Toxic epidermal necrolysis (TEN) and Stevens–Johnson syndrome (SJS) are entities on a spectrum of severe cutaneous reactions that are most commonly caused by medications. They exhibit severe blistering and sloughing of the skin (Fig. 195.2) with mucosal involvement (Fig. 195.3), and may have high morbidity and mortality. The distinction between TEN and SJS is based on the percentage of skin involved with SJS being < 10%, TEN being > 30%, and SJS/TEN overlap being 10% to 30% of the body surface area affected. The cumulative annual incidence of these entities has been estimated at 1.89 per million people. SJS is more common in children, whereas TEN is more common in adults. TEN is more common in women, and the incidence increases with age and immunosuppression [1]. HIV infection increases the risk of SJS/TEN with the incidence of TEN in HIV patients receiving trimethoprim-sulfamethoxazole, 8.4 per 100,000 exposures as opposed to 2.6 per 100,000 exposures in non-HIV infected individuals [2]. There appears to be a genetic component to SJS/TEN, as multiple studies have demonstrated HLA alleles related to hypersensitivity to specific medications, however, at this time human leukocyte antigen (HLA) testing is not clinically useful due to its expense [2].

Ninety five percent of patients with TEN have a history of drug exposure and there is a clear relationship to a drug in 80% of cases. Only half of SJS cases are related to medications with the remainder being attributed to infections, including mycoplasma, which may present as mucositis without typical skin manifestations. The most common causative medications along with relative risks listed in parentheses include: trimethoprim-sulfamethoxazole (172), carbamazepine
(90), NSAIDS (72), corticosteroids (54), phenytoin (53), allopurinol (52), phenobarbital (45), valproic acid (25), cephalosporins (14), quinolones (10), and aminopenicillins (6.7), with more recent reports implicating lamotrigine, rituximab, imatinib, lenalidomide [3]. The time from drug ingestion to clinical symptoms is generally 1 to 3 weeks, except for the aromatic anticonvulsants that can take up to 2 months to cause disease [4].

The cutaneous eruption may be heralded by a 1 to 3 day prodrome of fever and flu-like symptoms. The initial cutaneous finding is irregularly shaped erythematous to purpuric macules with irregular size and shape distributed on the face and trunk. This may evolve into flaccid blisters that may be easily enlarged with lateral pressure. The skin can become gray, which usually heralds full thickness epidermal sloughing. Mucosal involvement is present in 90% of patients with SJS and TEN, with the most common affected areas being the conjunctiva, oral cavity, and genitalia. Symptoms include severe skin pain and difficulty swallowing and urinating. Respiratory epithelium may also be involved with resultant dyspnea, pulmonary edema, and hypoxia.

The differential diagnosis includes staphylococcal scalded skin syndrome (SSSS), acute generalized exanthematous pustulosis (AGEP), severe acute GVHD, drug-induce linear IgA bullous dermatosis, and paraneoplastic pemphigus. The appropriate clinical setting and skin biopsy easily differentiate SJS/TEN from these entities. Two skin biopsies are recommended, one for frozen section and the other for routine H&E. Early lesions demonstrate necrotic keratinocytes, while advanced lesions reveal full-thickness epidermal necrosis, and a recent study indicates that the density of the dermal mononuclear cell infiltrate correlates with the severity of disease and mortality rate [5].

Prompt diagnosis and rapid cessation of the causative medication along with supportive therapy is the cornerstone of
therapy. Careful monitoring of fluid volume, electrolytes, renal function, nutritional status, and evaluation for signs of sepsis should be performed. For extensive body surface involvement, care should be provided in an ICU with staff accustomed to caring for patients with fragile and denuded skin, usually a burn unit. Uninvolved skin should not be manipulated, while involved skin should be covered with Vaseline impregnated gauze and a topical antibiotic ointment. Debridement of necrotic skin may be followed by placement of artificial membranes or biologic dressings such as xenografts or allografts. Daily bacterial cultures should be performed of involved skin and mucosa as well as blood, urine, and any intravenous catheters, as sepsis is the most common cause of mortality in patients with SJS/TEN. Systemic antibiotics should not be started unless signs of sepsis are present because of the risk of selecting for antibiotic resistant organisms, and prophylactic use of antibiotics has not been shown to improve outcome [2]. Patients should be followed by an ophthalmologist to avoid conjunctival scarring. Currently, there is no gold standard systemic therapy for TEN/SJS. Intravenous immunoglobulin (IVIG) has been used, based on its ability to bind Fas receptors, thought to be a major mediator of apoptosis in TEN/SJS. Unfortunately, there are no randomized double-blind trials to support its use, and while some studies have shown mortality benefit with doses more than 1 g per kg per day, others have shown no benefit or even increased mortality associated with its use [6]. Systemic corticosteroid pulse therapy early in the disease course has been shown to have benefit in preventing ocular complications, and topical high potency corticosteroids appear to prevent corneal epithelial stem cell loss and scarring [7]. There is some emerging evidence that high dose (1.5 mg/kg/day) pulse corticosteroids decreased TEN-associated mortality [2]. Other systemic treatments have been tried, but none are recommended at this time [8].

The mortality rate for SJS and TEN is 5% and 30%, respectively, and is directly related to the percentage of skin involved. Risk of mortality can be predicted using the SCORTEN algorithm. One point each is assigned for the presence of the following seven criteria: age > 40 years, presence of malignancy, heart rate > 120, initial epidermal detachment > 10%, serum urea nitrogen > 10 mmol per L, serum glucose > 14 mmol per L, and serum bicarbonate < 20 mmol per L. The points are added and the predicted mortality based upon this total is 0 to 1 (3.2%), 2 (12.1%), 3 (35.8%), 4 (58.3%), and 5 or more (90%) [9]. Healing of sloughed epidermis usually takes 3 weeks and survivors may experience ocular scarring and visual loss. If the causative medication is reintroduced, the disease may recur in less than 48 hours. Notably, a patient who experiences TEN to one class of medication is not predisposed to TEN in response to other medication classes; however, cross-reactivity may be seen between related drug classes such as penicillins and cephalosporins.

Drug rash with eosinophilia and systemic symptoms (DRESS) is a potentially fatal hypersensitivity reaction to medication, most commonly anticonvulsants [10]. The incidence is between 1/1,000 to 1/10,000 exposures and it is thought to occur with higher frequencies in patients of African ancestry [11].

Although the etiology of DRESS is not understood completely, alteration in drug detoxification pathways and a causative role for human herpesvirus 6 have been proposed [12,13]. DRESS is most commonly caused by the aromatic anticonvulsants, including phenobarbital, phenytoin, and carbamazepine. Of note, these drugs may cross-react. Other common
causes include allopurinol, sulfonamides, minocycline, and dapsone.

In contrast to other drug reactions, DRESS may develop as late as 4 to 6 weeks after the offending medication has been introduced. DRESS has even been reported to occur more than 1 year after initiating allopurinol. The rash is usually morbilliform, though erythroderma, pustules, vesicles, and purpuric areas may also be present. High fever and edema of the face are hallmarks of this entity. Systemic involvement may include pharyngitis, lymphadenopathy, hepatosplenomegaly, peripheral eosinophilia, abnormal liver function tests, arthralgias, pulmonary infiltrates, and interstitial nephritis. Allopurinol and minocycline are associated with severe DRESS, the former frequently causing renal failure, and the latter causing pneumonitis [14]. Circulating atypical lymphocytes may also be present [11]. High eosinophil count and multiple medical comorbidities were poor prognostic factors in one series of 30 patients with DRESS [15]. Another study found that vitamin D deficiency was common among patients with DRESS, and that myocarditis is an underdiagnosed systemic manifestation, which may be detected by cardioselective biomarkers, echo, or cardiac MRI [16].

The differential diagnosis includes AGEP, SJS, TEN, Kawasaki’s disease, and the hypereosinophilic syndrome. Histopathology of skin biopsies taken from patients with DRESS is variable and therefore not diagnostic [15]. The history of recent initiation of a suspect drug, the presence of atypical lymphocytes, peripheral eosinophilia, increased liver function tests, abnormal serum creatinine or urinalyses, and cutaneous eruption as described above, especially with facial edema, suggest the diagnosis of DRESS.

The most effective treatment is prompt diagnosis and cessation of the offending drug. Antipyretics may be used to treat the fever but they have no impact on disease outcome. Multiple independent case reports have suggested that systemic corticosteroid therapy may halt internal disease progression. Additionally, the disease has been reported to recur upon stopping corticosteroid treatment too soon. This has led many authorities to suggest treatment with systemic corticosteroids when there is internal involvement. However, no case control or randomized controlled trial data are available [17]. Thus, primary and secondary prevention of DRESS is of utmost importance. One must have knowledge of the most common causative drugs and an understanding of the cross-reactivity among the aromatic hydrocarbons. Mortality rates up to 10% have been reported and are primarily due to fulminant hepatitis.

Acute generalized exanthematous pustulosis (AGEP), also known as toxic pustuloderma [18] or pustular drug rash [19] is a very rare drug reaction that presents with fever, leukocytosis, and multiple pustules on a background of generalized erythema. There appears to be no sexual predilection and AGEP may occur at any age. Incidence rates have been estimated at 1 to 5 cases per million per year [20].

Drugs are responsible for at least 90% of AGEP cases. In a report of 97 cases from Europe, aminopenicillins (odds ratio [OR] = 23), macrolides (OR = 11), quinolones (OR = 33), hydroxychloroquine (OR = 39), calcium channel blockers (OR = 15), anticonvulsants (OR = 8), and corticosteroids (OR = 12) were the most common causative agents [21]. More recently, spider bites have been reported as triggers [22]. Patch testing with the offending agent is frequently positive reflecting the dominant role of T cells in the disorder.

The eruption is frequently sudden in onset and the majority of cases appear within 24 hours to several days of exposure to the offending agent. A fever of more than 38°C is followed by the appearance of tiny nonfollicular pustules on a background of generalized erythema and edema. Petechiae, purpura, vesicles, or target lesions may be present, and oral lesions may be observed in 20% of patients. The face and intertriginous areas are the most common presenting locations. Neutrophilia occurs in 90% and eosinophilia in 30% of patients. Liver function tests are usually normal and there is typically no systemic involvement, but lymphadenopathy is sometimes seen. The differential diagnosis includes pustular psoriasis, subcorneal pustular dermatosis, DRESS, and in severe cases, TEN. An acute onset and clinical history of a new drug favors AGEP over pustular psoriasis, whereas DRESS and TEN exhibit systemic involvement.

Discontinuation of the causative drug is the definitive treatment. Once the diagnosis is made and the causative drug is stopped, the pustules will resolve in less than 15 days with desquamation, and prognosis is excellent. Antipyretics may be used for symptomatic treatment of the fever and topical steroids may be used for symptomatic treatment of the rash, although neither will hasten the resolution of the eruption.

Toxic shock syndrome (TSS) is an acute febrile illness caused by toxin-producing strains of Staphylococcus aureus, presenting with fever, rash, and hypotension and often progressing to multiorgan failure [29]. A similar syndrome caused by Streptococcus pyogenes has also been described, known as streptococcal toxic shock syndrome (STSS) [30]. TSS is rare and more often seen in young women (yearly incidence of 1/100,000 women of reproductive age) than men, most likely due to its association with tampon use. Predisposing factors for TSS include menstruation, recent childbirth or surgery, burn wounds, intravenous drug use, pneumonia, and influenza. STSS has an estimated yearly incidence of 10 cases/100,000 population and shows no gender predilection [29]. Pathophysiology of both entities involves massive release of cytokines due to bacterial toxins acting as superantigens.

Both TSS and STSS present with high fever, headache, nausea and vomiting, and myalgias and arthralgias. Hypotension, metabolic acidosis, acute renal failure, elevated transaminases, thrombocytopenia, leukocytosis, disseminated intravascular coagulation, cardiomyopathy, and acute respiratory distress syndrome (ARDS) are often seen. Most patients with TSS do not have an obvious localized S. aureus infection. In contrast, 80% of patients with STSS have a clinically evident painful streptococcal soft tissue infection, often necrotizing fasciitis, usually of an extremity [29].

Skin findings are especially prominent in TSS, which classically presents with generalized macular (sunburn-like) erythema, but a scarlatiniform rash with accentuation of the flexures can also be seen. Erythema of the palms and soles, conjunctivae, and mucous membranes is also observed. The patient may develop a bright red “strawberry” tongue. The eruption is followed 1 to 2 weeks later by desquamation, especially of the palms and soles.

The differential diagnosis includes Rocky Mountain spotted fever, meningococcemia, Kawasaki’s disease, SSSS, scarlet fever, or a medication hypersensitivity reaction. Blood cultures are positive in 60% of cases of STSS, less often (< 15%) in TSS [29]. Diagnosis is on clinical grounds and requires four major criteria (fever > 38.9°C, diffuse macular erythroderma, desquamation 1 to 2 weeks later, hypotension, and poor peripheral perfusion) and at least three minor criteria (vomiting or diarrhea; severe myalgia or CPK twice normal; hyperemic mucous membranes; elevated urea or creatinine; elevated bilirubin, ALT, or AST; platelets < 100 × 10⁹/L; and disorientation or altered consciousness). TSS also has a specific T cell signature with early depletion of the V beta 2 subset followed by massive expansion, which can aid in early diagnosis [31]. Skin biopsy showing a neutrophilic and eosinophilic perivascular and interstitial infiltrate with scattered necrotic keratinocytes can be helpful.

Treatment is with supportive care (intravenous fluids and vasopressors), penicillinase-resistant antibiotics, and intravenous immunoglobulin (IVIG) or fresh frozen plasma (FFP). Nafcillin 1 to 2 g intravenously every 4 hours is the first line antibiotic for TSS and clindamycin 600 to 900 mg intravenously every 8 hours for STSS. As cases of TSS due to methicillin-resistant S. aureus (MRSA) are increasing in frequency, treatment with vancomycin (1 to 2 g IV every 24 hours) may sometimes be necessary [32]. In addition, prompt surgical exploration and drainage of suspected deep tissue infections is critical in cases of STSS in which necrotizing fasciitis may be present.

In one study of IVIG in STSS, 30 day survival improved from 34% to 67% and in the only randomized placebo controlled study of treatments for STSS, IVIG decreased mortality by 3.6-fold [33]. TSS has a case fatality rate of less than 5%, whereas mortality in STSS ranges from 30% to 70%, and significant morbidity, including renal failure, amputation, or hysterectomy may also occur [29,30].

Cellulitis is an acute bacterial infection of the skin and subcutaneous tissues. Erysipelas is a superficial form of cellulitis that is more indurated and well demarcated than other forms of cellulitis, in which the border between involved and uninvolved skin is indistinct. Cellulitis is common and more frequently affects men than women. The lower extremities are most often involved (73% of cases), followed by the upper extremities (19%), and head and neck (7%) [34].

Cellulitis is usually caused by group A beta-hemolytic streptococci or S. aureus, including MRSA [35], although it may also be caused by Group B streptococci, Haemophilus influenzae, Pseudomonas aeruginosa, and other bacteria, in
certain settings. Erysipelas is almost always caused by Group A streptococci. Predisposing factors for cellulitis include venous stasis disease, lymphedema, lower extremity ulceration, tinea pedis, and obesity. Bacteria on the skin surface enter through breaks in the skin and proliferate in the dermis and subcutaneous tissues, causing inflammation.

Patients with cellulitis present with erythema, swelling, warmth, and tenderness of a poorly demarcated area, usually on the leg, often in the setting of lower extremity swelling or dermatitis. If a line is drawn around the involved area, the area of redness is often seen to spread outward over hours to days. Patients frequently have tender local lymphadenopathy and/or lymphangitis. Fever or myalgias are sometimes present. In erysipelas, the skin is bright red and the borders are elevated and sharply demarcated from the uninvolved skin.

Cellulitis has a broad differential diagnosis, including contact dermatitis, superficial thrombophlebitis, deep venous thrombosis, necrotizing fasciitis, lipodermatosclerosis, and insect bites or stings [36,37]. One of the most commonly confused entities is simple stasis dermatitis, which is usually bilateral with scaling and hyperpigmentation of the distal lower extremities in addition to erythema and swelling. It is usually not tender unless ulceration is present.

Diagnosis of cellulitis and erysipelas is generally on clinical grounds. Blood cultures are of low yield (4% positive) unless the patient has signs of sepsis, and tissue cultures from needle aspirates are positive in only 10% to 20% of cases [38]. However, if the patient has an active ulcer, this may be cultured. Radiographic studies are usually unnecessary, although plain films or computed tomography (CT) may be of value to evaluate underlying osteomyelitis, and magnetic resonance imaging (MRI) may be used to differentiate cellulitis from necrotizing fasciitis [36]. If necrotizing fasciitis is strongly suspected, surgical debridement and intravenous antibiotics should be initiated immediately without waiting for radiologic or microbiologic studies.

Treatment of cellulitis is directed at the most likely bacterial causes, which are Streptococci and S. aureus. Initial treatment of the hospitalized patient is with beta-lactamase-resistant penicillins or cephalosporins such as cefazolin 1 g IV every 6 hours, nafcillin 1 to 1.5 g IV every 4 to 6 hours, or ceftriaxone 1 g IV every 24 hours. If MRSA is suspected, treatment is with vancomycin 1 to 2 g IV every 24 hours. As the cellulitis begins to resolve and the patient becomes afebrile, the patient may be converted to oral dicloxacillin or cephalexin 500 mg every 6 hours, for a total course of 7 to 14 days of antibiotics [36].

Local treatment of a cellulitic limb with elevation to reduce swelling and saline dressings to any open wounds may be helpful. Prognosis of patients with uncomplicated cellulitis is excellent but recurrences are common. Treatment of underlying tinea pedis with topical azole antifungals and of venous stasis or lymphedema with compression hosiery can help prevent recurrences [36].

Necrotizing fasciitis (NF) is a rapidly progressive infection involving the subcutis and fascia that typically occurs in the elderly, diabetics, alcohol abusers, and those with chronic cardiac disease or peripheral vascular disease. It is increasing in frequency among young, previously healthy individuals. NF may occur de novo, after surgery, or after penetration or even blunt trauma. Injection drug use is not an infrequent cause of NF [39]. The extremity is the usual site of involvement. When NF originates in the scrotum, it is known as Fournier’s gangrene. Most cases result from a polymicrobial infection. Pathogens may include Streptococci, S. aureus, enterococci, Escherichia coli, Pseudomonas, Bacteroides, and Clostridium spp. Community acquired MRSA has been reported more recently [40]. Invasive Group A Streptococcus is implicated in previously healthy patients. Other less frequent pathogens include Pseudomonas aeruginosa, Aeromonas hydrophila, and Vibrio vulnificus, Haemophilus influenzae type b.

The skin is initially shiny, erythematous, hot, tender, swollen, and tense. Pain is out of proportion to physical findings. Within 24 to 36 hours, skin color changes from red to dusky gray-blue, and bullae may develop. Deeper soft tissue may feel firm. With the destruction of cutaneous nerves, skin becomes anesthetic. The area becomes gangrenous by the fourth or fifth day, and patients appear toxic with fever, chills, tachycardia, shock, and leukocytosis.

NF may be difficult to differentiate from cellulitis, especially early in the course of disease. Features that suggest NF include: severe pain which may be out of proportion to physical findings, anesthesia of involved skin, rapid spread, edema and bulla formation, associated varicella infection, signs of shock, elevated creatine phosphokinase level, or NSAID use. NSAID use is implicated in disease progression through attenuation of signs and symptoms of inflammation that leads to a delay of diagnosis and treatment. MRI may help to discern extent of involvement. A newer tool called the laboratory risk indicator for necrotizing fasciitis uses a scoring system based on C-reactive protein, total white cell count, hemoglobin, sodium, creatinine, and glucose levels to help distinguish between necrotizing soft tissue infections and non-necrotizing infections, and in one retrospective study, was noted to predict mortality and amputation rate [41].

Early fasciotomy and immediate intravenous antimicrobial therapy based on initial Gram stain are crucial. Initial therapy usually involves a beta-lactam/beta-lactamase inhibitor. Hyperbaric oxygen therapy for anaerobic gram negative infection is controversial. Supportive care and attention to nutrition are important in optimizing postoperative wound healing. Even with early treatment, mortality may be between 20% and 40%. Poor prognostic factors include age over 50, diabetes, arteriosclerosis, delay of more than 7 days in diagnosis and surgical intervention, and infection involving the trunk rather than the extremity [42]. Other factors associated with mortality include STSS and immunocompromised state [39,43].

Staphylococcal scalded skin syndrome (SSSS) is a blistering, desquamative skin condition caused by the exfoliative toxins of S. aureus. Infants and young children are the most commonly affected, likely due to their immature immune and renal function, resulting in a lack of antitoxin antibodies and accumulation of exfoliative toxin. A few cases have been reported in adults who generally have underlying renal impairment or immunosuppression [44,45].

Two toxins, ETA and ETB, have been detected in human disease, with the majority caused by ETA. These toxins bind to and cleave desmoglein-1, a desmosomal protein in the superficial epidermis critical for binding between keratinocytes. Cleavage of this protein causes separation between keratinocytes in the upper layers of the epidermis and also of the superficial epidermis from deeper layers, with resulting fragile blisters and denuded skin [44,45].

In the localized form of SSSS, bullous impetigo, S. aureus enters the skin through a break or tear and elaborates exfoliative toxin that results in the development of blisters. Further spread is prevented by antibodies to the toxin. In generalized SSSS, the focus of infection is at a distant site, such as an abscess, pneumonia, osteomyelitis, or endocarditis. Frequently, however, a focus of infection is not found. A lack of protective antibodies
allows the toxin to reach the epidermis by hematogenous spread and cause widespread skin disease [44,45,46].

Whereas bullous impetigo has no associated systemic symptoms, generalized SSSS is associated with a prodrome of fever, malaise, and generalized erythema. This is followed by the formation of large blisters with clear or purulent fluid that easily rupture, leaving extensive areas of denuded skin. The degree of skin involvement may vary from focal blistering to entire body exfoliation. Significant pain and tenderness, hypothermia, fluid losses, secondary infection with Pseudomonas and other species, bacteremia, and sepsis may complicate the disease course [44,45].

SSSS should be considered for any presentation of fever and diffuse skin erythema. While the main differential diagnosis is toxic epidermal necrolysis, other conditions to consider include pemphigus foliaceus, scalding or chemical burns, GVHD, and epidermolysis bullosa. A thorough evaluation should include determination of the degree of denudation, identification of the source of infection, determination of fluid status, and a search for signs of secondary infection. Culture and Gram stain of the skin and focus of infection may identify S. aureus, but alone do not confirm the diagnosis of SSSS. Enzyme-linked immunosorbent assay (ELISA) can detect production of exotoxin from isolated S. aureus species, but should be used as confirmation of SSSS only, as false negatives can easily result if the pathogenic strain of bacteria is not detected on culture. Blood cultures are frequently positive in adults with SSSS [44,45].

Skin biopsy is the most useful diagnostic test, since it further distinguishes between SSSS and TEN. SSSS shows cleavage in the mid-epidermis with minimal associated inflammation. In TEN, cleavage occurs at the dermo-epidermal junction and there is cellular necrosis of the epidermis. TEN can also be distinguished clinically by the presence of mucosal involvement, a finding that is not seen in SSSS. Pemphigus foliaceus, an autoimmune blistering disorder caused by autoantibodies against desmoglein-1, can be difficult to distinguish both clinically and by routine histology [44,45]. Direct immunofluorescence will demonstrate anti-desmoglein antibodies in the epidermis of pemphigus foliaceus patients [47].

Treatment of generalized SSSS is with intravenous antibiotics targeting penicillin-resistant S. aureus. Aminoglycosides may be added if there are signs of secondary infection. Analgesia, fluid resuscitation, and wound care are other key elements of treatment. Use of steroids is contraindicated [44,45].

Exfoliation continues for 24 to 48 hours after institution of appropriate antibiotics. MRSA must be considered in any patient not responding to therapy after this time. Although the disease is rarely fatal in children, mortality in adults, even with treatment, is upward of 50% to 60%, when there are serious underlying medical conditions [44,45].

Neisseria meningitidis is a major cause of meningitis and sepsis in the United States, with an annual incidence of approximately 1 in 100,000. Meningococcal disease is often rapidly fatal due to shock and multiorgan failure. The majority of cases occur in winter and early spring. Infants and teenagers have the highest rates of infection. Meningococcal disease often occurs in localized outbreaks such as in schools or military barracks [48]. Most affected patients are previously healthy, but those with HIV, immunoglobulin deficiencies, asplenia, or inherited and acquired deficiencies of terminal complement components C5–C9 are at increased risk [48,49]. N. meningitidis is an aerobic gram positive diplococcus that only infects humans. Thirteen serotypes have been identified, of which groups A, B, C, Y, and W-135 are the major pathogens. A vaccine against types A, C, Y, and W-135 is in use for high-risk individuals. The bacteria inhabit the respiratory mucosa and are spread person to person through respiratory secretions. They possess virulence factors that allow invasion through the respiratory epithelium and into the bloodstream. There, they damage endothelium directly and release lipopolysaccharide endotoxin, which provokes massive release of tumor necrosis factor alpha, interleukins-1 and -6, and interferon-gamma. These cytokines promote vascular permeability, hypotension, and eventually multiorgan failure and disseminated intravascular coagulation [48,49].

Meningococcal disease may present in mild cases as a viral syndrome with fever, headache, nausea, vomiting, and arthralgias, but in fulminant cases, patients are severely ill with high fever, hypotension, and a hemorrhagic rash. Half of the cases will have meningitis with headache, stiff neck, and photophobia. Cutaneous findings are prominent in as many as 60% of patients with meningococcemia, with petechiae or purpura beginning at points of pressure on the trunk and extremities, but spreading to involve any body area. Urticarial and maculopapular lesions may also be observed early in the clinical course. As meningococcemia progresses, large areas of irregular gunmetal gray hemorrhage and necrosis may develop (Fig. 195.5) due to disseminated intravascular coagulation. In 10% to 20% of children with meningococcemia, purpura fulminans in combination with multiorgan failure and adrenal hemorrhage, the Waterhouse–Friderichsen syndrome, may occur [50].

The differential diagnosis of meningococcemia includes Rocky Mountain spotted fever, leukocytoclastic vasculitis, toxic shock syndrome, erythema multiforme, and other forms of bacterial sepsis. Diagnosis is usually based on blood or cerebrospinal fluid cultures, and in cases of meningococcal meningitis, gram staining of CSF is up to 90% sensitive. Newer polymerase chain reaction (PCR) tests for meningococcus are available, including the IS-1106, nspA, and ctrA TaqMan tests
[50,51]. Because meningococcal sepsis progresses rapidly and has a case fatality rate of up to 40%, treatment should never be delayed pending diagnosis.