Recognizing Emergent Dermatologic Conditions

Dermatologists discuss the clinical presentation and management of Rocky Mountain spotted fever, meningococcemia, necrotizing fasciitis, cutaneous anthrax, Stevens-Johnson syndrome, and toxic epidermal necrolysis.

By Deidre A. Buddin, MD, and Frederick C. Beddingfield III, MD, PhD

The skin is not only the body's largest organ but also the most visible. Cutaneous signs and symptoms are often early manifestations of systemic disease. By being familiar with the different types of eruptions associated with serious disease, the clinician can initiate the appropriate workup and diagnostic tests as well as early medical intervention, which can have a significant effect on outcome. This article will highlight several dermatologic emergencies related to systemic disease that require prompt diagnosis and treatment.
 

ROCKY MOUNTAIN SPOTTED FEVER

Rocky Mountain spotted fever (RMSF) has the highest mortality rate of any tick-borne illness in the United States. The clinician faces a dilemma when evaluating a patient presenting with potential signs and symptoms of RMSF. Consideration of the disease in the differential diagnosis and prompt treatment prior to confirmation of the diagnosis are critical with this readily treatable but potentially deadly illness.

Rocky Mountain spotted fever is caused by the organism Rickettsia rickettsii, an obligate intracellular gram-negative bacterium that is transmitted through the bite of a tick. The organism is spread by a variety of ticks located throughout the United States. About 90% of cases are seen between the months of April and September.

Patients most often present with symptoms 3 to 12 days after the tick bite, but many will not give a history of a bite. Initial symptoms may include fever, nausea, vomiting, severe headache, and muscle pain, essentially mimicking more common, viral illnesses, which may delay the diagnosis. Around the fourth day of fever, an eruption occurs on the ankles, wrists, and forehead. This eruption is initially blanching, rather than nonblanching or purpuric. It spreads to the trunk within 6 to 18 hours and becomes petechial and purpuric over the next two to four days.

Early recognition of the blanching macular eruption on the ankles, wrists, and forehead is vital, because the classic petechial rash associated with RMSF does not appear until approximately day six after the initial symptoms. A skin biopsy at the first sign of a rash can be helpful, although the diagnosis is usually a clinical one. A fluorescent antibody technique can be used against frozen sections of skin, which is specific but not sensitive. Ultimate confirmation of the diagnosis is usually made through serology. The indirect fluorescent antibody test detects IgM and IgG, which typically appear 10 to 14 days after infection. A titer of 1:64 is considered diagnostic.

Rocky Mountain spotted fever is classically described as a triad of a rash, fever, and a history of a tick bite. However, this triad is present in only 3% to 18% of cases. As noted earlier, many patients do not give a history of a tick bite, and in 10% to 20% of cases no rash is present. These are clearly the most diagnostically challenging cases with the highest percentage of fatal outcomes. Thrombocytopenia, hyponatremia, and increased liver function tests can be helpful clues when the diagnosis is uncertain. The presence of these laboratory findings suggests more serious disease.

A recent article in the Archives of Internal Medicine noted the following causes of delayed diagnosis, therapy, and poor outcome in RMSF:

     • waiting for a petechial rash to develop before diagnosis;
     • misdiagnosing the disease as gastroenteritis;
     • ruling out the diagnosis because there is no history of a tick bite;
     • using an inappropriate geographic exclusion;
     • using an inappropriate seasonal exclusion;
     • failing to treat on clinical suspicion;
     • failing to elicit an appropriate history; and
     • failing to treat with doxycycline.

Starting antibiotics on or before the fifth day of the illness is an important factor in decreasing mortality. Treatment should be initiated with doxycycline 100 mg twice a day orally or intravenously for seven days or for two days after the fever subsides. Alternatively, chloramphenicol can be started at 500 mg four times a day orally or intravenously or at 50 to 100 mg/kg/day. Again the treatment course is seven days or for two days after the fever subsides.

Rifampin and fluoroquinolones have been shown to have some activity in vitro and possibly in vivo. Although tetracyclines are not generally recommended in children under the age of nine, treatment with these drugs in a life-threatening situation, while awaiting confirmation of the diagnosis, is appropriate. In 1997, the American Academy of Pediatrics revised its guidelines for treating children with RMSF. Doxycycline became the preferred drug for treating children (regardless of age) due to the morbidity and mortality associated with the disease. Treatment with the tetracycline family of drugs has been associated with higher survival rates. Short courses of doxycycline to treat RMSF should not cause significant dental staining.
 

MENINGOCOCCEMIA

Meningococcemia is the leading cause of bacterial meningitis and sepsis in children and young adults in the United States. Because it is spread through respiratory secretions, people living in close quarters with an infected individual are at increased risk. For this reason, people who live in military barracks or college dormitories or even those in the presence of an infected person during a commercial airline flight of over eight hours' duration are at increased risk for acquiring the infection. Given its potential for a rapidly fatal outcome, it is vital that the clinician be familiar with the presentation of this disease.

Acute meningococcemia is caused by the gram-negative diplococcus Neisseria meningitidis. The incidence of the disease is higher in late winter and early spring. Patients initially present with nonspecific symptoms such as fever, nausea, vomiting, myalgias, and headache. Subsequent development of meningitis in these patients is indicated by nuchal rigidity and altered mental status with stupor and obtundation.

Within hours these patients can develop hypotension as well as a petechial eruption. Approximately 50% to 60% percent of patients present with a characteristic petechial rash on the trunk and lower extremities (see image below). However, lesions can also occur on the head, palms, soles, and mucous membranes, although this is less common and not characteristic. Petechial lesions are typically small and irregular, with a characteristic smudged appearance; they may also be raised with gun-metal-gray vesicular centers. This eruption can progress to large areas of ecchymoses, bullous hemorrhagic plaques, and frank necrosis. Although the petechial skin rash is more typical of acute meningococcemia, on rare occasions patients may present with a morbilliform, blanching, macular or papular eruption resembling a viral exanthem.

Meningococcemia. The petechial lesions of meningococcemia, which appear most often on the trunk and lower extremities, have a characteristic smudged appearance. Victor D. Newcomer Slide Collection

Young children without protective antibodies are at increased risk for acquiring the infection. Frequent use of day care facilities also puts children at increased risk. Patients who are immunosuppressed, such as those with asplenia, HIV infection, hematologic malignancies, and complement deficiencies, as well as those with concurrent upper respiratory infections at the time of exposure, are at increased risk as well.

Acute meningococcemia is a true medical emergency. The course of the disease is rapid and often complicated by seizures, disseminated intravascular coagulation, septic shock, bacterial endocarditis, purulent pericarditis, and massive bilateral adrenal hemorrhage. The diagnosis should be suspected in any patient presenting with fever and a petechial rash with or without signs of meningitis; it can be confirmed by demonstrating the bacteria on Gram's stain and culture of blood and cerebrospinal fluid. A skin biopsy from a petechial lesion does not reliably demonstrate the bacteria, so it should not be done as an initial workup. There is greater yield from an aspirate of a pustule or bulla, but care should be taken in making a diagnosis because of the gram-negative flora normally present on the skin.

Treatment of meningococcemia in adults is with penicillin G, 4 million units intravenously every four hours for five to seven days. In penicillin-allergic patients, treatment can be initiated with ceftriaxone or chloramphenicol. Nasal carriage rates in the general population are between 5% and 10%, and the nasopharynx is the only known human reservoir for the bacteria. Rifampin 600 mg twice a day for two days should be given to patients after recovery to eliminate nasal carriage. Alternatives include ciprofloxacin 500 mg orally for one dose or ceftriaxone 250 mg intramuscularly for one dose. The same course of rifampin, ciprofloxacin, or ceftriaxone should be given to all close contacts of the infected individual, such as household members and medical personnel. This chemoprophylaxis should be initiated promptly; ideally, it should start within 14 days of exposure.

A quadrivalent polysaccharide vaccine is available in the United States. Routine vaccination is not recommended due to the short duration of the vaccine's efficacy and its relative ineffectiveness in young children. The vaccine is recommended for use in control of outbreaks of serogroup C meningitis, in certain immunosuppressed individuals such as those with asplenia and terminal complement deficiencies, and in people intending to travel to high-risk areas such as sub-Saharan Africa.

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NECROTIZING FASCIITIS

Necrotizing fasciitis is a rapidly progressive and often fatal infection of the skin and underlying fascial planes (see image below). It can initially present like cellulitis, so it is important that this condition be considered in the differential diagnosis of cellulitis. Rapid diagnosis and initiation of appropriate therapy can have a significant effect on disease outcome and mortality.

Necrotizing fasciitis. Cutaneous findings probably gave little hint of the extent of damage from necrotizing fasciitis in this patient, seen here after surgical debridement was performed. Victor D. Newcomer Slide Collection

Necrotizing fasciitis is a rapidly developing infection in which patients present with erythema, edema, and extreme pain at the affected site, as well as fever. Typically, within one to two days of disease onset, patients develop a blue discoloration that may be associated with a bullous eruption. The affected area can become frankly gangrenous by day four to five of the illness. Unfortunately, the cutaneous findings do not correlate with the extent of the underlying necrosis, which is in fact more extensive than the cutaneous findings would suggest because of the spread of the infection along fascial planes. Eventual anesthesia of the skin is characteristic and represents damage to the subcutaneous nerves as well as occlusion of small blood vessels. Pain that is disproportionate to the clinical findings can be an initial clue to the diagnosis. Anesthesia and the presence of crepitance are later findings.

Necrotizing fasciitis can occur after surgical intervention or deep penetrating trauma; it can also develop from extension of a local skin infection or de novo. Individual risk factors include diabetes, peripheral vascular disease, and a history of drug or alcohol abuse. However, this infection also commonly occurs in patients without any predisposing illness. One form of the disease is caused by group A beta-hemolytic streptococcus and the other by a polymicrobial infection with anaerobic and aerobic bacteria.

Clinicians should have a high index of suspicion when a patient presents with acute onset of severe pain, erythema, and edema, usually of an extremity. Imaging studies such as conventional radiography, magnetic resonance imaging, and computed tomography are helpful in evaluating the depth of the infection and identifying the presence of gas in the soft tissues. Additional studies that help confirm the diagnosis include deep incisional biopsies that include fascia, fine-needle aspirates, and aerobic and anaerobic cultures.

Treatment should include prompt intervention with surgical debridement of the infected tissue, as well as appropriate intravenous antibiotics. Initial antibiotic coverage should be broad, covering anaerobes as well as aerobes until the specific causative organism is identified. Without appropriate and timely therapy, patients can develop systemic manifestations, including confusion, multiple organ failure, and systemic shock. It has been shown that if therapy and surgical debridement are initiated within four days of disease onset, the mortality rate declines from 73% to 12%.
 

CUTANEOUS ANTHRAX

Until recently, cutaneous anthrax was primarily a disease of workers employed in the animal products industry. After the terrorist-related 2001 outbreak, however, anthrax has become a disease that all physicians should be aware of and should be confident in diagnosing.

Anthrax is caused by infection with Bacillus anthracis, a large, encapsulated, spore-forming, gram-positive rod. Infection with B. anthracis can take three clinical forms: cutaneous, inhalational, and gastrointestinal. Here, we will focus on the presentation of cutaneous anthrax.

Cutaneous anthrax has an incubation time of approximately one to three days. The spore of the bacillus cannot penetrate intact epidermis, so the initial papule will usually develop at a site of previous trauma or abrasion to the epidermis. Lesions typically develop on the head, neck, and upper extremities because these areas are more prone to superficial trauma (see image). The initial lesion is an erythematous papule, which then develops a boggy, edematous base with a central vesicle or bulla that subsequently becomes hemorrhagic and necrotic. Satellite vesicles and pustules may develop.

Cutaneous anthrax. The initial erythematous papule of anthrax later turns boggy, with a hemorrhagic, necrotic central vesicle or bulla. Victor D. Newcomer Slide Collection

It is important to note that the lesions of cutaneous anthrax are painless. Patients may complain of burning or pruritus but not pain. Regional adenitis and low-grade fever typically accompany the classic cutaneous lesion, otherwise known as the "malignant pustule." In a subset of patients with cutaneous anthrax, the clinical presentation is more serious. These patients experience more severe constitutional symptoms, with high fevers and prostration as well as multiple hemorrhagic and necrotic plaques.

The diagnosis of cutaneous anthrax can be made by culture of either the vesicular fluid or the aspirate from beneath a necrotic eschar. Gram's stain of a smear from the above fluids can support the diagnosis initially, but a culture is needed to definitively identify the organism. Because nonpathogenic gram-positive bacilli can be confused with B. anthracis, a specific gamma bacteriophage is used to identify the infectious organism. Cultures from patients taking antibiotics are unlikely to yield positive results. In these cases, a skin biopsy from the edge of the lesion should be taken. Silver staining and immunohistochemical stains should then be used to identify the organism. Additionally, blood cultures should be sent. The organism can occasionally be cultured from the blood of patients with cutaneous anthrax.

The primary differential diagnosis for cutaneous anthrax includes staphylococcal infection, brown recluse spider bite, herpes simplex infection, and ecthyma. These should easily be differentiated due to the absence of pain and tenderness in cutaneous anthrax lesions.

A recent article in the Journal of the American Academy of Dermatology further outlined the algorithm for the management of cutaneous anthrax:

     • Notify your local department of health of a suspected case of anthrax.
     • Maintain universal precautions, although wearing a mask is not required.
     • Obtain sterile Dacron or rayon (not cotton-tipped) swabs of vesicular fluid or from the base of an eschar for gram stain and culture.
     • Obtain a full-thickness, 4-mm, punch biopsy specimen for histology, immunohistochemistry, and polymerase chain reaction (PCR) from the edge of either a vesicle or eschar (or preferably both, if present).
     • Draw one 5-ml tube of blood into a red-topped tube and label it "anthrax serology."
     • Draw one 5-ml tube of blood into a purple-topped tube for possible PCR by the Centers for Disease Control and Prevention.
     • Obtain blood cultures from febrile or hospitalized patients.
     • Initiate appropriate treatment.

Recommended treatment for cutaneous anthrax has typically been with penicillin. However, there is cause for concern here because an inducible penicillinase has been found with recent genomic sequencing of anthrax isolates. Isolates from the 2001 outbreak have been shown to be susceptible to quinolones, tetracyclines, rifampin, clindamycin, and aminoglycosides, among other drugs. First-line therapy for cutaneous anthrax in adults without associated systemic symptoms includes ciprofloxacin 500 mg twice a day or doxycycline 100 mg twice a day. Susceptibility testing should be done to direct further treatment.

Traditionally, a treatment course was 7 to 14 days or until the associated edema had resolved. However, it should be noted that patients affected by the 2001 outbreak, including those with cutaneous anthrax, were treated for a total of 60 days. There is also an anthrax vaccine. It has been shown that post-exposure treatment is optimized with administration of the vaccine, along with the appropriate antibiotic therapy.

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STEVENS-JOHNSON SYNDROME AND TOXIC EPIDERMAL NECROLYSIS

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) can be thought of as essentially the same disease, differing only in severity. Both SJS and TEN are mucocutaneous reactions that have been classified arbitrarily by how much body surface area is involved. Stevens-Johnson syndrome involves less than 10% of body surface area, while TEN involves more than 30%. Cases involving between 10% and 30% of body surface area are designated as SJS-TEN overlap. The incidence of both SJS and TEN is rare; estimates range from approximately one to two cases per million per year.

Drugs are the primary cause in 80% to 95% of TEN cases and 50% of SJS cases. More than 100 medications have been reported to cause SJS and TEN. The task of finding the implicated agent may seem daunting. However, there are medications that have been shown to be more commonly implicated. Medications containing sulfa moieties, for example, are at the top of the list. Because these drugs are commonly used for prophylaxis and treatment of Pneumocystis carinii pneumonia in HIV-infected individuals, they are playing an increasingly common role in the induction of SJS and TEN. This is compounded by the fact that HIV-infected patients as a group tend to be more susceptible to the development of SJS or TEN. Anticonvulsive agents such as phenytoin, carbamazepine, and phenobarbital are commonly implicated agents, as are nonsteroidal anti-inflammatory agents, allopurinol, and antibiotics such as cephalosporins, fluoroquinolones, and penicillins.

Though medications lead the list of causative factors, infections have also been implicated in SJS and TEN, particularly Mycoplasma pneumoniae infection and infection with hepatitis A, Epstein-Barr virus, adenovirus, and coxsackievirus. Acute graft-versus-host disease has also been shown to be a causative factor. Unfortunately, the development of TEN in acute graft-versus-host disease has a 100% mortality rate. Both SJS and TEN may also result from idiopathic causes.

Patients typically present with a prodrome of fever and other constitutional symptoms between 1 to 14 days before the onset of the rash. An eruption then starts on the face, neck, and trunk and rapidly spreads to the extremities. The eruption typically appears as pink macules or targetoid lesions that resemble pink patches with dusky centers. The skin is typically painful and tender to touch. Nikolsky's sign (extension of bullae with lateral pressure) is positive in these patients. Lesions typically coalesce and may form hemorrhagic or flaccid bullae. Areas of skin may begin to denude, leaving large red erosions (see image below). This typically occurs first at areas of pressure and trauma.

Toxic epidermal necrolysis. In this rare, usually drug-induced disorder, large areas of denuded skin may develop, especially in areas subject to pressure or trauma. Victor D. Newcomer Slide Collection

In severe cases of TEN, loss of fingernails, toenails, and eyebrows may occur. Development of the skin rash is paralleled by mucosal involvement. Typically, the oral mucosa, including the vermilion border of the lip, is involved, heralded by large areas of hemorrhagic crusting. This is usually accompanied by involvement of the conjunctiva and, less commonly, the anogenital mucosa.

The diagnosis can be made by performing a skin biopsy. In severe cases, frozen sections of the biopsy specimen are warranted for a more timely diagnosis. Treatment of these patients depends on the amount of body surface area involved. In cases of TEN with more than 30% of body surface involvement, transfer to a burn unit may be appropriate. These patients also require more extensive medical care; they may have internal organ involvement and electrolyte abnormalities and may develop hemodynamic shock, acute respiratory distress syndrome, seizures, myocardial infarction, and obtundation leading to a comatose state.

An extensive investigation should be made to eliminate the likely causative factor. It is very important to discontinue the implicated drug as soon as possible. Associated infections should be treated if they are suspected to be the underlying cause. Traditionally, treatment of patients with TEN involved systemic corticosteroids, but this has become controversial and many physicians are choosing not to treat patients in this manner. Intravenous immunoglobulin (IVIG) has been shown to be very promising in the treatment of TEN and SJS. Preliminary studies have shown that early treatment with IVIG at 1 g/kg/day for three days has greatly improved outcomes in patients. However, it should be noted that other studies have failed to show a benefit.

Mortality rates differ depending on disease severity. For SJS, the mortality rates range from 1% to 5%; for TEN, they are considerably higher, ranging from 5% to 50%. Poor prognostic factors include extensive skin involvement, old age, neutropenia, history of polypharmacy, and impaired renal function.
 

LIFESAVING DIAGNOSIS

Prompt diagnosis and treatment can greatly affect outcome in these rapidly developing and possibly fatal dermatologic emergencies. By being familiar with the clinical presentations of these diseases, particularly cutaneous signs and symptoms, the clinician can initiate the appropriate workup and make a timely and potentially lifesaving diagnosis.

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