Chapter 181. The Skin in Infective Endocarditis, Sepsis, Septic Shock, and Disseminated Intravascular Coagulation

Epidemiology

In the United States, the incidence of native-valve endocarditis is 1.7–6.2 cases per 100,000 person-years. The highest rate of infective endocarditis (IE) is seen in intravenous drug users, with an incidence estimated at 150–2,000 per 100,000 person-years. The risk of prosthetic valve IE decreases with time following valve implantation and the cumulative risk is about 2%–3% after 60 months.1

Etiology and Pathogenesis

IE can be subdivided by native valve versus prosthetic valve. The causative organisms in most cases of IE are Staphylococci or Streptococci, implicating skin as the initial site of infection in many cases. Native valve endocarditis occurs most commonly in the setting of valvular disease or in people who use intravenous drugs. Rheumatic valve disease has been replaced by aortic stenosis and mitral regurgitation, as the most common settings in which native valve endocarditis is encountered. At sites of endothelial injury, a sterile thrombus can occur which is particularly susceptible to seeding of bacteria from transient episodes of bacteremia. This can result in the development of valvular vegetations that can cause local tissue destruction and embolic events.

Intravenous drug users are particularly susceptible to IE even though most have no preexisting structural heart disease. More than half of the cases of IE in injection drug users are right sided, involving the tricuspid valve. The most common causative organism is Staphylococcus aureus.

Prosthetic valve endocarditis can be classified as early (in the first 2 months following valve replacement) or late (2 months or later). The newly placed prosthetic valve is particularly susceptible to bacterial colonization because the process of endothelialization does not occur until 2–6 months following surgery. Early prosthetic valve endocarditis is most commonly caused by Staphylococcus epidermidis followed by S. aureus. Late prosthetic valve endocarditis can be due to a variety of organisms including the so-called HACEK organisms (Haemophilus parainfluenzae, Haemophilus aphrophilus, Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, and Kinsella kinasae).

Most cases of nosocomial endocarditis are secondary to indwelling catheters or to surgical procedures, and are caused by Streptococci. However, nosocomial endocarditis in dialysis patients is most commonly due to S. aureus. Other less common causes of IE include fungi, Pseudomonas, Coxiella burnetii, Bartonella quintana, and Proprionobacteria acnes.

Clinical Findings

History

Patients with IE generally present with noncardiac complaints of fever, malaise, and anorexia. The presence of a murmur that is new or has changed in character is often present. Unexplained fever in a patient with a prosthetic heart valve should prompt an evaluation for endocarditis. The Duke criteria,2 (Box 181-1 are helpful in making the diagnosis of IE.

Cutaneous Lesions

Cutaneous signs of IE are nonspecific but may help the clinician in making the appropriate diagnosis. Cutaneous findings are caused either by embolic events, thrombosis, or focal vasculitis.

Splinter hemorrhages (Fig. 181-1) are 1–2 mm red–brown longitudinal streaks under the nail plate. They are seen in about 15% of patients with IE and are considered to be of greater diagnostic value if proximally located. Splinter hemorrhages associated with IE are the result of small capillary vasculitis, or from microemboli. In the absence of other signs or symptoms of IE, the mere presence of splinter hemorrhage is not specific enough evidence to warrant a workup. Crops of petechiae are commonly seen in the buccal membrane, soft palate, and extremities.

Janeway lesions are painless, irregular, nonblanchable, erythematous maculopapules that appear on the palms and soles and last days to weeks (eFig. 181-1.1). Histologically, thrombi are found in small vessels in the absence of vasculitis. Neutrophilic microabscesses can be seen in the dermis with occasional Gram-positive organisms. Osler's nodes present as painful red papulonodules with a pale center on the fingertips lasting days to weeks (eFig. 181-1.2). Osler's nodes are painful, perhaps due to involvement of the glomus bodies located in the fingertips. Histologically, neutrophilic microabscesses are present in the dermis, and arteriolar microemboli may contain Gram-positive cocci.

Septic emboli of valvular vegetation fragments can cause ischemia of distal extremities. Toes are most commonly involved, followed by fingers, and this condition presents as reticulated purpura similar to that seen in cholesterol emboli syndrome (see Chapter 174). While this condition generally resolves without sequelae, tissue necrosis or gangrene can result.

Related Physical Findings

The most common noncutaneous finding in IE is fever. Signs and symptoms related to the bacterial infection and septic emboli may include splenomegaly, microscopic hematuria, pneumonitis, cerebral vascular accident, meningoencephalitis, brain abscess, retinal hemorrhages (Roth spots), acute abdomen, myocardial infarction, pericarditis and congestive heart failure, arthralgias and arthritis, or chronic wasting disease.

Laboratory Tests

A positive blood culture is the most helpful laboratory test in making the diagnosis of IE. Other tests that may be abnormal in this setting include a positive rheumatoid factor, elevated erythrocyte sedimentation rate, C reactive protein, leukocytosis, or a urinalysis showing hematuria. Subacute bacterial endocarditis can be associated with the presence of antineutrophilic cytoplasmic antibodies (ANCAs).

Special Tests

Echocardiography allows the visualization of the valves and can provide information as to the level of myocardial involvement. Transthoracic echocardiography (TTE) is less invasive and less expensive than transesophageal echocardiography (TEE). However, the sensitivity and specificity of TTE are 60%–70% and 98%, respectively, whereas the sensitivity of TEE is 75%–95% without a compromise in specificity.

Differential Diagnosis

The differential diagnosis of splinter hemorrhages is reviewed in Box 181-2. Janeway lesions and Osler nodes can be similar in appearance to septic emboli and neutrophilic eccrine hidradenitis. Cases of culture-negative, ANCA-positive subacute bacterial endocarditis, particularly in the presence of cutaneous manifestations such as purpura, may mimic ANCA-associated vasculitis.

Complications

Cardiac complications of IE include congestive heart failure, extension of disease to the myocardium and pericarditis. Embolic complications include stroke, mycotic intracranial aneurisms and splenic abscess.1

Prognosis and Clinical Course

The overall mortality for IE has dropped by about 50% over the past 40 years and is currently about 28%.2 Prognosis depends on age, the nature of the responsible microorganism, the presence of emboli, and the extent of cardiac damage. Early diagnosis and treatment improve outcome.

Treatment

Appropriate antibiotic therapy should be initiated in suspected cases of IE after blood cultures have been drawn. Long-term (4–6 weeks) parenteral antibiotics, usually with a penicillin derivative, are used to treat streptococcal or staphylococcal IE. Antibiotic treatment has been shown to reduce the risk of subsequent embolism. Treatment of infective endocarditis caused by other organisms is reviewed elsewhere.5 Indications for surgical treatment include persistent bacteremia, despite 7 days of parenteral antibiotic therapy, prosthetic valve endocarditis, the presence of large vegetations, severe valvular dysfunction, and infection with Pseudomonas, C. burnetii, or fungus.6

Prevention

Currently, prophylactic antibiotics for skin surgery are not indicated for procedures performed on noninfected, surgically scrubbed skin regardless of cardiac history. Guidelines issued by the American Heart Association in May 2007 shifted from recommending antibiotic prophylaxis for patients at increased risk for IE, to recommending IE prophylaxis for patient who have a high risk of an adverse outcome associated with IE who are to have a procedure that involves a contaminated or infected wound, or surgery on oral or nasal mucosa.7 For dermatologists, this would include patients with a prosthetic heart valve, a personal history of IE, valvulopathy in a cardiac transplant patient, or an unrepaired cyanotic heart defect.

Epidemiology

Sepsis, most commonly from Gram-positive bacteria, is the 10th leading cause of death in the United States. A review of approximately 750 million hospitalizations over 22 years in the United States showed that sepsis accounts for 1.3% of all hospital admissions. The incidence of sepsis has been steadily increasing since 1971 although the mortality rate has been dropping.8

Etiology and Pathogenesis

The prevailing presumption has been that sepsis is a result of uncontrolled activation of the inflammatory response to pathogens. This increased inflammation leads to uncontrolled coagulation, which in turn causes the release of more inflammatory mediators. Sepsis is often characterized by an initial burst of immunologic activation, including a surge in TNF-α production. This is thought to be mediated by binding of specific pathogen-associated molecules to toll-like receptors found on cells of the immune system. Toll-like receptors activate signaling through transcription factors such as nuclear factor-κB (NF-κB) that activate the expression of a cascade of inflammatory cytokines. However, this is followed by a relative decrease in immunity with impaired delayed type hypersensitivity, a loss of critical cells of the immune response including B cells, CD4+ helper T cells, and dendritic cells, and the inability to clear infection.9

Sepsis is often complicated by impaired organ function. Autopsy studies revealed that even in the setting of profound organ dysfunction, cell death is minimal and not sufficient to account for the clinical picture. Thus, sepsis appears to activate a state of cellular hibernation in which cells reduce their activities to only those required for cell survival. This would explain why organ function is often regained in those patients who recover from sepsis.

Clinical Findings

History

The septic patient is usually febrile, or in some cases hypothermic, with tachycardia and tachypnea. Patients with severe sepsis can also have dysfunction of major organ systems and those in septic shock develop hypotension that is refractory to the administration of fluid.

Cutaneous Lesions

The causative organism in sepsis is not always identifiable by routine culture. In some cases, the cutaneous exam can provide clues to the identity of the responsible pathogen, providing a valuable clinical tool in the management of the septic patient.

Erythroderma in the septic patient suggests staphylococcal or streptococcal toxic shock syndrome (TSS). Patients with TSS are usually young and otherwise healthy. Patients with staphylococcal TSS are much more likely to be erythrodermic but much less likely to have positive blood culture than are patients with streptococcal TSS. Streptococcal TSS is commonly associated with a soft tissue infection.

The finding of pustules on the skin of a septic patient, particularly in the neonate or immunocompromised individual, may be suggestive of fungal infection, particularly with Candida species. Congenital candidiasis, most often seen in infants born to mothers with vaginal candidiasis, is generally a skin-limited disease. However, in the septic infant with pustules, candidemia should be considered.

The vasculitis and coagulopathy that can occur in the septic patient may cause purpura, sometimes prominent in the nail fold small capillaries (Fig. 181-2). Purpura is particularly prominent in those patients with thrombocytopenia. Such infections are seen most commonly in oncology patients undergoing bone marrow transplantation. In the immunocompromised host, opportunistic fungal infection, such as with Aspergillus sp., Fusarium sp., and Candida sp., often presents as erythematous papules, petechiae, or pustules that progress to purpuric lesions (Fig. 181-3).

Pustules due to disseminated gonococcemia are acrally located, typically tender and a characteristic gun-metal gray color, hemorrhagic or black, and are most commonly seen in the otherwise healthy adolescent or young adult (eFig. 181-3.1). Gram stain of the pustule will reveal intracellular Gram-negative diplococci. In its most extreme form, meningococcemia can cause purpura fulminans (see below). Pustules may also be secondary to a local inoculation site, as in the case of staphylococcal sepsis.

Cellulitis is characterized by intense local inflammation in the presence of relatively few infectious organisms and blood cultures are rarely positive (see Chapter 179). Most commonly occurring on the legs, the affected extremity is typically erythematous, hyperemic, and edematous. The most common causes of cellulitis are S. aureus and Group A Streptococcus. Rarely, anaerobic organisms including clostridial species and other anaerobic bacteria species such as Bacteroides, Peptostreptococcus, or Peptococcus are the causative organism. In immunosuppressed patients, Cryptococcus neoformans can also cause cellulitis, particularly in the setting of AIDS. Patients with liver compromise can develop cellulitis from Vibrio vulnificus, a Gram-negative bacterium that lives in warm marine environments and becomes concentrated in filter-feeding shellfish. Infection occurs either via consumption of contaminated organisms such as raw oysters, or through contact with infected waster. Mortality rates exceed 40% in those with V. vulnificus sepsis.10

A more aggressive local soft tissue infection, necrotizing fasciitis, can be associated with positive blood cultures later in the course of the disease due to hematogenous seeding by the organisms. Clinically, necrotizing fasciitis is rapidly progressive, initially painful, and accompanied by fever and leukocytosis (see Chapter 179). Blood cultures are frequently positive. After several days, the involved area may become anesthetic secondary to destruction of cutaneous nerves.11

Ecthyma gangrenosum (see Chapter 180) begins as an erythematous papule that expands and eventually becomes a necrotic bulla. Lesions are most commonly seen between the umbilicus and the knees. Classic ecthyma gangrenosum represents cutaneous seeding of bacteria, usually Pseudomonas aeruginosa, from a hematogenous source, and is seen almost exclusively in neutropenic patients, often in association with an underlying malignancy. Nonclassical cases have been reported with Aeromonas hydrophila, Escherichia coli, Citrobacter freundii, and Corynebacterium diptheriae, fungal infection including Candida, Aspergillus, Fusarium, and mucormycosis-causing species, and even herpes simplex virus.12

Related Physical Findings

Sepsis is defined as infection plus systemic inflammation and is characterized by hyper- or hypothermia, tachycardia and tachypnea. Sepsis is further subdivided into severe sepsis, which is defined as infection with systemic inflammation and organ dysfunction. The organ systems commonly affected in sepsis include the renal, hepatic, central nervous, pulmonary, gastrointestinal, and cardiovascular systems. Septic shock occurs when patients with severe sepsis also have hypotension (SBP <90) refractory to fluid administration.

Laboratory Tests

The septic patient will generally have a white blood cell count greater than 12 × 109/L or less than 4 × 109/L, or a bandemia of greater than 10%. Elevated CRP and procalcitonin levels are common. Organ dysfunction can manifest as low cardiac output, elevated creatinine, thrombocytopenia, and elevated INR or PTT, or hyperbilirubinemia.13 Blood cultures can be helpful in guiding treatment of the septic patients, however, only 30%–50% of septic patients will have positive blood cultures.14

Special Tests

Special tests including imaging studies and culture of suspected involved tissue can sometimes be helpful in identifying the source of infection in the septic patient.

Differential Diagnosis

The differential diagnosis of skin findings in the septic patient is reviewed in Box 181-3.

Complications

Complications of sepsis include death, loss of limbs due to hypoperfusion and permanent organ dysfunction.

Prognosis and Clinical Course

There are over 750,000 cases of sepsis each year in the United States and mortality rate from severe sepsis and septic shock is 30%–60%.15

Treatment

Treatment of sepsis is usually done in an intensive care unit and involves the use of antimicrobial drugs, chosen empirically or on the basis of the culture of a particular microorganism started as soon as possible, but no longer than one hour after the diagnosis of severe sepsis or septic shock is mad. Choice of antibiotic therapy should be reevaluated on a daily basis to minimize toxicity and maximize efficacy. The administration of activated drotrecogin-α has been shown to reduce mortality in cases of sever sepsis. Patient outcomes in sepsis haven been shown to improve with the use of standardized treatment protocols. Supportive care is important to preserve organ function.

Prevention

The prevention of sepsis in a hospital setting is achieved by the implementation of basic infection control measures including routine hand washing and the minimization and regular replacement of indwelling catheters. In patients who are immunocompromised, particularly in the setting of organ transplantation or AIDS, the use of prophylactic antibiotics can help to reduce the incidence of sepsis.

Epidemiology

The incidence of disseminated intravascular coagulation (DIC) is not known. Approximately 15% of septic patients may develop DIC.

Etiology and Pathogenesis

DIC represents systemic activation of the coagulation cascade. This leads to fibrin deposition in the vasculature, which can cause organ ischemia and death. In addition, the consumption of platelets and coagulation factors can lead to bleeding. DIC occurs most commonly secondary to an underlying disorder as listed in Box 181-4.

In DIC, coagulation activation is tissue factor dependent (i.e., extrinsic or factor VIIa pathway). Inflammatory cytokines, such as TNF-α, promote damage to endothelial cells and activation of mononuclear cells. These cells then produce tissue factor that binds to factor VIIa and activates downstream coagulation cascades. Thrombin generation is amplified by defective anticoagulant mechanisms and results in increased fibrin deposition. The fibrin that is generated fails to be degraded by the fibrinolytic system. In the healthy state, antithrombin regulates thrombin activity. In DIC, antithrombin levels are low due to continuous consumption, degradation by neutrophil elastase and impaired synthesis due to liver failure in some settings. Fibrinolysis is inhibited by plasminogen activator inhibitor type I (PAI-1). Studies show that individuals with high plasma levels of PAI-1 are at higher risk of mortality in DIC. This correlates with a mutation in PAI-1 that is associated with higher PAI-1 plasma concentrations. Thus, some individuals may be genetically predisposed to fatal outcomes from DIC due to a point mutation in PAI-1.16

The infection, most commonly associated with DIC, is meningococcal sepsis. However, DIC has been reported following viral and other bacterial infections. Many recent reports suggest an emergence of sepsis due to Staphylococcus, particularly those isolates containing exotoxins including, staphylococcal enterotoxin serotypes B and C (SEB and SEC), toxic shock syndrome toxin-1 (TSST-1), and Panton–Valentine leukocidin (PVL), a leukocyte toxin believed to be important in the pathophysiology of skin and soft-tissue infections and necrotizing pneumonia, as a factor in initiating DIC.17

DIC can also be associated with obstetric complications including preeclampsia, abruption, and amniotic fluid embolism. In these cases, the placenta appears to play a central role in the hemostatic pathway.

Clinical Findings

History

DIC is always secondary to an underlying condition or disorder, and thus the patient will generally first present with the antecedent condition. Often, patients with DIC will develop simultaneous bleeding, thrombosis, and multiorgan failure. Platelet count is not useful in predicting a patient's risk of thrombosis as clots can form even in the setting of thrombocytopenia. The onset of DIC in the neonatal period is suggestive of protein C or S deficiency.

Cutaneous Lesions

The most characteristic cutaneous finding in DIC is noninflammatory purpura with extensive microvascular occlusion referred to as purpura fulminans (Fig. 181-4). Patients will have diffuse bleeding, hemorrhagic necrosis of tissue, and skin necrosis (eFig 181-4.1). Patients with purpura fulminans may present with ischemic digits or extremities that, if left untreated, can progress to gangrene.

Related Physical Findings

In its most extreme form, patients with DIC will develop the Waterhouse–Friderichsen syndrome, most commonly seen in meningococcal sepsis (see Chapter 180). This is a syndrome of multiorgan failure characterized by a petechiae or purpura, coagulopathy, cardiovascular collapse, and bilateral adrenal hemorrhage.

Laboratory Tests

DIC is characterized by laboratory evidence of massive activation of the coagulation cascade and the destruction of platelets. Platelet counts are generally less than 100,000. Platelet counts tend to be lowest in acute sepsis-associated DIC and increased in chronic DIC associated with malignancy. Because of the high conversion of fibrinogen to fibrin, soluble fibrin monomers and the d-dimer assay are usually elevated. The prothrombin time is usually prolonged to at least 1.2 times the upper limit of normal as well. Several scoring systems exist that assign numerical values to particular laboratory findings and allow the calculation of a single numerical score that is helpful in predicting the presence of and mortality from DIC as reviewed elsewhere.18

Differential Diagnosis

The differential diagnosis of DIC includes other conditions causing small and midsize vessel thrombotic occlusions leading to organ failure and microangiopathic hemolysis. This includes thrombocytopenic thrombotic purpura, the hemolytic uremic syndrome, and the HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome seen in obstetric patients.

Complications

Complications of DIC include tissue necrosis and infection, often requiring amputation of limbs or digits, multiorgan failure (particularly the Waterhouse–Friderichsen syndrome), and death.

Prognosis/Clinical Course

The mortality risk is doubled in patients with DIC who are septic or have experienced trauma.

Treatment

Because DIC is always secondary to another condition, the most important factor in the management of DIC is treatment of the underlying cause. However, replacement of components consumed during DIC and inhibition of the coagulation cascade has an important role as well. Despite the conventional wisdom that replacement of platelets and coagulation factors in the patient with DIC adds “fuel to the fire”, more recent clinical trials have not shown this to be the case. These studies have demonstrated a survival benefit to treating patients with DIC with low-dose heparin or activated protein C.18 Asymptomatic DIC is treated with low molecular weight heparin, synthetic protease inhibitor (SPI), or antithrombin. The marked bleeding type of DIC is treated with SPI; fresh-frozen plasma and platelets are added in cases of severe bleeding. Finally, in organ failure type DIC, antithrombin is used in addition to supportive care.

There is very little published experience regarding the treatment of the cutaneous necrosis seen in DIC. Skin necrosis secondary to DIC is similar to that seen in full thickness cutaneous burns. Excision of necrotic tissue and coverage with autografts, and/or amputation of extremities are possible treatment options.19

Prevention

Most interventions in DIC are aimed at minimizing organ damage and bleeding. Prevention of DIC itself can be achieved by the prompt diagnosis and treatment of its causes, particularly sepsis.