Dillon Clarey, MD

Acute generalized pustular psoriasis (GPP) is a rare severe variant of psoriasis characterized by the sudden widespread eruption of sterile pustules.^1,2 The cutaneous manifestations of GPP also may be accompanied by signs of systemic inflammation, including fever, malaise, and leukocytosis.² Complications are common and may be life-threatening, especially in older patients with comorbid diseases.³ Generalized pustular psoriasis most commonly occurs in patients with a preceding history of psoriasis, but it also may occur de novo.⁴ Generalized pustular psoriasis is associated with notable morbidity and mortality, and relapses are common.^3,4 Many triggers of GPP have been identified, including initiation and withdrawal of various medications, infections, pregnancy, and other conditions.^5,6 Although GPP most often occurs in adults, it also may arise in children and infants.³ In pregnancy, GPP is referred to as impetigo herpetiformis, despite having no etiologic ties with either herpes simplex virus or staphylococcal or streptococcal infection. Impetigo herpetiformis is considered one of the most dangerous dermatoses of pregnancy because of high rates of associated maternal and fetal morbidity.^6,7

Acute GPP has proven to be a challenging disease to treat due to the rarity and relapsing-remitting nature of the disease; additionally, there are relatively few randomized controlled trials investigating the efficacy and safety of treatments for GPP. This review summarizes the features of GPP, including the pathophysiology of the disease, clinical and histological manifestations, and recommendations for management based on a PubMed search of articles indexed for MEDLINE using MeSH terms pertaining to the disease, including generalized pustular psoriasis, impetigo herpetiformis, and von Zumbusch psoriasis.

Pathophysiology

The pathophysiology of GPP is only partially understood, but it is thought to have a distinct pattern of immune activation compared with plaque psoriasis.⁸ Although there is a considerable amount of overlap and cross-talk among cytokine pathways, GPP generally is driven by innate immunity and unrestrained IL-36 cytokine activity. In contrast, adaptive immune responses—namely the tumor necrosis factor (TNF) α, IL-23, IL-17, and IL-22 axes—underlie plaque psoriasis.^8-10

Proinflammatory IL-36 cytokines α, β, and γ, which are all part of the IL-1 superfamily, bind to the IL-36 receptor (IL-36R) to recruit and activate immune cells via various mediators, including IL-1β; IL-8; and chemokines CXCL1, CXCL2, and CXCL8.³ The IL-36 receptor antagonist (IL-36ra) acts to inhibit this inflammatory cascade.^3,8 Microarray analyses of skin biopsy samples have shown that overexpression of IL-17A, TNF-α, IL-1, and IL-36 are seen in both GPP and plaque psoriasis lesions, but GPP lesions had higher expression of IL-1β, IL-36α, and IL-36γ and elevated neutrophil chemokines—CXCL1, CXCL2, and CXCL8—compared with plaque psoriasis lesions.⁸

Gene Mutations Associated With GPP

There are 3 gene mutations that have been associated with pustular variants of psoriasis, though these mutations account for a minority of cases of GPP.⁴ Genetic screenings are not routinely indicated in patients with GPP, but they may be warranted in severe cases when a familial pattern of inheritance is suspected.⁴

IL36RN—The gene IL36RN codes the anti-inflammatory IL-36ra. Loss-of-function mutations in IL36RN lead to impairment of IL-36ra and consequently hyperactivity of the proinflammatory responses triggered by IL-36.³ Homozygous and heterozygous mutations in IL36RN have been observed in both familial and sporadic cases of GPP.^11-13 Subsequent retrospective analyses have identified the presence of IL36RN mutations in patients with GPP with frequencies ranging from 23% to 37%.^14-17IL36RN mutations are thought to be more common in patients without concomitant plaque psoriasis and have been associated with severe disease and early disease onset.¹⁵

CARD14—A gain-of-function mutation in CARD14 results in overactivation of the proinflammatory nuclear factor κB pathway and has been implicated in cases of GPP with concurrent psoriasis vulgaris. Interestingly, this may suggest distinct etiologies underlying GPP de novo and GPP in patients with a history of psoriasis.^18,19

AP1S3—A loss-of-function mutation in AP1S3 results in abnormal endosomal trafficking and autophagy as well as increased expression of IL-36α.^20,21

Clinical Presentation and DiagnosisCutaneous Manifestations of GPP

Generalized pustular psoriasis is characterized by the onset of widespread 2- to 3-mm sterile pustules on erythematous skin or within psoriasiform plaques⁴ (Figure). In patients with skin of color, the erythema may appear less obvious or perhaps slightly violaceous compared to White skin. Pustules may coalesce to form “lakes” of pus.⁵ Cutaneous symptoms include pain, burning, and pruritus. Associated mucosal findings may include cheilitis, geographic tongue, conjunctivitis, and uveitis.⁴

The severity of symptoms can vary greatly among patients as well as between flares within the same patient.^2,3 Four distinct patterns of GPP have been described. The von Zumbusch pattern is characterized by a rapid, generalized, painful, erythematous and pustular eruption accompanied by fever and asthenia. The pustules usually resolve after several days with extensive scaling. The annular pattern is characterized by annular, erythematous, scaly lesions with pustules present centrifugally. The lesions enlarge by centrifugal expansion over a period of hours to days, while healing occurs centrally. The exanthematic type is an acute eruption of small pustules that abruptly appear and disappear within a few days, usually from infection or medication initiation. Sometimes pustules appear within or at the edge of existing psoriatic plaques in a localized pattern—the fourth pattern—often following the exposure to irritants (eg, tars, anthralin).⁵

Impetigo Herpetiformis—Impetigo herpetiformis is a form of GPP associated with pregnancy. It generally presents early in the third trimester with symmetric erythematous plaques in flexural and intertriginous areas with pustules present at lesion margins. Lesions expand centrifugally, with pustulation present at the advancing edge.^6,7 Patients often are acutely ill with fever, delirium, vomiting, and tetany. Mucous membranes, including the tongue, mouth, and esophagus, also may be involved. The eruption typically resolves after delivery, though it often recurs with subsequent pregnancies, with the morbidity risk rising with each successive pregnancy.⁷

Systemic and Extracutaneous Manifestations of GPP

Although the severity of GPP is highly variable, skin manifestations often are accompanied by systemic manifestations of inflammation, including fever and malaise. Common laboratory abnormalities include leukocytosis with peripheral neutrophilia, a high serum C-reactive protein level, hypocalcemia, and hypoalbuminemia.²² Abnormal liver enzymes often are present and result from neutrophilic cholangitis, with alternating strictures and dilations of biliary ducts observed on magnetic resonance imaging.²³ Additional laboratory abnormalities are provided in Table 2. Other extracutaneous findings associated with GPP include arthralgia, edema, and characteristic psoriatic nail changes.⁴ Fatal complications include acute respiratory distress syndrome, renal dysfunction, cardiovascular shock, and sepsis.^24,25

Histologic Features

Given the potential for the skin manifestations of GPP to mimic other disorders, a skin biopsy is warranted to confirm the diagnosis. Generalized pustular psoriasis is histologically characterized by the presence of subcorneal macropustules (ie, spongiform pustules of Kogoj) formed by neutrophil infiltration into the spongelike network of the epidermis.⁶ Otherwise, the architecture of the epithelium in GPP is similar to that seen with plaque psoriasis, with parakeratosis, acanthosis, rete-ridge elongation, diminished stratum granulosum, and thinning of the suprapapillary epidermis, though the inflammatory cell infiltrate and edema are markedly more severe in GPP than plaque psoriasis.^3,4

Differential Diagnosis

There are many other cutaneous pustular diagnoses that must be ruled out when evaluating a patient with GPP (Table 1).²⁶ Acute generalized exanthematous pustulosis (AGEP) is a common mimicker of GPP that is differentiated histologically by the presence of eosinophils and necrotic keratinocytes.⁴ In addition to its distinct histopathologic findings, AGEP is classically associated with recent initiation of certain medications, most commonly penicillins, macrolides, quinolones, sulfonamides, terbinafine, and diltiazem.²⁷ In contrast, GPP more commonly is related to withdrawal of corticosteroids as well as initiation of some biologic medications, including anti-TNF agents.³ Generalized pustular psoriasis should be suspected over AGEP in patients with a personal or family history of psoriasis, though GPP may arise in patients with or without a history of psoriasis. Acute generalized exanthematous pustulosis usually is more abrupt in both onset and resolution compared with GPP, with clearance of pustules within a few days to weeks following cessation of the triggering factor.⁴

Other pustular variants of psoriasis (eg, palmoplantar pustular psoriasis, acrodermatitis continua of Hallopeau) are differentiated from GPP by their chronicity and localization to palmoplantar and/or ungual surfaces.⁵ Other differential diagnoses are listed in Table 1.

Diagnostic Criteria for GPP

Diagnostic criteria have been proposed for GPP (Table 2), including (1) the presence of sterile pustules, (2) systemic signs of inflammation, (3) laboratory abnormalities, (4) histopathologic confirmation of spongiform pustules of Kogoj, and (5) recurrence of symptoms.²² To definitively diagnose GPP, all 5 criteria must be met. To rule out mimickers, it may be worthwhile to perform Gram staining, potassium hydroxide preparation, in vitro cultures, and/or immunofluorescence testing.⁶

Treatment

Given the high potential for mortality associated with GPP, the most essential component of management is to ensure adequate supportive care. Any temperature, fluid, or electrolyte imbalances should be corrected as they arise. Secondary infections also must be identified and treated, if present, to reduce the risk for fatal complications, including systemic infection and sepsis. Precautions must be taken to ensure that serious end-organ damage, including hepatic, renal, and respiratory dysfunction, is avoided.

Adjunctive topical intervention often is initiated with bland emollients, corticosteroids, calcineurin inhibitors, and/or vitamin D derivatives to help soothe skin symptoms, but treatment with systemic therapies usually is warranted to achieve symptom control.^2,25 Importantly, there are no systemic or topical agents that have specifically been approved for the treatment of GPP in Europe or the United States.³ Given the absence of universally accepted treatment guidelines, therapeutic agents for GPP usually are selected based on clinical experience while also taking the extent of involvement and disease severity into consideration.³

Treatment Recommendations for Adults

Oral Systemic Agents—Treatment guidelines set forth by the National Psoriasis Foundation (NPF) in 2012 proposed that first-line therapies for GPP should be acitretin, cyclosporine, methotrexate, and infliximab.²⁸ However, since those guidelines were established, many new biologic therapies have been approved for the treatment of psoriasis and often are considered in the treatment of psoriasis subtypes, including GPP.²⁹ Although retinoids previously were considered to be a preferred first-line therapy, they are associated with a high incidence of adverse effects and must be used with caution in women of childbearing age.⁶ Oral acitretin at a dosage of 0.75 to 1.0 mg/kg/d has been shown to result in clinical improvement within 1 to 2 weeks, and a maintenance dosage of 0.125 to 0.25 mg/kg/d is required for several months to prevent recurrence.³⁰ Methotrexate—5.0 to 15.0 mg/wk, or perhaps higher in patients with refractory disease, increased by 2.5-mg intervals until symptoms improve—is recommended by the NPF in patients who are unresponsive or cannot tolerate retinoids, though close monitoring for hematologic abnormalities is required. Cyclosporine 2.5 to 5.0 mg/kg/d is considered an alternative to methotrexate and retinoids; it has a faster onset of action, with improvement reported as early as 2 weeks after initiation of therapy.^1,28 Although cyclosporine may be effective in the acute phase, especially in severe cases of GPP, long-term use of cyclosporine is not recommended because of the potential for renal dysfunction and hypertension.³¹

Biologic Agents—More recent evidence has accumulated supporting the efficacy of anti-TNF agents in the treatment of GPP, suggesting the positioning of these agents as first line. A number of case series have shown dramatic and rapid improvement of GPP with intravenous infliximab 3 to 5 mg/kg, with results observed hours to days after the first infusion.^32-37 Thus, infliximab is recommended as first-line treatment in severe acute cases, though its efficacy as a maintenance therapy has not been sufficiently investigated.⁶ Case reports and case series document the safety and efficacy of adalimumab 40 to 80 mg every 1 to 2 weeks^38,39 and etanercept 25 to 50 mg twice weekly^40-42 in patients with recalcitrantGPP. Therefore, these anti-TNF agents may be considered in patients who are nonresponsive to treatment with infliximab.

Rarely, there have been reports of paradoxical induction of GPP with the use of some anti-TNF agents,^43-45 which may be due to a cytokine imbalance characterized by unopposed IFN-α activation.⁶ In patients with a history of GPP after initiation of a biologic, treatment with agents from within the offending class should be avoided.

The IL-17A monoclonal antibodies secukinumab, ixekizumab, and brodalumab have been shown in open-label phase 3 studies to result in disease remission at 12 weeks.^46-48 Treatment with guselkumab, an IL-23 monoclonal antibody, also has demonstrated efficacy in patients with GPP.⁴⁹ Ustekinumab, an IL-12/23 inhibitor, in combination with acitretin also has been shown to be successful in achieving disease remission after a few weeks of treatment.⁵⁰

More recent case reports have shown the efficacy of IL-1 inhibitors including gevokizumab, canakinumab, and anakinra in achieving GPP clearance, though more prospective studies are needed to evaluate their efficacy.^51-53 Given the etiologic association between IL-1 disinhibition and GPP, future investigations of these therapies as well as those that target the IL-36 pathway may prove to be particularly interesting.

Phototherapy and Combination Therapies—Phototherapy may be considered as maintenance therapy after disease control is achieved, though it is not considered appropriate for acute cases.²⁸ Combination therapies with a biologic plus a nonbiologic systemic agent or alternating among various biologics may allow physicians to maximize benefits and minimize adverse effects in the long term, though there is insufficient evidence to suggest any specific combination treatment algorithm for GPP.²⁸

Treatment Recommendations for Pediatric Patients

Based on a small number of case series and case reports, the first-line treatment strategy for children with GPP is similar to adults. Given the notable adverse events of most oral systemic agents, biologic therapies may emerge as first-line therapy in the pediatric population as more evidence accumulates.²⁸

Treatment Recommendations for Pregnant Patients

Systemic corticosteroids are widely considered to be the first-line treatments for the management of impetigo herpetiformis.⁷ Low-dose prednisone (15–30 mg/d) usually is effective, but severe cases may require increasing the dosage to 60 mg/d.⁶ Given the potential for rebound flares upon withdrawal of systemic corticosteroids, these agents must be gradually tapered after the resolution of symptoms.

Certolizumab pegol also is an attractive option in pregnant patients with impetigo herpetiformis because of its favorable safety profile and negligible mother-to-infant transfer through the placenta or breast milk. It has been shown to be effective in treating GPP and impetigo herpetiformis during pregnancy in recently published case reports.^54,55 In refractory cases, other TNF-α inhibitors (eg, adalimumab, infliximab, etanercept) or cyclosporine may be considered. However, cautious medical monitoring is warranted, as little is known about the potential adverse effects of these agents to the mother and fetus.^28,56 Data from transplant recipients along with several case reports indicate that cyclosporine is not associated with an increased risk for adverse effects during pregnancy at a dose of 2 to 3 mg/kg.^57-59 Both methotrexate and retinoids are known teratogens and are therefore contraindicated in pregnant patients.⁵⁶

If pustules do not resolve in the postpartum period, patients should be treated with standard GPP therapies. However, long-term and population studies are lacking regarding the potential for infant exposure to systemic agents in breast milk. Therefore, the NPF recommends avoiding breastfeeding while taking systemic medications, if possible.⁵⁶

Limitations of Treatment Recommendations

The ability to generate an evidence-based treatment strategy for GPP is limited by a lack of high-quality studies investigating the efficacy and safety of treatments in patients with GPP due to the rarity and relapsing-remitting nature of the disease, which makes randomized controlled trials difficult to conduct. The quality of the available research is further limited by the lack of validated outcome measures to specifically assess improvements in patients with GPP, such that results are difficult to synthesize and compare among studies.³¹

Conclusion

Although limited, the available research suggests that treatment with various biologics, especially infliximab, is effective in achieving rapid clearance in patients with GPP. In general, biologics may be the most appropriate treatment option in patients with GPP given their relatively favorable safety profiles. Other oral systemic agents, including acitretin, cyclosporine, and methotrexate, have limited evidence to support their use in the acute phase, but their safety profiles often limit their utility in the long-term. Emerging evidence regarding the association of GPP with IL36RN mutations suggests a unique role for agents targeting the IL-36 or IL-1 pathways, though this has yet to be thoroughly investigated.

Acute generalized pustular psoriasis (GPP) is a rare severe variant of psoriasis characterized by the sudden widespread eruption of sterile pustules.^1,2 The cutaneous manifestations of GPP also may be accompanied by signs of systemic inflammation, including fever, malaise, and leukocytosis.² Complications are common and may be life-threatening, especially in older patients with comorbid diseases.³ Generalized pustular psoriasis most commonly occurs in patients with a preceding history of psoriasis, but it also may occur de novo.⁴ Generalized pustular psoriasis is associated with notable morbidity and mortality, and relapses are common.^3,4 Many triggers of GPP have been identified, including initiation and withdrawal of various medications, infections, pregnancy, and other conditions.^5,6 Although GPP most often occurs in adults, it also may arise in children and infants.³ In pregnancy, GPP is referred to as impetigo herpetiformis, despite having no etiologic ties with either herpes simplex virus or staphylococcal or streptococcal infection. Impetigo herpetiformis is considered one of the most dangerous dermatoses of pregnancy because of high rates of associated maternal and fetal morbidity.^6,7

Acute GPP has proven to be a challenging disease to treat due to the rarity and relapsing-remitting nature of the disease; additionally, there are relatively few randomized controlled trials investigating the efficacy and safety of treatments for GPP. This review summarizes the features of GPP, including the pathophysiology of the disease, clinical and histological manifestations, and recommendations for management based on a PubMed search of articles indexed for MEDLINE using MeSH terms pertaining to the disease, including generalized pustular psoriasis, impetigo herpetiformis, and von Zumbusch psoriasis.

Pathophysiology

The pathophysiology of GPP is only partially understood, but it is thought to have a distinct pattern of immune activation compared with plaque psoriasis.⁸ Although there is a considerable amount of overlap and cross-talk among cytokine pathways, GPP generally is driven by innate immunity and unrestrained IL-36 cytokine activity. In contrast, adaptive immune responses—namely the tumor necrosis factor (TNF) α, IL-23, IL-17, and IL-22 axes—underlie plaque psoriasis.^8-10

Proinflammatory IL-36 cytokines α, β, and γ, which are all part of the IL-1 superfamily, bind to the IL-36 receptor (IL-36R) to recruit and activate immune cells via various mediators, including IL-1β; IL-8; and chemokines CXCL1, CXCL2, and CXCL8.³ The IL-36 receptor antagonist (IL-36ra) acts to inhibit this inflammatory cascade.^3,8 Microarray analyses of skin biopsy samples have shown that overexpression of IL-17A, TNF-α, IL-1, and IL-36 are seen in both GPP and plaque psoriasis lesions, but GPP lesions had higher expression of IL-1β, IL-36α, and IL-36γ and elevated neutrophil chemokines—CXCL1, CXCL2, and CXCL8—compared with plaque psoriasis lesions.⁸

Gene Mutations Associated With GPP

There are 3 gene mutations that have been associated with pustular variants of psoriasis, though these mutations account for a minority of cases of GPP.⁴ Genetic screenings are not routinely indicated in patients with GPP, but they may be warranted in severe cases when a familial pattern of inheritance is suspected.⁴

IL36RN—The gene IL36RN codes the anti-inflammatory IL-36ra. Loss-of-function mutations in IL36RN lead to impairment of IL-36ra and consequently hyperactivity of the proinflammatory responses triggered by IL-36.³ Homozygous and heterozygous mutations in IL36RN have been observed in both familial and sporadic cases of GPP.^11-13 Subsequent retrospective analyses have identified the presence of IL36RN mutations in patients with GPP with frequencies ranging from 23% to 37%.^14-17IL36RN mutations are thought to be more common in patients without concomitant plaque psoriasis and have been associated with severe disease and early disease onset.¹⁵

CARD14—A gain-of-function mutation in CARD14 results in overactivation of the proinflammatory nuclear factor κB pathway and has been implicated in cases of GPP with concurrent psoriasis vulgaris. Interestingly, this may suggest distinct etiologies underlying GPP de novo and GPP in patients with a history of psoriasis.^18,19

AP1S3—A loss-of-function mutation in AP1S3 results in abnormal endosomal trafficking and autophagy as well as increased expression of IL-36α.^20,21

Clinical Presentation and DiagnosisCutaneous Manifestations of GPP

Generalized pustular psoriasis is characterized by the onset of widespread 2- to 3-mm sterile pustules on erythematous skin or within psoriasiform plaques⁴ (Figure). In patients with skin of color, the erythema may appear less obvious or perhaps slightly violaceous compared to White skin. Pustules may coalesce to form “lakes” of pus.⁵ Cutaneous symptoms include pain, burning, and pruritus. Associated mucosal findings may include cheilitis, geographic tongue, conjunctivitis, and uveitis.⁴

The severity of symptoms can vary greatly among patients as well as between flares within the same patient.^2,3 Four distinct patterns of GPP have been described. The von Zumbusch pattern is characterized by a rapid, generalized, painful, erythematous and pustular eruption accompanied by fever and asthenia. The pustules usually resolve after several days with extensive scaling. The annular pattern is characterized by annular, erythematous, scaly lesions with pustules present centrifugally. The lesions enlarge by centrifugal expansion over a period of hours to days, while healing occurs centrally. The exanthematic type is an acute eruption of small pustules that abruptly appear and disappear within a few days, usually from infection or medication initiation. Sometimes pustules appear within or at the edge of existing psoriatic plaques in a localized pattern—the fourth pattern—often following the exposure to irritants (eg, tars, anthralin).⁵

Impetigo Herpetiformis—Impetigo herpetiformis is a form of GPP associated with pregnancy. It generally presents early in the third trimester with symmetric erythematous plaques in flexural and intertriginous areas with pustules present at lesion margins. Lesions expand centrifugally, with pustulation present at the advancing edge.^6,7 Patients often are acutely ill with fever, delirium, vomiting, and tetany. Mucous membranes, including the tongue, mouth, and esophagus, also may be involved. The eruption typically resolves after delivery, though it often recurs with subsequent pregnancies, with the morbidity risk rising with each successive pregnancy.⁷

Systemic and Extracutaneous Manifestations of GPP

Although the severity of GPP is highly variable, skin manifestations often are accompanied by systemic manifestations of inflammation, including fever and malaise. Common laboratory abnormalities include leukocytosis with peripheral neutrophilia, a high serum C-reactive protein level, hypocalcemia, and hypoalbuminemia.²² Abnormal liver enzymes often are present and result from neutrophilic cholangitis, with alternating strictures and dilations of biliary ducts observed on magnetic resonance imaging.²³ Additional laboratory abnormalities are provided in Table 2. Other extracutaneous findings associated with GPP include arthralgia, edema, and characteristic psoriatic nail changes.⁴ Fatal complications include acute respiratory distress syndrome, renal dysfunction, cardiovascular shock, and sepsis.^24,25

Histologic Features

Given the potential for the skin manifestations of GPP to mimic other disorders, a skin biopsy is warranted to confirm the diagnosis. Generalized pustular psoriasis is histologically characterized by the presence of subcorneal macropustules (ie, spongiform pustules of Kogoj) formed by neutrophil infiltration into the spongelike network of the epidermis.⁶ Otherwise, the architecture of the epithelium in GPP is similar to that seen with plaque psoriasis, with parakeratosis, acanthosis, rete-ridge elongation, diminished stratum granulosum, and thinning of the suprapapillary epidermis, though the inflammatory cell infiltrate and edema are markedly more severe in GPP than plaque psoriasis.^3,4

Differential Diagnosis

There are many other cutaneous pustular diagnoses that must be ruled out when evaluating a patient with GPP (Table 1).²⁶ Acute generalized exanthematous pustulosis (AGEP) is a common mimicker of GPP that is differentiated histologically by the presence of eosinophils and necrotic keratinocytes.⁴ In addition to its distinct histopathologic findings, AGEP is classically associated with recent initiation of certain medications, most commonly penicillins, macrolides, quinolones, sulfonamides, terbinafine, and diltiazem.²⁷ In contrast, GPP more commonly is related to withdrawal of corticosteroids as well as initiation of some biologic medications, including anti-TNF agents.³ Generalized pustular psoriasis should be suspected over AGEP in patients with a personal or family history of psoriasis, though GPP may arise in patients with or without a history of psoriasis. Acute generalized exanthematous pustulosis usually is more abrupt in both onset and resolution compared with GPP, with clearance of pustules within a few days to weeks following cessation of the triggering factor.⁴

Other pustular variants of psoriasis (eg, palmoplantar pustular psoriasis, acrodermatitis continua of Hallopeau) are differentiated from GPP by their chronicity and localization to palmoplantar and/or ungual surfaces.⁵ Other differential diagnoses are listed in Table 1.

Diagnostic Criteria for GPP

Diagnostic criteria have been proposed for GPP (Table 2), including (1) the presence of sterile pustules, (2) systemic signs of inflammation, (3) laboratory abnormalities, (4) histopathologic confirmation of spongiform pustules of Kogoj, and (5) recurrence of symptoms.²² To definitively diagnose GPP, all 5 criteria must be met. To rule out mimickers, it may be worthwhile to perform Gram staining, potassium hydroxide preparation, in vitro cultures, and/or immunofluorescence testing.⁶

Treatment

Given the high potential for mortality associated with GPP, the most essential component of management is to ensure adequate supportive care. Any temperature, fluid, or electrolyte imbalances should be corrected as they arise. Secondary infections also must be identified and treated, if present, to reduce the risk for fatal complications, including systemic infection and sepsis. Precautions must be taken to ensure that serious end-organ damage, including hepatic, renal, and respiratory dysfunction, is avoided.

Adjunctive topical intervention often is initiated with bland emollients, corticosteroids, calcineurin inhibitors, and/or vitamin D derivatives to help soothe skin symptoms, but treatment with systemic therapies usually is warranted to achieve symptom control.^2,25 Importantly, there are no systemic or topical agents that have specifically been approved for the treatment of GPP in Europe or the United States.³ Given the absence of universally accepted treatment guidelines, therapeutic agents for GPP usually are selected based on clinical experience while also taking the extent of involvement and disease severity into consideration.³

Treatment Recommendations for Adults

Oral Systemic Agents—Treatment guidelines set forth by the National Psoriasis Foundation (NPF) in 2012 proposed that first-line therapies for GPP should be acitretin, cyclosporine, methotrexate, and infliximab.²⁸ However, since those guidelines were established, many new biologic therapies have been approved for the treatment of psoriasis and often are considered in the treatment of psoriasis subtypes, including GPP.²⁹ Although retinoids previously were considered to be a preferred first-line therapy, they are associated with a high incidence of adverse effects and must be used with caution in women of childbearing age.⁶ Oral acitretin at a dosage of 0.75 to 1.0 mg/kg/d has been shown to result in clinical improvement within 1 to 2 weeks, and a maintenance dosage of 0.125 to 0.25 mg/kg/d is required for several months to prevent recurrence.³⁰ Methotrexate—5.0 to 15.0 mg/wk, or perhaps higher in patients with refractory disease, increased by 2.5-mg intervals until symptoms improve—is recommended by the NPF in patients who are unresponsive or cannot tolerate retinoids, though close monitoring for hematologic abnormalities is required. Cyclosporine 2.5 to 5.0 mg/kg/d is considered an alternative to methotrexate and retinoids; it has a faster onset of action, with improvement reported as early as 2 weeks after initiation of therapy.^1,28 Although cyclosporine may be effective in the acute phase, especially in severe cases of GPP, long-term use of cyclosporine is not recommended because of the potential for renal dysfunction and hypertension.³¹

Biologic Agents—More recent evidence has accumulated supporting the efficacy of anti-TNF agents in the treatment of GPP, suggesting the positioning of these agents as first line. A number of case series have shown dramatic and rapid improvement of GPP with intravenous infliximab 3 to 5 mg/kg, with results observed hours to days after the first infusion.^32-37 Thus, infliximab is recommended as first-line treatment in severe acute cases, though its efficacy as a maintenance therapy has not been sufficiently investigated.⁶ Case reports and case series document the safety and efficacy of adalimumab 40 to 80 mg every 1 to 2 weeks^38,39 and etanercept 25 to 50 mg twice weekly^40-42 in patients with recalcitrantGPP. Therefore, these anti-TNF agents may be considered in patients who are nonresponsive to treatment with infliximab.

Rarely, there have been reports of paradoxical induction of GPP with the use of some anti-TNF agents,^43-45 which may be due to a cytokine imbalance characterized by unopposed IFN-α activation.⁶ In patients with a history of GPP after initiation of a biologic, treatment with agents from within the offending class should be avoided.

The IL-17A monoclonal antibodies secukinumab, ixekizumab, and brodalumab have been shown in open-label phase 3 studies to result in disease remission at 12 weeks.^46-48 Treatment with guselkumab, an IL-23 monoclonal antibody, also has demonstrated efficacy in patients with GPP.⁴⁹ Ustekinumab, an IL-12/23 inhibitor, in combination with acitretin also has been shown to be successful in achieving disease remission after a few weeks of treatment.⁵⁰

More recent case reports have shown the efficacy of IL-1 inhibitors including gevokizumab, canakinumab, and anakinra in achieving GPP clearance, though more prospective studies are needed to evaluate their efficacy.^51-53 Given the etiologic association between IL-1 disinhibition and GPP, future investigations of these therapies as well as those that target the IL-36 pathway may prove to be particularly interesting.

Phototherapy and Combination Therapies—Phototherapy may be considered as maintenance therapy after disease control is achieved, though it is not considered appropriate for acute cases.²⁸ Combination therapies with a biologic plus a nonbiologic systemic agent or alternating among various biologics may allow physicians to maximize benefits and minimize adverse effects in the long term, though there is insufficient evidence to suggest any specific combination treatment algorithm for GPP.²⁸

Treatment Recommendations for Pediatric Patients

Based on a small number of case series and case reports, the first-line treatment strategy for children with GPP is similar to adults. Given the notable adverse events of most oral systemic agents, biologic therapies may emerge as first-line therapy in the pediatric population as more evidence accumulates.²⁸

Treatment Recommendations for Pregnant Patients

Systemic corticosteroids are widely considered to be the first-line treatments for the management of impetigo herpetiformis.⁷ Low-dose prednisone (15–30 mg/d) usually is effective, but severe cases may require increasing the dosage to 60 mg/d.⁶ Given the potential for rebound flares upon withdrawal of systemic corticosteroids, these agents must be gradually tapered after the resolution of symptoms.

Certolizumab pegol also is an attractive option in pregnant patients with impetigo herpetiformis because of its favorable safety profile and negligible mother-to-infant transfer through the placenta or breast milk. It has been shown to be effective in treating GPP and impetigo herpetiformis during pregnancy in recently published case reports.^54,55 In refractory cases, other TNF-α inhibitors (eg, adalimumab, infliximab, etanercept) or cyclosporine may be considered. However, cautious medical monitoring is warranted, as little is known about the potential adverse effects of these agents to the mother and fetus.^28,56 Data from transplant recipients along with several case reports indicate that cyclosporine is not associated with an increased risk for adverse effects during pregnancy at a dose of 2 to 3 mg/kg.^57-59 Both methotrexate and retinoids are known teratogens and are therefore contraindicated in pregnant patients.⁵⁶

If pustules do not resolve in the postpartum period, patients should be treated with standard GPP therapies. However, long-term and population studies are lacking regarding the potential for infant exposure to systemic agents in breast milk. Therefore, the NPF recommends avoiding breastfeeding while taking systemic medications, if possible.⁵⁶

Limitations of Treatment Recommendations

The ability to generate an evidence-based treatment strategy for GPP is limited by a lack of high-quality studies investigating the efficacy and safety of treatments in patients with GPP due to the rarity and relapsing-remitting nature of the disease, which makes randomized controlled trials difficult to conduct. The quality of the available research is further limited by the lack of validated outcome measures to specifically assess improvements in patients with GPP, such that results are difficult to synthesize and compare among studies.³¹

Conclusion

Although limited, the available research suggests that treatment with various biologics, especially infliximab, is effective in achieving rapid clearance in patients with GPP. In general, biologics may be the most appropriate treatment option in patients with GPP given their relatively favorable safety profiles. Other oral systemic agents, including acitretin, cyclosporine, and methotrexate, have limited evidence to support their use in the acute phase, but their safety profiles often limit their utility in the long-term. Emerging evidence regarding the association of GPP with IL36RN mutations suggests a unique role for agents targeting the IL-36 or IL-1 pathways, though this has yet to be thoroughly investigated.

Acute generalized pustular psoriasis (GPP) is a rare severe variant of psoriasis characterized by the sudden widespread eruption of sterile pustules.^1,2 The cutaneous manifestations of GPP also may be accompanied by signs of systemic inflammation, including fever, malaise, and leukocytosis.² Complications are common and may be life-threatening, especially in older patients with comorbid diseases.³ Generalized pustular psoriasis most commonly occurs in patients with a preceding history of psoriasis, but it also may occur de novo.⁴ Generalized pustular psoriasis is associated with notable morbidity and mortality, and relapses are common.^3,4 Many triggers of GPP have been identified, including initiation and withdrawal of various medications, infections, pregnancy, and other conditions.^5,6 Although GPP most often occurs in adults, it also may arise in children and infants.³ In pregnancy, GPP is referred to as impetigo herpetiformis, despite having no etiologic ties with either herpes simplex virus or staphylococcal or streptococcal infection. Impetigo herpetiformis is considered one of the most dangerous dermatoses of pregnancy because of high rates of associated maternal and fetal morbidity.^6,7

Acute GPP has proven to be a challenging disease to treat due to the rarity and relapsing-remitting nature of the disease; additionally, there are relatively few randomized controlled trials investigating the efficacy and safety of treatments for GPP. This review summarizes the features of GPP, including the pathophysiology of the disease, clinical and histological manifestations, and recommendations for management based on a PubMed search of articles indexed for MEDLINE using MeSH terms pertaining to the disease, including generalized pustular psoriasis, impetigo herpetiformis, and von Zumbusch psoriasis.

Pathophysiology

The pathophysiology of GPP is only partially understood, but it is thought to have a distinct pattern of immune activation compared with plaque psoriasis.⁸ Although there is a considerable amount of overlap and cross-talk among cytokine pathways, GPP generally is driven by innate immunity and unrestrained IL-36 cytokine activity. In contrast, adaptive immune responses—namely the tumor necrosis factor (TNF) α, IL-23, IL-17, and IL-22 axes—underlie plaque psoriasis.^8-10

Proinflammatory IL-36 cytokines α, β, and γ, which are all part of the IL-1 superfamily, bind to the IL-36 receptor (IL-36R) to recruit and activate immune cells via various mediators, including IL-1β; IL-8; and chemokines CXCL1, CXCL2, and CXCL8.³ The IL-36 receptor antagonist (IL-36ra) acts to inhibit this inflammatory cascade.^3,8 Microarray analyses of skin biopsy samples have shown that overexpression of IL-17A, TNF-α, IL-1, and IL-36 are seen in both GPP and plaque psoriasis lesions, but GPP lesions had higher expression of IL-1β, IL-36α, and IL-36γ and elevated neutrophil chemokines—CXCL1, CXCL2, and CXCL8—compared with plaque psoriasis lesions.⁸

Gene Mutations Associated With GPP

There are 3 gene mutations that have been associated with pustular variants of psoriasis, though these mutations account for a minority of cases of GPP.⁴ Genetic screenings are not routinely indicated in patients with GPP, but they may be warranted in severe cases when a familial pattern of inheritance is suspected.⁴

IL36RN—The gene IL36RN codes the anti-inflammatory IL-36ra. Loss-of-function mutations in IL36RN lead to impairment of IL-36ra and consequently hyperactivity of the proinflammatory responses triggered by IL-36.³ Homozygous and heterozygous mutations in IL36RN have been observed in both familial and sporadic cases of GPP.^11-13 Subsequent retrospective analyses have identified the presence of IL36RN mutations in patients with GPP with frequencies ranging from 23% to 37%.^14-17IL36RN mutations are thought to be more common in patients without concomitant plaque psoriasis and have been associated with severe disease and early disease onset.¹⁵

CARD14—A gain-of-function mutation in CARD14 results in overactivation of the proinflammatory nuclear factor κB pathway and has been implicated in cases of GPP with concurrent psoriasis vulgaris. Interestingly, this may suggest distinct etiologies underlying GPP de novo and GPP in patients with a history of psoriasis.^18,19

AP1S3—A loss-of-function mutation in AP1S3 results in abnormal endosomal trafficking and autophagy as well as increased expression of IL-36α.^20,21

Clinical Presentation and DiagnosisCutaneous Manifestations of GPP

Generalized pustular psoriasis is characterized by the onset of widespread 2- to 3-mm sterile pustules on erythematous skin or within psoriasiform plaques⁴ (Figure). In patients with skin of color, the erythema may appear less obvious or perhaps slightly violaceous compared to White skin. Pustules may coalesce to form “lakes” of pus.⁵ Cutaneous symptoms include pain, burning, and pruritus. Associated mucosal findings may include cheilitis, geographic tongue, conjunctivitis, and uveitis.⁴

The severity of symptoms can vary greatly among patients as well as between flares within the same patient.^2,3 Four distinct patterns of GPP have been described. The von Zumbusch pattern is characterized by a rapid, generalized, painful, erythematous and pustular eruption accompanied by fever and asthenia. The pustules usually resolve after several days with extensive scaling. The annular pattern is characterized by annular, erythematous, scaly lesions with pustules present centrifugally. The lesions enlarge by centrifugal expansion over a period of hours to days, while healing occurs centrally. The exanthematic type is an acute eruption of small pustules that abruptly appear and disappear within a few days, usually from infection or medication initiation. Sometimes pustules appear within or at the edge of existing psoriatic plaques in a localized pattern—the fourth pattern—often following the exposure to irritants (eg, tars, anthralin).⁵

Impetigo Herpetiformis—Impetigo herpetiformis is a form of GPP associated with pregnancy. It generally presents early in the third trimester with symmetric erythematous plaques in flexural and intertriginous areas with pustules present at lesion margins. Lesions expand centrifugally, with pustulation present at the advancing edge.^6,7 Patients often are acutely ill with fever, delirium, vomiting, and tetany. Mucous membranes, including the tongue, mouth, and esophagus, also may be involved. The eruption typically resolves after delivery, though it often recurs with subsequent pregnancies, with the morbidity risk rising with each successive pregnancy.⁷

Systemic and Extracutaneous Manifestations of GPP

Although the severity of GPP is highly variable, skin manifestations often are accompanied by systemic manifestations of inflammation, including fever and malaise. Common laboratory abnormalities include leukocytosis with peripheral neutrophilia, a high serum C-reactive protein level, hypocalcemia, and hypoalbuminemia.²² Abnormal liver enzymes often are present and result from neutrophilic cholangitis, with alternating strictures and dilations of biliary ducts observed on magnetic resonance imaging.²³ Additional laboratory abnormalities are provided in Table 2. Other extracutaneous findings associated with GPP include arthralgia, edema, and characteristic psoriatic nail changes.⁴ Fatal complications include acute respiratory distress syndrome, renal dysfunction, cardiovascular shock, and sepsis.^24,25

Histologic Features

Given the potential for the skin manifestations of GPP to mimic other disorders, a skin biopsy is warranted to confirm the diagnosis. Generalized pustular psoriasis is histologically characterized by the presence of subcorneal macropustules (ie, spongiform pustules of Kogoj) formed by neutrophil infiltration into the spongelike network of the epidermis.⁶ Otherwise, the architecture of the epithelium in GPP is similar to that seen with plaque psoriasis, with parakeratosis, acanthosis, rete-ridge elongation, diminished stratum granulosum, and thinning of the suprapapillary epidermis, though the inflammatory cell infiltrate and edema are markedly more severe in GPP than plaque psoriasis.^3,4

Differential Diagnosis

There are many other cutaneous pustular diagnoses that must be ruled out when evaluating a patient with GPP (Table 1).²⁶ Acute generalized exanthematous pustulosis (AGEP) is a common mimicker of GPP that is differentiated histologically by the presence of eosinophils and necrotic keratinocytes.⁴ In addition to its distinct histopathologic findings, AGEP is classically associated with recent initiation of certain medications, most commonly penicillins, macrolides, quinolones, sulfonamides, terbinafine, and diltiazem.²⁷ In contrast, GPP more commonly is related to withdrawal of corticosteroids as well as initiation of some biologic medications, including anti-TNF agents.³ Generalized pustular psoriasis should be suspected over AGEP in patients with a personal or family history of psoriasis, though GPP may arise in patients with or without a history of psoriasis. Acute generalized exanthematous pustulosis usually is more abrupt in both onset and resolution compared with GPP, with clearance of pustules within a few days to weeks following cessation of the triggering factor.⁴

Other pustular variants of psoriasis (eg, palmoplantar pustular psoriasis, acrodermatitis continua of Hallopeau) are differentiated from GPP by their chronicity and localization to palmoplantar and/or ungual surfaces.⁵ Other differential diagnoses are listed in Table 1.

Diagnostic Criteria for GPP

Diagnostic criteria have been proposed for GPP (Table 2), including (1) the presence of sterile pustules, (2) systemic signs of inflammation, (3) laboratory abnormalities, (4) histopathologic confirmation of spongiform pustules of Kogoj, and (5) recurrence of symptoms.²² To definitively diagnose GPP, all 5 criteria must be met. To rule out mimickers, it may be worthwhile to perform Gram staining, potassium hydroxide preparation, in vitro cultures, and/or immunofluorescence testing.⁶

Treatment

Given the high potential for mortality associated with GPP, the most essential component of management is to ensure adequate supportive care. Any temperature, fluid, or electrolyte imbalances should be corrected as they arise. Secondary infections also must be identified and treated, if present, to reduce the risk for fatal complications, including systemic infection and sepsis. Precautions must be taken to ensure that serious end-organ damage, including hepatic, renal, and respiratory dysfunction, is avoided.

Adjunctive topical intervention often is initiated with bland emollients, corticosteroids, calcineurin inhibitors, and/or vitamin D derivatives to help soothe skin symptoms, but treatment with systemic therapies usually is warranted to achieve symptom control.^2,25 Importantly, there are no systemic or topical agents that have specifically been approved for the treatment of GPP in Europe or the United States.³ Given the absence of universally accepted treatment guidelines, therapeutic agents for GPP usually are selected based on clinical experience while also taking the extent of involvement and disease severity into consideration.³

Treatment Recommendations for Adults

Oral Systemic Agents—Treatment guidelines set forth by the National Psoriasis Foundation (NPF) in 2012 proposed that first-line therapies for GPP should be acitretin, cyclosporine, methotrexate, and infliximab.²⁸ However, since those guidelines were established, many new biologic therapies have been approved for the treatment of psoriasis and often are considered in the treatment of psoriasis subtypes, including GPP.²⁹ Although retinoids previously were considered to be a preferred first-line therapy, they are associated with a high incidence of adverse effects and must be used with caution in women of childbearing age.⁶ Oral acitretin at a dosage of 0.75 to 1.0 mg/kg/d has been shown to result in clinical improvement within 1 to 2 weeks, and a maintenance dosage of 0.125 to 0.25 mg/kg/d is required for several months to prevent recurrence.³⁰ Methotrexate—5.0 to 15.0 mg/wk, or perhaps higher in patients with refractory disease, increased by 2.5-mg intervals until symptoms improve—is recommended by the NPF in patients who are unresponsive or cannot tolerate retinoids, though close monitoring for hematologic abnormalities is required. Cyclosporine 2.5 to 5.0 mg/kg/d is considered an alternative to methotrexate and retinoids; it has a faster onset of action, with improvement reported as early as 2 weeks after initiation of therapy.^1,28 Although cyclosporine may be effective in the acute phase, especially in severe cases of GPP, long-term use of cyclosporine is not recommended because of the potential for renal dysfunction and hypertension.³¹

Biologic Agents—More recent evidence has accumulated supporting the efficacy of anti-TNF agents in the treatment of GPP, suggesting the positioning of these agents as first line. A number of case series have shown dramatic and rapid improvement of GPP with intravenous infliximab 3 to 5 mg/kg, with results observed hours to days after the first infusion.^32-37 Thus, infliximab is recommended as first-line treatment in severe acute cases, though its efficacy as a maintenance therapy has not been sufficiently investigated.⁶ Case reports and case series document the safety and efficacy of adalimumab 40 to 80 mg every 1 to 2 weeks^38,39 and etanercept 25 to 50 mg twice weekly^40-42 in patients with recalcitrantGPP. Therefore, these anti-TNF agents may be considered in patients who are nonresponsive to treatment with infliximab.

Rarely, there have been reports of paradoxical induction of GPP with the use of some anti-TNF agents,^43-45 which may be due to a cytokine imbalance characterized by unopposed IFN-α activation.⁶ In patients with a history of GPP after initiation of a biologic, treatment with agents from within the offending class should be avoided.

The IL-17A monoclonal antibodies secukinumab, ixekizumab, and brodalumab have been shown in open-label phase 3 studies to result in disease remission at 12 weeks.^46-48 Treatment with guselkumab, an IL-23 monoclonal antibody, also has demonstrated efficacy in patients with GPP.⁴⁹ Ustekinumab, an IL-12/23 inhibitor, in combination with acitretin also has been shown to be successful in achieving disease remission after a few weeks of treatment.⁵⁰

More recent case reports have shown the efficacy of IL-1 inhibitors including gevokizumab, canakinumab, and anakinra in achieving GPP clearance, though more prospective studies are needed to evaluate their efficacy.^51-53 Given the etiologic association between IL-1 disinhibition and GPP, future investigations of these therapies as well as those that target the IL-36 pathway may prove to be particularly interesting.

Phototherapy and Combination Therapies—Phototherapy may be considered as maintenance therapy after disease control is achieved, though it is not considered appropriate for acute cases.²⁸ Combination therapies with a biologic plus a nonbiologic systemic agent or alternating among various biologics may allow physicians to maximize benefits and minimize adverse effects in the long term, though there is insufficient evidence to suggest any specific combination treatment algorithm for GPP.²⁸

Treatment Recommendations for Pediatric Patients

Based on a small number of case series and case reports, the first-line treatment strategy for children with GPP is similar to adults. Given the notable adverse events of most oral systemic agents, biologic therapies may emerge as first-line therapy in the pediatric population as more evidence accumulates.²⁸

Treatment Recommendations for Pregnant Patients

Systemic corticosteroids are widely considered to be the first-line treatments for the management of impetigo herpetiformis.⁷ Low-dose prednisone (15–30 mg/d) usually is effective, but severe cases may require increasing the dosage to 60 mg/d.⁶ Given the potential for rebound flares upon withdrawal of systemic corticosteroids, these agents must be gradually tapered after the resolution of symptoms.

Certolizumab pegol also is an attractive option in pregnant patients with impetigo herpetiformis because of its favorable safety profile and negligible mother-to-infant transfer through the placenta or breast milk. It has been shown to be effective in treating GPP and impetigo herpetiformis during pregnancy in recently published case reports.^54,55 In refractory cases, other TNF-α inhibitors (eg, adalimumab, infliximab, etanercept) or cyclosporine may be considered. However, cautious medical monitoring is warranted, as little is known about the potential adverse effects of these agents to the mother and fetus.^28,56 Data from transplant recipients along with several case reports indicate that cyclosporine is not associated with an increased risk for adverse effects during pregnancy at a dose of 2 to 3 mg/kg.^57-59 Both methotrexate and retinoids are known teratogens and are therefore contraindicated in pregnant patients.⁵⁶

If pustules do not resolve in the postpartum period, patients should be treated with standard GPP therapies. However, long-term and population studies are lacking regarding the potential for infant exposure to systemic agents in breast milk. Therefore, the NPF recommends avoiding breastfeeding while taking systemic medications, if possible.⁵⁶

Limitations of Treatment Recommendations

The ability to generate an evidence-based treatment strategy for GPP is limited by a lack of high-quality studies investigating the efficacy and safety of treatments in patients with GPP due to the rarity and relapsing-remitting nature of the disease, which makes randomized controlled trials difficult to conduct. The quality of the available research is further limited by the lack of validated outcome measures to specifically assess improvements in patients with GPP, such that results are difficult to synthesize and compare among studies.³¹

Conclusion

Although limited, the available research suggests that treatment with various biologics, especially infliximab, is effective in achieving rapid clearance in patients with GPP. In general, biologics may be the most appropriate treatment option in patients with GPP given their relatively favorable safety profiles. Other oral systemic agents, including acitretin, cyclosporine, and methotrexate, have limited evidence to support their use in the acute phase, but their safety profiles often limit their utility in the long-term. Emerging evidence regarding the association of GPP with IL36RN mutations suggests a unique role for agents targeting the IL-36 or IL-1 pathways, though this has yet to be thoroughly investigated.

What is West Nile virus? How is it contracted, and who can become infected?

West Nile virus (WNV) is a single-stranded RNA virus of the Flaviviridae family and Flavivirus genus, a lineage that also includes the yellow fever, dengue, Zika, Japanese encephalitis, and Saint Louis encephalitis viruses.¹ Birds serve as the reservoir hosts of WNV, and mosquitoes acquire the virus during feeding.² West Nile virus then is transmitted to humans primarily by bites from Culex mosquitoes, which are especially prevalent in wooded areas during peak mosquito season (summer through early fall in North America).¹ Mosquitoes also can infect horses; however, humans and horses are dead-end hosts, meaning they do not pass the virus on to other biting mosquitoes.³ There also have been rare reports of transmission of WNV through blood and donation as well as mother-to-baby transmission.²

What is the epidemiology of WNV in the United States?

Since the introduction of WNV to the United States in 1999, it has become an important public health concern, with 48,183 cases and 2163 deaths reported since 1999.^2,3 In 2018, Nebraska had the highest number of cases of WNV (n=251), followed by California (n=217), North Dakota (n=204), Illinois (n=176), and South Dakota (n=169).³ West Nile virus is endemic to all 48 contiguous states and Canada, though the Great Plains region is especially affected by WNV due to several factors, such as a greater percentage of rural land, forests, and irrigated areas.⁴ The Great Plains region also has been thought to be an ecological niche for a more virulent species (Culex tarsalis) compared to other regions in the United States.⁵

The annual incidence of WNV in the United States peaked in 2003 at 9862 cases (up from 62 cases in 1999), then declined gradually until 2008 to 2011, during which the incidence was stable at 700 to 1100 new cases per year. However, there was a resurgence of cases (n=5674) in 2012 that steadied at around 2200 cases annually in subsequent years.⁶ Although there likely are several factors affecting WNV incidence trends in the United States, interannual changes in temperature and precipitation have been described. An increased mean annual temperature (from September through October, the end of peak mosquito season) and an increased temperature in winter months (from January through March, prior to peak mosquito season) have both been associated with an increased incidence of WNV.⁷ An increased temperature is thought to increase population numbers of mosquitoes both by increasing reproductive rates and creating ideal breeding environments via pooled water areas.⁸ Depending on the region, both above average and below average precipitation levels in the United States can increase WNV incidence the following year.^7,9

What are the signs and symptoms of WNV infection?

Up to 80% of those infected with WNV are asymptomatic.³ After an incubation period of roughly 2 to 14 days, the remaining 20% may develop symptoms of West Nile fever (WNF), typically a self-limited illness that consists of 3 to 10 days of nonspecific symptoms such as fever, headache, fatigue, muscle pain and/or weakness, eye pain, gastrointestinal tract upset, and a macular rash that usually presents on the trunk or extremities.^1,3 Less than 1% of patients affected by WNV develop neuroinvasive disease, including meningitis, encephalitis, and/or acute flaccid paralysis.¹⁰ West Nile virus neuroinvasive disease can cause permanent neurologic sequelae such as muscle weakness, confusion, memory loss, and fatigue; it carries a mortality rate of 10% to 30%, which is mainly dependent on older age and immunosuppression status.^1,10

What is the reported spectrum of cutaneous findings in WNV?

Of the roughly 20% of patients infected with WNV that develop WNF, approximately 25% to 50% will develop an associated rash.¹ It most commonly is described as a morbilliform or maculopapular rash located on the chest, back, and arms, usually sparing the palms and soles, though 1 case report noted involvement with these areas (Figure).^11,12 It typically appears 5 days after symptom onset, can be associated with defervescence, and lasts less than a week.^1,13 Pruritus and dysesthesia are sometimes present.¹³ Other rare presentations that have been reported include an ill-defined pseudovesicular rash with erythematous papules on the palms and pink, scaly, psoriasiform papules on the feet and thighs, as well as neuroinvasive WNV leading to purpura fulminans.^14,15 A diffuse, erythematous, petechial rash on the face, neck, trunk, and extremities was reported in a pediatric patient, but there have been no reports of a petechial rash associated with WNV in adult patients.¹⁶ These findings suggest some potential variability in the presentation of the WNV rash.

What role does the presence of rash play diagnostically and prognostically?

The rash of WNV has been implicated as a potential prognostic factor in predicting more favorable outcomes.¹⁷ Using 2002 data from the Illinois Department of Public Health and 2003 data from the Colorado Department of Public Health, Huhn and Dworkin¹⁷ found the age-adjusted risk of encephalitis and death to be decreased in WNV patients with a rash (relative risk, 0.44; 95% CI, 0.21-0.92). The reasons for this are not definitively known, but we hypothesize that the rash may prompt patients to seek earlier medical attention or indicate a more robust immune response. Additionally, a rash in WNV more commonly is seen in younger patients, whereas WNV neuroinvasive disease is more common in older patients, who also tend to have worse outcomes.¹⁰ One study found rash to be the only symptom that demonstrated a significant association with seropositivity (overall risk=6.35; P<.05; 95% CI, 3.75-10.80) by multivariate analysis.¹⁸

How is WNV diagnosed? What are the downsides to WNV testing?

Given that the presenting symptoms of WNV and WNF are nonspecific, it becomes challenging to arrive at the diagnosis based solely on physical examination. As such, the patient’s clinical and epidemiologic history, such as timing, pattern, and appearance of the rash or recent history of mosquito bites, is key to arriving at the correct diagnosis. With clinical suspicion, possible diagnostic tests include an IgM enzyme-linked immunosorbent assay (ELISA) for WNV, a plaque reduction neutralization test (PNRT), and blood polymerase chain reaction (PCR).

An ELISA is a confirmatory test to detect IgM antibodies to WNV in the serum. Because IgM seroconversion typically occurs between days 4 and 10 of symptom onset, there is a high probability of initial false-negative testing within the first 8 days after symptom onset.^19,20 Clinical understanding of this fact is imperative, as an initial negative ELISA does not rule out WNV, and a retest is warranted if clinical suspicion is high. In addition to a high initial false-negative rate with ELISA, there are several other limitations to note. IgM antibodies remain elevated for 1 to 3 months or possibly up to a year in immunocompromised patients.¹ Due to this, false positives may be present if there was a recent prior infection. Enzyme-linked immunosorbent assay may not distinguish from different flaviviruses, including the yellow fever, dengue, Zika, Japanese encephalitis, and Saint Louis encephalitis viruses. Seropositivity has been estimated in some states, including 1999 data from New York (2.6%), 2003 data from Nebraska (9.5%), and 2012-2014 data from Connecticut (8.5%).^21-23 Regional variance may be expected, as there also were significant differences in WNV seropositivity between different regions in Nebraska (P<.001).²³

Because ELISA testing for WNV has readily apparent flaws, other tests have been utilized in its diagnosis. The PNRT is the most specific test, and it works by measuring neutralizing antibody titers for different flaviviruses. It has the ability to determine cross-reactivity with other flaviviruses; however, it does not discriminate between a current infection and a prior infection or prior flavivirus vaccine (ie, yellow fever vaccine). Despite this, a positive PNRT can lend credibility to a positive ELISA test and determine specificity for WNV for those with no prior flavivirus exposure.²⁴ According to the Centers for Disease Control and Prevention (CDC), this test can be performed by the CDC or in reference laboratories designated by the CDC.³ Additionally, some state health laboratories may perform PRNTs.

Viral detection with PCR currently is used to screen blood donations and may be beneficial for immunocompromised patients that lack the ability to form a robust antibody response or if a patient presents early, as PCR works best within the first week of symptom onset.¹ Tilley et al²⁵ showed that a combination of PCR and ELISA were able to accurately predict 94.2% of patients (180/191) with documented WNV on a first blood sample compared to 45% and 58.1% for only viral detection or ELISA, respectively. Based on costs from a Midwest academic center, antibody detection tests are around $100 while PCR may range from $500 to $1000 and is only performed in reference laboratories. Although these tests remain in the repertoire for WNV diagnosis, financial stewardship is important.

If there are symptoms of photophobia, phonophobia, nuchal rigidity, loss of consciousness, or marked personality changes, a lumbar puncture for WNV IgM in the cerebrospinal fluid can be performed. As with most viral infections, cerebrospinal fluid findings normally include an elevated protein and lymphocyte count, but neutrophils may be predominantly elevated if the infection is early in its course.²⁶

What are the management options?

To date, there is no curative treatment for WNV, and management is largely supportive. For WNF, over-the-counter pain medications may be helpful to reduce fever and pain. If more severe disease develops, hospitalization for further supportive care may be needed.²⁷ If meningitis or encephalitis is suspected, broad-spectrum antibiotics may need to be started until other common etiologies are ruled out.²⁸

How can you prevent WNV infection?

Disease prevention largely consists of educating the public to avoid heavily wooded areas, especially in areas of high prevalence and during peak months, and to use protective clothing and insect repellant that has been approved by the Environmental Protection Agency.³ Insect repellants approved by the Environmental Protection Agency contain ingredients such as DEET (N, N-diethyl-meta-toluamide), picaridin, IR3535 (ethyl butylacetylaminopropionate), and oil of lemon eucalyptus, which have been proven safe and effective.²⁹ Patients also can protect their homes by using window screens and promptly repairing screens with holes.³

What is the differential diagnosis for WNV?

The differential diagnosis for fever with generalized maculopapular rash broadly ranges from viral etiologies (eg, WNV, Zika, measles), to tick bites (eg, Rocky Mountain spotted fever, ehrlichiosis), to drug-induced rashes. A detailed patient history inquiring on recent sick contacts, travel (WNV in the Midwest, ehrlichiosis in the Southeast), environmental exposures (ticks, mosquitoes), and new medications (typically 7–10 days after starting) is imperative to narrow the differential.³⁰ In addition, the distribution, timing, and clinical characteristics of the rash may aid in diagnosis, along with an appropriately correlated clinical picture. West Nile virus likely will present in the summer in mid central geographic locations and often develops on the trunk and extremities as a blanching, generalized, maculopapular rash around 5 days after symptom onset or with defervescence.¹

What is West Nile virus? How is it contracted, and who can become infected?

West Nile virus (WNV) is a single-stranded RNA virus of the Flaviviridae family and Flavivirus genus, a lineage that also includes the yellow fever, dengue, Zika, Japanese encephalitis, and Saint Louis encephalitis viruses.¹ Birds serve as the reservoir hosts of WNV, and mosquitoes acquire the virus during feeding.² West Nile virus then is transmitted to humans primarily by bites from Culex mosquitoes, which are especially prevalent in wooded areas during peak mosquito season (summer through early fall in North America).¹ Mosquitoes also can infect horses; however, humans and horses are dead-end hosts, meaning they do not pass the virus on to other biting mosquitoes.³ There also have been rare reports of transmission of WNV through blood and donation as well as mother-to-baby transmission.²

What is the epidemiology of WNV in the United States?

Since the introduction of WNV to the United States in 1999, it has become an important public health concern, with 48,183 cases and 2163 deaths reported since 1999.^2,3 In 2018, Nebraska had the highest number of cases of WNV (n=251), followed by California (n=217), North Dakota (n=204), Illinois (n=176), and South Dakota (n=169).³ West Nile virus is endemic to all 48 contiguous states and Canada, though the Great Plains region is especially affected by WNV due to several factors, such as a greater percentage of rural land, forests, and irrigated areas.⁴ The Great Plains region also has been thought to be an ecological niche for a more virulent species (Culex tarsalis) compared to other regions in the United States.⁵

The annual incidence of WNV in the United States peaked in 2003 at 9862 cases (up from 62 cases in 1999), then declined gradually until 2008 to 2011, during which the incidence was stable at 700 to 1100 new cases per year. However, there was a resurgence of cases (n=5674) in 2012 that steadied at around 2200 cases annually in subsequent years.⁶ Although there likely are several factors affecting WNV incidence trends in the United States, interannual changes in temperature and precipitation have been described. An increased mean annual temperature (from September through October, the end of peak mosquito season) and an increased temperature in winter months (from January through March, prior to peak mosquito season) have both been associated with an increased incidence of WNV.⁷ An increased temperature is thought to increase population numbers of mosquitoes both by increasing reproductive rates and creating ideal breeding environments via pooled water areas.⁸ Depending on the region, both above average and below average precipitation levels in the United States can increase WNV incidence the following year.^7,9

What are the signs and symptoms of WNV infection?

Up to 80% of those infected with WNV are asymptomatic.³ After an incubation period of roughly 2 to 14 days, the remaining 20% may develop symptoms of West Nile fever (WNF), typically a self-limited illness that consists of 3 to 10 days of nonspecific symptoms such as fever, headache, fatigue, muscle pain and/or weakness, eye pain, gastrointestinal tract upset, and a macular rash that usually presents on the trunk or extremities.^1,3 Less than 1% of patients affected by WNV develop neuroinvasive disease, including meningitis, encephalitis, and/or acute flaccid paralysis.¹⁰ West Nile virus neuroinvasive disease can cause permanent neurologic sequelae such as muscle weakness, confusion, memory loss, and fatigue; it carries a mortality rate of 10% to 30%, which is mainly dependent on older age and immunosuppression status.^1,10

What is the reported spectrum of cutaneous findings in WNV?

Of the roughly 20% of patients infected with WNV that develop WNF, approximately 25% to 50% will develop an associated rash.¹ It most commonly is described as a morbilliform or maculopapular rash located on the chest, back, and arms, usually sparing the palms and soles, though 1 case report noted involvement with these areas (Figure).^11,12 It typically appears 5 days after symptom onset, can be associated with defervescence, and lasts less than a week.^1,13 Pruritus and dysesthesia are sometimes present.¹³ Other rare presentations that have been reported include an ill-defined pseudovesicular rash with erythematous papules on the palms and pink, scaly, psoriasiform papules on the feet and thighs, as well as neuroinvasive WNV leading to purpura fulminans.^14,15 A diffuse, erythematous, petechial rash on the face, neck, trunk, and extremities was reported in a pediatric patient, but there have been no reports of a petechial rash associated with WNV in adult patients.¹⁶ These findings suggest some potential variability in the presentation of the WNV rash.

What role does the presence of rash play diagnostically and prognostically?

The rash of WNV has been implicated as a potential prognostic factor in predicting more favorable outcomes.¹⁷ Using 2002 data from the Illinois Department of Public Health and 2003 data from the Colorado Department of Public Health, Huhn and Dworkin¹⁷ found the age-adjusted risk of encephalitis and death to be decreased in WNV patients with a rash (relative risk, 0.44; 95% CI, 0.21-0.92). The reasons for this are not definitively known, but we hypothesize that the rash may prompt patients to seek earlier medical attention or indicate a more robust immune response. Additionally, a rash in WNV more commonly is seen in younger patients, whereas WNV neuroinvasive disease is more common in older patients, who also tend to have worse outcomes.¹⁰ One study found rash to be the only symptom that demonstrated a significant association with seropositivity (overall risk=6.35; P<.05; 95% CI, 3.75-10.80) by multivariate analysis.¹⁸

How is WNV diagnosed? What are the downsides to WNV testing?

Given that the presenting symptoms of WNV and WNF are nonspecific, it becomes challenging to arrive at the diagnosis based solely on physical examination. As such, the patient’s clinical and epidemiologic history, such as timing, pattern, and appearance of the rash or recent history of mosquito bites, is key to arriving at the correct diagnosis. With clinical suspicion, possible diagnostic tests include an IgM enzyme-linked immunosorbent assay (ELISA) for WNV, a plaque reduction neutralization test (PNRT), and blood polymerase chain reaction (PCR).

An ELISA is a confirmatory test to detect IgM antibodies to WNV in the serum. Because IgM seroconversion typically occurs between days 4 and 10 of symptom onset, there is a high probability of initial false-negative testing within the first 8 days after symptom onset.^19,20 Clinical understanding of this fact is imperative, as an initial negative ELISA does not rule out WNV, and a retest is warranted if clinical suspicion is high. In addition to a high initial false-negative rate with ELISA, there are several other limitations to note. IgM antibodies remain elevated for 1 to 3 months or possibly up to a year in immunocompromised patients.¹ Due to this, false positives may be present if there was a recent prior infection. Enzyme-linked immunosorbent assay may not distinguish from different flaviviruses, including the yellow fever, dengue, Zika, Japanese encephalitis, and Saint Louis encephalitis viruses. Seropositivity has been estimated in some states, including 1999 data from New York (2.6%), 2003 data from Nebraska (9.5%), and 2012-2014 data from Connecticut (8.5%).^21-23 Regional variance may be expected, as there also were significant differences in WNV seropositivity between different regions in Nebraska (P<.001).²³

Because ELISA testing for WNV has readily apparent flaws, other tests have been utilized in its diagnosis. The PNRT is the most specific test, and it works by measuring neutralizing antibody titers for different flaviviruses. It has the ability to determine cross-reactivity with other flaviviruses; however, it does not discriminate between a current infection and a prior infection or prior flavivirus vaccine (ie, yellow fever vaccine). Despite this, a positive PNRT can lend credibility to a positive ELISA test and determine specificity for WNV for those with no prior flavivirus exposure.²⁴ According to the Centers for Disease Control and Prevention (CDC), this test can be performed by the CDC or in reference laboratories designated by the CDC.³ Additionally, some state health laboratories may perform PRNTs.

Viral detection with PCR currently is used to screen blood donations and may be beneficial for immunocompromised patients that lack the ability to form a robust antibody response or if a patient presents early, as PCR works best within the first week of symptom onset.¹ Tilley et al²⁵ showed that a combination of PCR and ELISA were able to accurately predict 94.2% of patients (180/191) with documented WNV on a first blood sample compared to 45% and 58.1% for only viral detection or ELISA, respectively. Based on costs from a Midwest academic center, antibody detection tests are around $100 while PCR may range from $500 to $1000 and is only performed in reference laboratories. Although these tests remain in the repertoire for WNV diagnosis, financial stewardship is important.

If there are symptoms of photophobia, phonophobia, nuchal rigidity, loss of consciousness, or marked personality changes, a lumbar puncture for WNV IgM in the cerebrospinal fluid can be performed. As with most viral infections, cerebrospinal fluid findings normally include an elevated protein and lymphocyte count, but neutrophils may be predominantly elevated if the infection is early in its course.²⁶

What are the management options?

To date, there is no curative treatment for WNV, and management is largely supportive. For WNF, over-the-counter pain medications may be helpful to reduce fever and pain. If more severe disease develops, hospitalization for further supportive care may be needed.²⁷ If meningitis or encephalitis is suspected, broad-spectrum antibiotics may need to be started until other common etiologies are ruled out.²⁸

How can you prevent WNV infection?

Disease prevention largely consists of educating the public to avoid heavily wooded areas, especially in areas of high prevalence and during peak months, and to use protective clothing and insect repellant that has been approved by the Environmental Protection Agency.³ Insect repellants approved by the Environmental Protection Agency contain ingredients such as DEET (N, N-diethyl-meta-toluamide), picaridin, IR3535 (ethyl butylacetylaminopropionate), and oil of lemon eucalyptus, which have been proven safe and effective.²⁹ Patients also can protect their homes by using window screens and promptly repairing screens with holes.³

What is the differential diagnosis for WNV?

The differential diagnosis for fever with generalized maculopapular rash broadly ranges from viral etiologies (eg, WNV, Zika, measles), to tick bites (eg, Rocky Mountain spotted fever, ehrlichiosis), to drug-induced rashes. A detailed patient history inquiring on recent sick contacts, travel (WNV in the Midwest, ehrlichiosis in the Southeast), environmental exposures (ticks, mosquitoes), and new medications (typically 7–10 days after starting) is imperative to narrow the differential.³⁰ In addition, the distribution, timing, and clinical characteristics of the rash may aid in diagnosis, along with an appropriately correlated clinical picture. West Nile virus likely will present in the summer in mid central geographic locations and often develops on the trunk and extremities as a blanching, generalized, maculopapular rash around 5 days after symptom onset or with defervescence.¹

What is West Nile virus? How is it contracted, and who can become infected?

West Nile virus (WNV) is a single-stranded RNA virus of the Flaviviridae family and Flavivirus genus, a lineage that also includes the yellow fever, dengue, Zika, Japanese encephalitis, and Saint Louis encephalitis viruses.¹ Birds serve as the reservoir hosts of WNV, and mosquitoes acquire the virus during feeding.² West Nile virus then is transmitted to humans primarily by bites from Culex mosquitoes, which are especially prevalent in wooded areas during peak mosquito season (summer through early fall in North America).¹ Mosquitoes also can infect horses; however, humans and horses are dead-end hosts, meaning they do not pass the virus on to other biting mosquitoes.³ There also have been rare reports of transmission of WNV through blood and donation as well as mother-to-baby transmission.²

What is the epidemiology of WNV in the United States?

Since the introduction of WNV to the United States in 1999, it has become an important public health concern, with 48,183 cases and 2163 deaths reported since 1999.^2,3 In 2018, Nebraska had the highest number of cases of WNV (n=251), followed by California (n=217), North Dakota (n=204), Illinois (n=176), and South Dakota (n=169).³ West Nile virus is endemic to all 48 contiguous states and Canada, though the Great Plains region is especially affected by WNV due to several factors, such as a greater percentage of rural land, forests, and irrigated areas.⁴ The Great Plains region also has been thought to be an ecological niche for a more virulent species (Culex tarsalis) compared to other regions in the United States.⁵

The annual incidence of WNV in the United States peaked in 2003 at 9862 cases (up from 62 cases in 1999), then declined gradually until 2008 to 2011, during which the incidence was stable at 700 to 1100 new cases per year. However, there was a resurgence of cases (n=5674) in 2012 that steadied at around 2200 cases annually in subsequent years.⁶ Although there likely are several factors affecting WNV incidence trends in the United States, interannual changes in temperature and precipitation have been described. An increased mean annual temperature (from September through October, the end of peak mosquito season) and an increased temperature in winter months (from January through March, prior to peak mosquito season) have both been associated with an increased incidence of WNV.⁷ An increased temperature is thought to increase population numbers of mosquitoes both by increasing reproductive rates and creating ideal breeding environments via pooled water areas.⁸ Depending on the region, both above average and below average precipitation levels in the United States can increase WNV incidence the following year.^7,9

What are the signs and symptoms of WNV infection?

Up to 80% of those infected with WNV are asymptomatic.³ After an incubation period of roughly 2 to 14 days, the remaining 20% may develop symptoms of West Nile fever (WNF), typically a self-limited illness that consists of 3 to 10 days of nonspecific symptoms such as fever, headache, fatigue, muscle pain and/or weakness, eye pain, gastrointestinal tract upset, and a macular rash that usually presents on the trunk or extremities.^1,3 Less than 1% of patients affected by WNV develop neuroinvasive disease, including meningitis, encephalitis, and/or acute flaccid paralysis.¹⁰ West Nile virus neuroinvasive disease can cause permanent neurologic sequelae such as muscle weakness, confusion, memory loss, and fatigue; it carries a mortality rate of 10% to 30%, which is mainly dependent on older age and immunosuppression status.^1,10

What is the reported spectrum of cutaneous findings in WNV?

Of the roughly 20% of patients infected with WNV that develop WNF, approximately 25% to 50% will develop an associated rash.¹ It most commonly is described as a morbilliform or maculopapular rash located on the chest, back, and arms, usually sparing the palms and soles, though 1 case report noted involvement with these areas (Figure).^11,12 It typically appears 5 days after symptom onset, can be associated with defervescence, and lasts less than a week.^1,13 Pruritus and dysesthesia are sometimes present.¹³ Other rare presentations that have been reported include an ill-defined pseudovesicular rash with erythematous papules on the palms and pink, scaly, psoriasiform papules on the feet and thighs, as well as neuroinvasive WNV leading to purpura fulminans.^14,15 A diffuse, erythematous, petechial rash on the face, neck, trunk, and extremities was reported in a pediatric patient, but there have been no reports of a petechial rash associated with WNV in adult patients.¹⁶ These findings suggest some potential variability in the presentation of the WNV rash.

What role does the presence of rash play diagnostically and prognostically?

The rash of WNV has been implicated as a potential prognostic factor in predicting more favorable outcomes.¹⁷ Using 2002 data from the Illinois Department of Public Health and 2003 data from the Colorado Department of Public Health, Huhn and Dworkin¹⁷ found the age-adjusted risk of encephalitis and death to be decreased in WNV patients with a rash (relative risk, 0.44; 95% CI, 0.21-0.92). The reasons for this are not definitively known, but we hypothesize that the rash may prompt patients to seek earlier medical attention or indicate a more robust immune response. Additionally, a rash in WNV more commonly is seen in younger patients, whereas WNV neuroinvasive disease is more common in older patients, who also tend to have worse outcomes.¹⁰ One study found rash to be the only symptom that demonstrated a significant association with seropositivity (overall risk=6.35; P<.05; 95% CI, 3.75-10.80) by multivariate analysis.¹⁸

How is WNV diagnosed? What are the downsides to WNV testing?

Given that the presenting symptoms of WNV and WNF are nonspecific, it becomes challenging to arrive at the diagnosis based solely on physical examination. As such, the patient’s clinical and epidemiologic history, such as timing, pattern, and appearance of the rash or recent history of mosquito bites, is key to arriving at the correct diagnosis. With clinical suspicion, possible diagnostic tests include an IgM enzyme-linked immunosorbent assay (ELISA) for WNV, a plaque reduction neutralization test (PNRT), and blood polymerase chain reaction (PCR).

An ELISA is a confirmatory test to detect IgM antibodies to WNV in the serum. Because IgM seroconversion typically occurs between days 4 and 10 of symptom onset, there is a high probability of initial false-negative testing within the first 8 days after symptom onset.^19,20 Clinical understanding of this fact is imperative, as an initial negative ELISA does not rule out WNV, and a retest is warranted if clinical suspicion is high. In addition to a high initial false-negative rate with ELISA, there are several other limitations to note. IgM antibodies remain elevated for 1 to 3 months or possibly up to a year in immunocompromised patients.¹ Due to this, false positives may be present if there was a recent prior infection. Enzyme-linked immunosorbent assay may not distinguish from different flaviviruses, including the yellow fever, dengue, Zika, Japanese encephalitis, and Saint Louis encephalitis viruses. Seropositivity has been estimated in some states, including 1999 data from New York (2.6%), 2003 data from Nebraska (9.5%), and 2012-2014 data from Connecticut (8.5%).^21-23 Regional variance may be expected, as there also were significant differences in WNV seropositivity between different regions in Nebraska (P<.001).²³

Because ELISA testing for WNV has readily apparent flaws, other tests have been utilized in its diagnosis. The PNRT is the most specific test, and it works by measuring neutralizing antibody titers for different flaviviruses. It has the ability to determine cross-reactivity with other flaviviruses; however, it does not discriminate between a current infection and a prior infection or prior flavivirus vaccine (ie, yellow fever vaccine). Despite this, a positive PNRT can lend credibility to a positive ELISA test and determine specificity for WNV for those with no prior flavivirus exposure.²⁴ According to the Centers for Disease Control and Prevention (CDC), this test can be performed by the CDC or in reference laboratories designated by the CDC.³ Additionally, some state health laboratories may perform PRNTs.

Viral detection with PCR currently is used to screen blood donations and may be beneficial for immunocompromised patients that lack the ability to form a robust antibody response or if a patient presents early, as PCR works best within the first week of symptom onset.¹ Tilley et al²⁵ showed that a combination of PCR and ELISA were able to accurately predict 94.2% of patients (180/191) with documented WNV on a first blood sample compared to 45% and 58.1% for only viral detection or ELISA, respectively. Based on costs from a Midwest academic center, antibody detection tests are around $100 while PCR may range from $500 to $1000 and is only performed in reference laboratories. Although these tests remain in the repertoire for WNV diagnosis, financial stewardship is important.

If there are symptoms of photophobia, phonophobia, nuchal rigidity, loss of consciousness, or marked personality changes, a lumbar puncture for WNV IgM in the cerebrospinal fluid can be performed. As with most viral infections, cerebrospinal fluid findings normally include an elevated protein and lymphocyte count, but neutrophils may be predominantly elevated if the infection is early in its course.²⁶

What are the management options?

To date, there is no curative treatment for WNV, and management is largely supportive. For WNF, over-the-counter pain medications may be helpful to reduce fever and pain. If more severe disease develops, hospitalization for further supportive care may be needed.²⁷ If meningitis or encephalitis is suspected, broad-spectrum antibiotics may need to be started until other common etiologies are ruled out.²⁸

How can you prevent WNV infection?

Disease prevention largely consists of educating the public to avoid heavily wooded areas, especially in areas of high prevalence and during peak months, and to use protective clothing and insect repellant that has been approved by the Environmental Protection Agency.³ Insect repellants approved by the Environmental Protection Agency contain ingredients such as DEET (N, N-diethyl-meta-toluamide), picaridin, IR3535 (ethyl butylacetylaminopropionate), and oil of lemon eucalyptus, which have been proven safe and effective.²⁹ Patients also can protect their homes by using window screens and promptly repairing screens with holes.³

What is the differential diagnosis for WNV?

The differential diagnosis for fever with generalized maculopapular rash broadly ranges from viral etiologies (eg, WNV, Zika, measles), to tick bites (eg, Rocky Mountain spotted fever, ehrlichiosis), to drug-induced rashes. A detailed patient history inquiring on recent sick contacts, travel (WNV in the Midwest, ehrlichiosis in the Southeast), environmental exposures (ticks, mosquitoes), and new medications (typically 7–10 days after starting) is imperative to narrow the differential.³⁰ In addition, the distribution, timing, and clinical characteristics of the rash may aid in diagnosis, along with an appropriately correlated clinical picture. West Nile virus likely will present in the summer in mid central geographic locations and often develops on the trunk and extremities as a blanching, generalized, maculopapular rash around 5 days after symptom onset or with defervescence.¹