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Are You Confident of the Diagnosis?
What you should be alert for in the history
Patients with progressive vaccinia (PV) have been given the smallpox vaccination (or have been exposed to a vaccinee) and have significant underlying immunocompromise (eg, HIV, underlying malignancy, transplant recipient) preventing them from controlling and eradicating the vaccinia infection.
PV lesions begin as normal smallpox vaccination takes (papule –> pustular-vesicular lesion) but continue to slowly expand with a bullous leading edge (Figure 1) Pain, pruritus and/or erythema are classically absent from the PV lesion and therefore it may go unrecognized until it has become quite large. A normal smallpox vaccination take will peak in size between 7-10 days and is usually accompanied by pruritus, mild fever, axillary lymphadenopathy and a small rim of erythema. In a normal host the vaccine take will regress and form an eschar. If the lesion is continuing to enlarge after 2 weeks, you should suspect PV and look for underlying host conditions not appreciated/identified at the time of vaccination.
Figure 1.
Progressive vaccinia in a patient with acute myeloid leukemia.
Expected results of diagnostic studies
The most helpful diagnostic to perform during the confirmatory phase of PV is PCR for orthopoxvirus (can be performed at any state or local laboratory participating in the Centers for Disease Control (CDC) Laboratory Response Network (LRN), PCR for vaccinia (species specific; can be performed at CDC or research laboratories) and culture for vaccinia virus to demonstrate viable virus/continued viral replication. ELISA for orthopoxvirus will usually be negative (unable to mount sufficient immunity). Punch biopsy in conjunction with immunohistochemical (IHC) staining for orthopoxvirus can be suggestive as well. No imaging studies are particularly helpful.
Diagnosis confirmation
The differential diagnosis is fairly limited if the patient is a known smallpox vaccinee. Superinfection of a smallpox vaccination site (accompanied by pain, erythema, possibly toxic appearance) should be excluded by culture of the site. In patients who may develop PV as a result of contact with a vaccinee, the diagnosis may be more elusive if this historical fact is missed.
Parapoxvirus lesions, orf (sheep, goats), pseudocowpox (cattle), or sealpox (seals) may have a similar appearance in immunocompromised hosts. Patients may also be exposed to vaccinia virus in a laboratory setting, but good occupational practices will hopefully limit such employees to those with intact immune systems. A good history of potential exposures, including animals, active duty personnel (i.e. smallpox vaccinees) and laboratory strains will help narrow the differential diagnosis.
Who is at Risk for Developing this Disease?
There are two essential components to the development of progressive vaccinia: (1) exposure to the smallpox vaccination (which contains live vaccinia virus) and (2) significant systemic immunocompromise (eg, HIV infection, chemotherapy recipients). Patients may be the primary vaccine recipient or may be infected during contact with a vaccine recipient. Careful screening of patients prior to receipt of the smallpox vaccination has kept the incidence of this complication less than 1 in 1 million.
What is the Cause of the Disease?
Etiology
Progressive vaccinia (PV) represents the unchecked viral replication of vaccinia virus and expansion of a smallpox vaccination site in an immunocompromised host.
Pathophysiology
Failure to mount sufficient humoral and cellular responses to vaccinia virus results in slow, progressive enlargement of a local vaccinia infection (smallpox vaccination site), which requires improvement of host immune function and antivirals/biologics for cure.
Systemic Implications and Complications
Although PV represents unchecked local replication of the vaccinia virus, viremia can develop and disseminate to other parts of the body. Blood samples and suspicious new lesions can be sampled for evidence of viable vaccinia virus DNA using PCR, DNAse (if it degrades with DNAse, it represents naked DNA only, not whole virus), and culture. Management should be maximized in this setting and the prognosis would be even more grave.
Treatment Options
Treatment options are summarized in Table I.
Table I.
| Medical | Surgical | Physical |
|---|---|---|
| Topical imiquimod (1 packet/day)Topical ST 246® (e-IND) (per manufacturer) | Debride eschars | n/a |
| Oral ST 246® (e-IND) (per manufacturer; daily dosing)Oral CMX001® (e-IND) (per manufacturer; weekly dosing) | Wide excision if all medical therapy is failing | |
| Vaccinia Immune Globulin – intravenous (VIG-IV) 6,000-24,000 IU/kg)Intravenous cidofovir (5mg/kg iv over 1 hour; may repeat in 1 week) | Limb amputation if wide excision failed to control infection |
Once progressive vaccinia (PV) is confirmed, in addition to minimizing the patient’s immunosuppression (to the degree possible), the clinician should (1) order Vaccinia Immune Globulin intravenous (VIG-IV) from the strategic national stockpile (SNS) and (2) consider obtaining ST 246® and/or CMX001® on compassionate use via the manufacturer, FDA, and the medical facility’s Institutional Board of Review (IRB). In the meantime, using available agents such as topical imiquimod as well as one dose of cidofovir (assuming normal renal function) would be prudent.
As the case progresses one could consider local debridement of eschars to minimize sequestration of viable virus. If the lesion continues to expand unchecked despite maximal management, wide excision of the PV lesion or even amputation of the affected upper extremity might be considered.
Optimal Therapeutic Approach for this Disease
Progressive vaccinia is extremely rare and lethal if not treated aggressively. The most important aspect to management of this condition is reversal of immunosuppression, when possible. In addition, use of at least vaccinia immunoglobulin intravenous (VIG-IV) and one or more antiviral is recommended. The only two FDA-approved treatments are VIG-IV and cidofovir. VIG-IV is only available through the Department of Defense and the Strategic National Stockpile (SNS).
Delivery of VIG-IV can be expected within 12-24 hours. While waiting for delivery, the use of available agents (cidofovir and topical imiquimod) is prudent. If the patient has poor renal function or is at increased risk for nephrotoxicity, the clinician may want to withhold cidofovir.
There are two promising anti-orthopoxvirus agents in clinical trials: ST 246® (SIGA Technologies Inc.) and CMX001® (Chimerix Inc.) which may be utilized under compassionate use protocols. They are both oral agents with good bioavailability and have not been implicated in end-organ toxicity and as they operate by different mechanisms they may be therapeutically synergistic.
The use of any and all available agents may be necessary to cure this infection and interval lesion sampling (swabs) for orthopoxvirus PCR/culture is recommended to evaluate the response the therapy. Successful treatment will occur over weeks to months depending on the lesion size and the degree of underlying immunosuppression.
Patient Management
There are three main aspects to management of the patient with progressive vaccinia (PV): (1) reversal of the underlying immunosuppresion if possible (eg, tapering corticosteroids, stopping chemotherapy, treating their HIV infection), (2) treatment of the vaccinia infection (see treatment options), and (3) infection control practices. Regarding infection control, because PV lesions can be very large in size and they are caused by actively replicating virus, there is potential for spread to visitors and health care providers. For this reason, patients with PV should be placed in contact precautions and visitors and health care providers who are pregnant or significantly immunocompromised should be restricted. It is even preferable to have health care providers who have been vaccinated for smallpox at some point.
Unusual Clinical Scenarios to Consider in Patient Management
Superinfection of the primary lesion may occur and worsening in appearance despite initial regression with antivirals/VIG-IV should make the clinician suspicious for bacterial superinfection. A simple swab/wound culture can confirm this and in the meantime, coverage for common bacteria such as Staphylococcus aureus is prudent.
What is the Evidence?
Cono, J, Casey, CG, Bell, DM. “Centers for Disease Control and Prevention. Smallpox vaccination and adverse events: guidance for clinicians”. MMWR. vol. 52. 2003. pp. 1-28. (This compendium of adverse events related to the smallpox vaccination is an essential reference for all clinicians who evaluate these vaccine recipients.)
Nell, P, Kohl, KS, Graham, PL. “Progressive vaccinia as an adverse event following exposure to vaccinia virus: case definition and guidelines of data collection and analysis, and presentation of immunization safety data”. Vaccine. vol. 25. 2007. pp. 5735-44. (This paper provides the consensus guidelines for confirmation of suspect progressive vaccinia cases [clinical and virologic criteria].)
“Progressive vaccinia in a military smallpox vaccinee — United States, 2009”. MMWR Morb Mortal Wkly Rep. vol. 58. 2009. pp. 532-36. (This report describes the only case of progressive vaccinia [PV] in the past decade. This patient with acute myelogenous leukemia required VIG-IV and two investigational agents [ST-246® and CMX001®] to finally eradicate his infection.)
Vellozzi, C, Lane, JM, Averhoff, F. “Generalized vaccinia, progressive vaccinia and eczema vaccinatum are rare following smallpox (vaccinia) vaccination: United States surveillance: 2003”. Clin Infect Dis. vol. 41. 2005. pp. 689-97. (This report summarizes the freqency of rare but potentially life threatening complications of the smallpox vaccination.)
Jordan, R, Goff, A, Frimm, A. “ST-246® antiviral efficacy in a non-human primate monkepox model: determination of the minimal effective dose and human dose justification”. Antimicrob Agents Chemother. vol. 53. 2009. pp. 1817-22. (This paper focuses on use of the FDA animal rule to justify the use of animal data to support the IND application for ST-246® for use in human orthopoxvirus infections. This agent has provided 100% protection to non-human primates that received a lethal dose of monkeypox. Since human orthopoxvirus infections are rare outside of the Congo Basin, the authors summarize the evidence for the safety and efficacy in non-human primates to support its use in humans.)
Parker, S, Touchette, E, Oberle, C. “Efficacy of therapeutic intervention with an oral ether-lipid analogue of cidofovir (CMX001®) in a lethal mousepox model”. Antiviral Research. vol. 77. 2008. pp. 39-49. (Similar article evaluating animal data [mice infected with lethal dose of ectromelia virus] in support of human use of CMX001®.)
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