 weeks should be evaluated for an underlying immunodeficiency,
and diagnosis of and treatment for PV should be considered.
Health-care providers should report suspected cases of PV or other
adverse events to the Vaccine Adverse Event Reporting System (VAERS).
Suspected cases of PV also should be reported to state health
officials and CDC for clinical consultation and to obtain select
therapeutics available only through the SNS. State health departments
should call the CDC Emergency Operations Center at 770-488-7100.

This patient's protracted clinical course is consistent with
previously published cases reports and surveillance summaries. The
development of progressive vaccinia, historically observed in
patients with cellular immunodeficiencies, often leads to
superinfection and subsequent sepsis (that is, fungal, parasitic, and
bacterial infections resulting in toxic or septicemic shock, then
ultimately death). Past treatment typically included massive doses of
VIG, administration of thiosemicarbazone, blood products, and
supportive care for accompanying infections (7,9). The improvement of
progressive vaccinia in this patient was associated with receipt of
VIGIV (the only licensed product for treatment of vaccinia adverse
events stockpiled by the SNS), ST-246, and CMX001, and an increase in
lymphocyte count. The use of 2 antiviral agents with different
mechanisms of action (see note 1) was enabled by the research and
development of medical countermeasures for smallpox preparedness
activities, as well as the use of the emergency IND process. As of
[18 May 2009], the patient had shed nearly all of the scab material
on and around the vaccination site.

The rapid mobilization of military, CDC, FDA, NIH, drug manufacturer,
and academic and health-care human resources to review the case's
status and to provide daily, then biweekly laboratory findings that
guided treatment recommendations, was enabled by smallpox public
health preparedness research and training efforts.

Continuing medical education and reinforcement of training related to
the prevention, early recognition, and treatment of smallpox
vaccine-related adverse events should be part of smallpox vaccination
programs. The patient described in this report received VIGIV in the
amount originally estimated to treat 30 persons. The extraordinary
amounts of VIGIV used to treat this single case of PV underscore the
need to reevaluate the adequacy of the national stockpiled supply of
this or other medical countermeasures (treatment or prophylactic).
Such reevaluation, with additional focus on immunocompromised hosts,
will aid in the smallpox vaccination program planning and overall
smallpox preparedness efforts.

1. CDC: Recommendations for using smallpox vaccine in a pre-event
vaccination program. Supplemental recommendations of the Advisory
Committee on Immunization Practices (ACIP) and the Healthcare
Infection Control Practices Advisory Committee (HICPAC). MMWR 2003;
52 (No. RR-7) [available at
2. Vellozzi C, Lane JM, Averhoff F, et al: Generalized vaccinia,
progressive vaccinia, and eczema vaccinatum are rare following
smallpox (vaccinia) vaccination: United States surveillance, 2003.
Clin Infect Dis 2005; 41: 689-97 [abstract available at
3. Redfield RR, Wright DC, James WD, Jones TS, Brown C, Burke DS:
Disseminated vaccinia in a military recruit with human
immunodeficiency virus (HIV) disease. N Engl J Med 1987; 316: 673-6.
4. Nell P, Kohl KS, Graham PL, et al: Progressive vaccinia as an
adverse event following exposure to vaccinia virus: case definition
and guidelines of data collection, analysis, and presentation of
immunization safety data. Vaccine 2007; 25: 5735-44.
5. CDC. Surveillance guidelines for smallpox vaccine (vaccinia)
adverse reactions. MMWR 2006; 55 (No. RR-1) [available at
6. Aragon TJ, Ulrich S, Fernyak S, Rutherford GW: Risks of serious
complications and death from smallpox vaccination: a systematic
review of the United States experience, 1963-1968. BMC Public Health
2003; 3: 26 [abstract available at
7. Maurer DM, Harrington B, Lane JM: Smallpox vaccine:
contraindications, administration, and adverse reactions. Am Fam
Physician 2003; 68: 889-96 [available at
8. Fulginiti VA, Papier A, Lane JM, Neff JM, Henderson DA: Smallpox
vaccination: a review, part II. Adverse events. Clin Infect Dis 2003;
37: 251-71
9. Bray M, Wright ME: Progressive vaccinia. Clin Infect Dis 2003; 36:
766-74 [abstract available at ].
10. Quenelle, DC, Prichard MN, Keith KA, et al: Synergistic efficacy
of the combination of ST-246 with CMX001 against orthopoxviruses.
Antimicrob Agents Chemother 2007; 51: 4118-24 [available at

Note 1. ST-246 prevents viral egress, whereas CMX001 inhibits viral
replication, and some data suggest they are synergistic in vitro (10).
Note 2. * Information about US Department of Defense policies
regarding smallpox vaccination and screening before smallpox
vaccination is available at . CDC's
clinical evaluation tools for smallpox vaccine adverse reactions are
available at .

Communicated by:

[The essential message of this episode is that future cases of PV
likely will require similar intensive and multidisciplinary clinical
consultation. Experts with background in vaccine safety, PV
treatment, clinical virology, infectious disease, and
immunodeficiencies should be engaged.

The extraordinary amounts of VIGIV used to treat this single case of
PV underscore the need to reevaluate the adequacy of the national
stockpiled supply of this or other medical countermeasures (treatment
or prophylactic). Such reevaluation, with additional focus on
immunocompromised hosts, will aid in the smallpox vaccination program
planning and overall smallpox preparedness efforts.

The text of the original article (available at the source URL above)
is accompanied by graphic images of the progressive vaccinia lesion
over a period of 8 weeks. - Mod.CP]

[see also:
Smallpox vaccination adverse events - USA (12) 20030712.1716
Smallpox vaccination adverse events - USA (11): few 20030620.1519
Smallpox vaccination adverse events - USA (10) 20030404.0825
Smallpox vaccination adverse events - USA (09) 20030329.0781
Smallpox vaccination adverse events - USA (08) 20030327.0772
Smallpox vaccination adverse events - USA (07) 20030326.0749
Smallpox vaccination, adverse events - USA (06) 20030314.0635
Smallpox vaccination, adverse events - USA (05) 20030311.0592
Smallpox vaccination, adverse events - USA (04) 20030307.0569
Smallpox vaccination, adverse events - USA (03) 20030306.0557
Smallpox vaccination, adverse events - USA (02) 20030306.0556
Smallpox vaccination, adverse events - USA 20030301.0515
Smallpox vaccination, adverse event monitoring - USA 20030206.0324
Smallpox vaccination strategies 20030103.0018]

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