Vesicular Rash

Poxviruses Including Smallpox and Monkeypox

Poxviruses are double-stranded DNA viruses that are relevant because of concerns regarding possible bioterrorism with smallpox.^1,² Additionally, outbreaks of monkeypox infection in humans have been detected, albeit rarely.³ The poxviruses and their major clinical manifestations are listed in Table 145-1. In general, a common feature of poxviruses is that they cause vesicular skin eruptions.

TABLE 145-1 Common Clinical Manifestations of Poxviruses

Virus	Clinical Manifestations
Variola (smallpox)	Diffuse vesicular rash; systemic disease
Monkeypox	Vesicular rash
Vaccinia (cowpox)	Vesicular rash; postinfectious encephalitis
Parapoxvirus	Orf (localized vesicular lesion)
Molluscipoxvirus	Molluscum contagiosum
Tanapox virus	Vesicular rash

Smallpox

The last case of endemic smallpox occurred in Somalia in 1977, and eradication of the disease was declared in 1980.⁴ The virus (variola) has been maintained in some laboratories—the last known case of laboratory-acquired smallpox occurred in the United Kingdom in 1978. In part as a result of this accident, the number of laboratories that retained the virus was reduced from 76 to just 2. These laboratories are at the Centers for Disease Control and Prevention (CDC) in Atlanta in the United States and the Vektor Institute in Novosibirsk, Russia. It is not known if all other laboratories destroyed their stocks of virus—therefore, the potential exists for a deliberate release of variola as an act of bioterrorism.^1,⁵

The incubation period for smallpox is 7 to 17 days (mean 10-12).⁴ A prodromal phase which consists of abrupt onset of severe headache, backache, and fever occurs. The fever often reaches 40°C, but then subsides. The rash then begins; initial lesions are small, red macules, which over 2 to 3 days become macular then vesicular. The lesions commence on the face and extremities, then cover the entire body including palms and soles of feet. The lesions subsequently may umbilicate and crust.

The rash of smallpox could be confused with monkeypox, generalized vaccinia and eczema vaccinatum, chickenpox, coxsackievirus infection, herpes simplex virus (HSV) infection (especially eczema herpeticum), rickettsialpox, insect bites, drug eruptions, and acne. A classic feature of smallpox is that the lesions are all at the same stage of development. In contrast, with chickenpox, individual lesions are present at different stages. With chickenpox, fever occurs with the onset of the rash.

It is well known that smallpox is associated with significant mortality; however it is not clear what the likelihood of mortality would be in patients who receive good supportive care, such as exists in modern intensive care units (ICUs). There are many reasons for the mortality associated with smallpox. Substantial amounts of fluid and protein can be lost by febrile persons with numerous weeping lesions. In some patients, death may occur before the appearance of any rash, since this prodromal period is associated with significant viremia. A hemorrhagic form of smallpox also is associated with high mortality.⁴ Encephalitis occurs in fewer than 1% of patients infected. Secondary bacterial infections of the skin lesions may occur and are heralded by a second temperature spike.⁴ Although cough is not usually a prominent symptom of smallpox, secondary bacterial pneumonia may occur, particularly in patients with severe disease.

The CDC recommends an algorithmic approach to the diagnosis of smallpox (this is described in detail at http://www.bt.cdc.gov/agent/smallpox). Patients can be subdivided into low-risk, moderate-risk, and high-risk groups depending on a variety of variables (Boxes 145-1 and 145-2). Patients at low or moderate risk for smallpox should undergo polymerase chain reaction (PCR) testing of the skin lesion for varicella-zoster virus (VZV) infection, HSV, plus enterovirus. Patients at moderate risk should undergo consultation by infectious diseases or dermatology specialists. Electron microscopy should be performed if PCR for these viruses is negative. If rapid testing for VZV and HSV is negative for a moderate-risk patient, the adequacy of specimen collection should be confirmed. If there is ongoing clinical suspicion for smallpox, local and state health departments should be consulted. For patients at high risk for smallpox, all testing should be performed at the CDC. This testing should include variola real-time PCR, Orthopoxvirus real-time PCR, and nonvariola Orthopoxvirus real-time PCR, in addition to tests for VZV, HSV, and enteroviruses.

There is no approved treatment for smallpox.⁴ Prevention of secondary cases is crucial. A suspected case of smallpox should be managed in a negative-pressure room. Additionally, strict respiratory and contact isolation is essential (detailed instructions are Available at: http://www.bt.cdc.gov/agent/smallpox).⁴

Vaccinia

Vaccinia is the poxvirus used in smallpox immunization. Primary vaccination results in a vesicle at the site of vaccination, usually within 3 to 5 days. This vesicle becomes pustular or is surrounded by induration or congestion 6 to 8 days after vaccination. Rarely, a generalized rash characterized by multiple small, vesicular lesions occurs. Occasionally, severe complications result from smallpox vaccination. If vaccinia is administered to a person with an immunologic deficiency, progressive necrosis at the site of vaccination may occur (vaccinia necrosum). Secondarily, lesions may spread to other parts of the body. Such cases may be fatal. Patients with eczema may develop dissemination of vaccinia virus in the abnormal skin, leading to a generalized rash (eczema vaccinatum or Kaposi varicelliform eruption). Vaccinia immunoglobulin (0.6 mL/kg every 24 hours) can be prescribed for disseminated infection.

Encephalitis due to vaccinia may occur 1 to 2 weeks after vaccination and is associated with a mortality of 10% to 30%. Myocardial infarction, pericarditis, myocarditis, and dilated cardiomyopathy have been observed after smallpox vaccination. In 2003, 37,901 potential bioterrorism first responders received smallpox vaccine in the United States. There were 822 reports of adverse events; 100 of 822 were serious, resulting in 85 hospitalizations, 2 permanent disabilities, 10 life-threatening illnesses, and 3 deaths. Among the 100 serious adverse events, 21 cases were myocarditis and/or pericarditis, 10 cases were ischemic cardiac events, 2 cases were generalized vaccinia, and 1 case was postvaccinial encephalitis. Serious adverse events were more common among older revaccinees than in younger first-time recipients.⁶

From December 2002 to January 2004, the U.S. Department of Defense vaccinated 578,286 military personnel with vaccinia.⁶ Thirty cases of suspected contact transfer of vaccinia were reported.⁶ Contact transfer is the spread of vaccinia from a recipient of the smallpox vaccine to another person. This spread occurs because the live virus used in the vaccine is present on the skin at the site of the vaccination. Spread of the virus to other parts of the body (autoinoculation) also can occur via the same mechanism. No cases of vaccinia necrosum or eczema vaccinatum were observed in the people with contact transfer of the virus.

Monkeypox

Monkeypox was first recognized in 1958 as a disease of primates. The disease subsequently was recognized in rodents. Beginning in 1970, cases in humans were reported in central Africa.⁷ In 2003, cases occurred in the United States in residents of the Midwest who had contact with imported prairie dogs.³ Patients developed vesicular skin lesions and fever/sweats. Although case-fatality rates of 4% to 22% have been observed in outbreaks of the infection in Africa, none of the 11 patients in the American outbreak died.³

Herpesviruses

HSV, VZV, and herpes B virus all are capable of causing vesicular skin rash and other systemic manifestations of disease. The herpesviruses are large, enveloped DNA viruses that exhibit lifelong latent infection.^8,⁹ The eight known human herpesviruses are HSV types 1 and 2; VZV; cytomegalovirus (CMV); human herpesvirus (HHV) types 6, 7, and 8; and Epstein-Barr virus (EBV).

Herpes Simplex Virus

HSV infections are found worldwide. Characteristically, HSV-1 is associated with orolabial disease, and HSV-2 is associated with genital infection, although this is not a rigid distinction. Primary infections (first infections with HSV-1 or HSV-2) are usually associated with mucosal lesions and systemic signs and symptoms. Mucosal and cutaneous lesions are vesicular and usually localized, although disseminated infection may occur rarely. Patients with atopic eczema or severe burns may develop extensive infections.

Primary HSV infection may have severe complications. Aseptic meningitis may occur and is more common with HSV-2. Meningeal symptoms usually start 3 to 12 days after the onset of genital lesions. Transverse myelitis and autonomic nervous system dysfunction also may occur in conjunction with primary genital HSV infection. HSV encephalitis in adults usually is not associated with primary infection. Potentially, reactivation of latent HSV-1 infection in trigeminal or autonomic nerve roots may be associated with extension of virus into the central nervous system (CNS) via the enervation of the middle cranial fossa. Occasionally, patients with primary HSV infection develop hepatitis, pneumonia, or thrombocytopenia.

By virtue of the establishment of latency, HSV-1 or HSV-2 may reactivate. HSV reactivations may be less severe than primary infections. In immunocompromised hosts, however, reactivation of HSV-1 or HSV-2 may be associated with disseminated infection or severe local esophagitis, hepatitis, or pneumonia. Neonatal herpes, occurring in an infant of a mother with primary or reactivation infection at the time of delivery, carries a high risk of disseminated fatal infection.

HSV-1 encephalitis is frequently seen in the ICU and is characterized by confusion or coma accompanied by a cerebrospinal fluid (CSF) lymphocytosis. Magnetic resonance imaging (MRI) of the brain may show temporal lobe lesions. Testing of CSF by PCR for HSV-1 is typically positive.

Diagnosis of HSV-1 or HSV-2 infection causing a vesicular skin lesion can be suspected clinically by the presence of multiple vesicular lesions on an erythematous base, occurring in the orolabial or anogenital areas. A precise diagnosis can be established easily by use of PCR on scrapings from lesions. Results can be available within hours of specimen collection.

Varicella-Zoster Virus

Primary VZV infection causes chickenpox, whereas reactivation infection causes shingles (zoster). Chickenpox is characterized by multiple vesicular lesions, whereas shingles is characterized by a unilateral vesicular eruption with a dermatomal distribution. Immunocompromised patients with shingles may develop disseminated cutaneous infection that may resemble chickenpox.

Chickenpox usually is associated with fever, constitutional symptoms, and a vesicular skin rash. Most skin lesions are small vesicular lesions with an erythematous base. Successive crops of lesions occur over 2 to 4 days, so lesions at all stages from fresh vesicles to crusted lesions are present simultaneously.

Secondary bacterial infection of vesicular lesions is relatively common, with infection involving Staphylococcus aureus and Streptococcus pyogenes being most common. One manifestation of secondary bacterial infection is the occurrence of fever after the fever associated with onset of chickenpox has subsided. Severe infection with toxic shock syndrome may result.^10,¹¹

Chickenpox is associated with pneumonia in 1 in 400 cases of infection.^12,¹³ A larger proportion of people may have some pulmonary involvement, but it is typically asymptomatic. Pregnant women and immunocompromised patients are at high risk of life-threatening pneumonia. Chickenpox pneumonia is generally manifested by cough and shortness of breath 3 to 5 days after the onset of the rash. Chest radiography typically shows a reticulonodular infiltrate. Respiratory failure may occur.

Neurologic complications of chickenpox include encephalitis, acute cerebellar ataxia (one in about 4,000 cases),¹⁴ and cerebral angiitis. Encephalitis due to VZV is less common than pneumonia but nevertheless may be life threatening. The typical manifestation is onset of headaches followed by depression in level of consciousness occurring in an adult within 2 weeks of chickenpox. Acute cerebellar ataxia is more common in children 1 to 3 weeks after the onset of chickenpox. Ataxia and slurred speech may occur, but usually with complete resolution.

As with HSV infections, the rash of chickenpox or shingles can usually be diagnosed confidently on clinical grounds or confirmed by PCR of scrapings of a skin lesion. PCR can also be performed on CSF to diagnose VZV encephalitis.¹⁴

Herpes B Virus (Cercopithecine herpesvirus 1)

Herpes B virus (Cercopithecine herpesvirus 1) infection is a relatively benign disease of monkeys. However, herpes B virus infection of humans, usually occurring from monkey bites or scratches, is a severe and potentially fatal disease. Monkeys of the Macaca genus (rhesus and cynomolgus monkeys) are considered highest risk. An incubation period of 2 to 14 days usually is observed after the bite or scratch. Initial symptoms are nonspecific but include fever, malaise, and headache. A cluster of small vesicles may occur at the bite site. A severe encephalomyelitis may ensue, with death occurring in days. In the United States, only one reference laboratory is equipped to identify the virus. Prompt and exhaustive cleaning of wounds, followed by early initiation of acyclovir or valacyclovir, may prevent the occurrence of severe disease. Additional information with contacts is Available at: http://www.cdc.gov/niosh/docs/99-100/.^15,¹⁶

Fever in Immunocompromised Patients

Numerous viruses can cause fever as a presenting symptom. In the absence of specific manifestations such as pneumonia or encephalitis, viral infections are rarely life threatening. The onset of fever in immunocompromised individuals may, however, be the harbinger of severe overwhelming viral infection.

Cytomegalovirus

CMV infection is a classic cause of severe infection in immunocompromised hosts, especially transplant recipients and patients with human immunodeficiency virus (HIV) infection.¹⁷^–¹⁹ Infection can be primary or due to reactivation. The risk of end-organ CMV infection depends on the degree of immunosuppression and whether infection is primary or reactivation. For solid-organ transplant recipients, there is a significant risk of primary infection in patients who were seronegative for CMV before transplantation and received an organ from a seropositive donor.^17,¹⁹

The organs commonly affected by CMV infection include the esophagus, colon, retina, and lungs. Virtually any organ can be infected, however, including the CNS. Some patients present with a syndrome of fever, malaise, and hematologic abnormalities, without specific end-organ abnormalities.

Given the high risk of CMV infection in solid-organ transplant recipients, strategies should be employed to prevent CMV infection.^17,^20,²¹ Two options are prophylaxis or preemptive therapy. Prophylaxis implies the administration of preventive therapy to all persons at risk.¹⁷ In contrast, preemptive therapy is the administration of antiviral therapy only to persons at highest risk, as determined by a positive result on a regularly monitored blood test for CMV infection.¹⁷ Such therapy is given even if the patient is asymptomatic. Detection of CMV by PCR is used most often for early detection of CMV infection.

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