skin diseases in intensive care medicine

108 Review Article DOI: 10.1111/j.1610-0387.2008.06753.x

JDDG | 2˙2009 (Band 7) © The Authors • Journal compilation © Blackwell Verlag GmbH, Berlin • JDDG • 1610-0379/2009/0702

Skin diseases in intensive care medicineMatthias Fischer1, Thomas William1, Johannes Wohlrab2

(1) Department of Dermatology and Venereology, HELIOS-Clinic Aue, Aue, Germany(2) Department of Dermatology and Venereology, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany

JDDG; 2009 • 7:108–115 Submitted: 25.1.2008 | Accepted: 5.3.2008

Keywords• dermatology• intensive care medicine• adverse drug reaction

SummaryThough most dermatoses are not life-threatening, skin diseases play an impor-tant role in intensive care medicine. Skin findings in intensive care patients mayreflect the underlying disease or be complications of intensive medical care.Most important are drug reactions, infections, bacterial toxin reactions, erythro-derma, ANCA-positive vasculitides (such as Wegener granulomatosis) andbleeding disorders.

IntroductionModern intensive care medicine with itscore specialties anesthesiology, surgery,internal medicine and pediatrics is espe-cially characterized by interdisciplinarycare of patients [1]. Specialties such asdermatology, where diseases requiringintensive care are rare, serve more therole of consultant within such a concept.Nonetheless, skin diseases in reality arefrequent in an intensive care setting. Ba-dia and coworkers found a prevalence ofskin disease requiring treatment of10.4 % among patients on an interdis-ciplinary intensive care unit [2]. Fur-ther, intensive care patients with addi-tional dermatologic disease have longerstays in the intensive care unit andhigher SAPSII scores than patients withhealthy skin [2]. In an intensive care setting cutaneousinfections are the most common skindiseases with 29 %, followed by drugreactions (21.6 %), damage caused bypatient positioning (9.7 %), vasculi-tides (7.1 %), contact dermatitis

(5.2 %), preexistent skin diseases (3.7 %)and asteatotic eczema (1.9 %) [3]. Insome instances (3 %), no clear diagno-sis can be made due to the uncharacter-istic clinical features [3]. Beyond thesefrequent skin diseases that occur in in-tensive care medicine, the consultingdermatologist may be confronted bythe entire spectrum of clinical derma-tology [3, 4]. Clinical evaluation of cu-taneous findings is then not rarelymade more difficult by atypical mor-phology and disease courses caused onthe one hand by the altered immunestatus of the patient (multiple organdysfunction syndrome) [5], and on theother hand by cofactors such as edema-tous tissue, long-term immobilizationor external injury. In the followingpages, various frequent and importantskin diseases in the intensive care unitwill be presented from the perspectiveof the dermatologic consultant (sum-mary in Table 1). These dermatoses canbe the reason for intensive care or acomplication thereof.

Adverse drug reactionsWith a frequency of over 21 %, adversedrug reactions are a common cause ofskin disease, which occasionally is life-threatening, in intensive care patients[3]. Clinical findings are usually charac-terized by a macular exanthem which of-ten additionally features an urticarial orpapular component. Further clinical fea-tures include symmetric distribution,lack of prodrome (e.g. fever, generalmalaise) and lack of pruritus-althoughthe later may be hard to judge. Frequent cause of such drug eruptionsare antibiotics (mainly penicillins) andchemotherapeutic agents as well as lessoften anticonvulsive drugs, allopurinol,diuretics and nonsteroidal anti-inflam-matory agents [6–8]. The pathomech-anisms of adverse drug reactions are di-verse. Generalized urticaria as anexpression of an intolerance reaction oran allergic reaction of the immediatetype is responsible for 15–25 % of ad-verse cutaneous drug reactions in hospi-talized patients [6, 7]. Hemodynamic

Skin diseases in intensive care medicine Review Article 109

© The Authors • Journal compilation © Blackwell Verlag GmbH, Berlin • JDDG • 1610-0379/2009/0702 JDDG | 2˙2009 (Band 7)

Cardinal sign/symptom

Frequency[%]

Differential diagnosesFurther clinical characteristics

Histology Comment

Erythema 34.6

Erysipelas / soft tissueinfection

• Fever• Reduced general

condition• Clinical diagnosis

Necrotizing fasciitis

• Edema• Wrinkled skin surface• Strong pain• Fulminant course

• Clinical diagnosis

• Often mixed infection • Elevated muscle enzymes• Serum sodium lowered• Strive for MRI

Candidal intertrigo

• Brownish erythema ofskin folds

• Satellite lesions• Perhaps pustules

• Clinical diagnosis• Identification of

fungal elements inthe stratum corneum

Contact dermatitis • Scales, infiltration• Perhaps weeping papules

• Clinical diagnosis• Spongiosis, perhaps

acanthosis

Blisters / exfoliation

19.7

TEN• Mucous membrane

involvement• See Table 2

• Subepidermal bliste-ring

• Epidermal necrosis

• SCORTEN forprognosis (see text)

Subcorneal staphylococcal scaldedsyndrome

• No mucous membraneinvolvement

• Subcorneal detach-ment

• Immunosuppression?• Renal function?

Exanthema 16.4Drug reaction

• Symmetry• Pruritus• Acute/subacute

development

• Variable• Often eosinophilic

granulocytes• Usually lymphocytes

Pathogen-inducedexanthema

• Fever and other signs ofinfection

• Clinical/ laboratorydiagnosis

• Perhaps serologic diagnostics

Hemorrhages 5.2

Disseminatedintravascular coagulation

• initial purpura• Extensive bleeding• (Acral) necroses • Fulminant course

• Thrombosis of smallvessels

• Erythrocyte extrava-sation

• Necroses of epider-mis and dermis

Allergic vasculitis • Palpable purpura• Leukocytoclastic

vasculitis

Thrombocytopenicpurpura

• Non-palpable purpura• Clinical/ laboratory

diagnosis

• Thrombocytopenia?• Consider

thrombocytopathy

Pustules 4.5AGEP

• Flexural accentuation• Perhaps fever/ reduced

well-being

• Intraepidermal neutrophilic granulocyte nests

• Cytotoxic damage tobasal layer

Folliculitis • Follicular association • Clinical diagnosis• Occlusion• Usually S. aureus

Ulcerations 4.5

Decubitus

• Erythema• Circumscribed

epidermolysis/ blisters• Necroses

• Clinical diagnosis• Note special locations

(see text)

Vasculitides• Pain• Livedo racemosa• Perhaps fever

• Variable• Perhaps granulomas• Perhaps

leukocytoclasia

• ANCAs? • Anti-phospholipid

antibodies?

Table1: Selected cardinal signs and symptoms and differential diagnoses of frequent and relevant skin diseases inintensive care medicine. Relative frequency of cardinal signs and symptoms according to [3]. Therapeutic conse-quences are mentioned in the text.

disorders ranging to anaphylactic shockas well as bronchospasm can also occur.The appearance of signs and symptomswithin minutes of administration of theresponsible drug is typical. Therapy con-sists in the administration of antihista-mines, corticosteroids and perhaps cate-cholamines. Just as in all other adversedrug reactions the responsible drug mustbe avoided in the future. Much more often than urticaria, delayedreactions which manifest with a latencyof days to weeks develop [9, 10] andclinically appear as exanthems [9].Nonetheless, potentially life-threateningsevere drug reactions also belong to de-layed adverse cutaneous drug reactions.These various clinical presentations are

mostly based on an infiltration of theskin by T lymphocytes, with a domi-nance of CD4-positive cells apparentlycorrelating with macular-papular rasheswhile blistering up to widespread exfoli-ation of the skin being associated withCD8-positive cytotoxic T lymphocytes[11]. The multiplicity of T-cell-mediatedadverse drug reactions is only beginningto be understood. Beyond the dominantT-cell subpopulation and the herewithassociated cytokine release [9, 12, 13],genetic factors as well as viral infections(EBV, HHV-6, CMV, HIV) may also beof importance [9]. Severe cytotoxic cutaneous reactions areusually the result of CD8-mediated drugreactions which can progress to wide-

spread exfoliation [14]. Great impor-tance is attributed to the cytokine TNF�[15]. Depending on the involved surfacearea erythema multiforme (EM),Stevens-Johnson syndrome (SJS) andtoxic epidermal necrolysis (TEN; for-merly: “drug-induced Lyell syndrome”)are differentiated (Table 2, Figure 1, 2).At present there is no verified parameterknown for clinical use to reliably identifythose patients with drug eruptions whowill develop TEN in the further course.Therefore, critical clinical observation ofdrug eruptions will continue to play acentral role. Clinical warning signs andsymptoms indicating the development ofsuch a cytotoxic reaction are pain, lividexanthems, blisters, target lesions, mu-cous membrane erosions and fever. Sub-clinical blistering can be tested by tan-gential pressure on the skin (Nikolsky Isign). In practice it is also useful to delin-eate the borders of individual lesions witha waterproof marker in order to recognizeexpansion of the exanthem. A biopsy fre-quently makes a more precise diagnosispossible. The prognosis of TEN can bepredicted with the help of SCORTEN[16]. No gold standard for the treatmentof TEN exists. While the administrationof high-dose corticosteroids is effectivein most T cell-mediated drug eruptionsand is the approach of choice, its effec-tiveness in TEN is limited and leads viaan increased infection risk to an in-creased mortality rate [17]. Therapeuticapproaches reported to be effective arepresented in Table 2 [15, 17–20].

110 Review Article Skin diseases in intensive care medicine


Table 2: Classification of cytotoxic drug reactions [modified according to 14, 17].

EM: Erythema multiforme, SJS: Stevens-Johnson syndrome, TEN: toxic epidermal necrolysis, BSA: body surface area, CS: corticosteroids.

EM SJS SJS/TEN overlapTEN with maculae

TEN on erythema

Clinicalfeatures

• <10 % of BSA involved

• Target lesions withacral accentuation

• Erosive mucousmembranes

• < 10 % of BSA involved• Confluent macular

exanthema accentuated on trunk

• Exfoliation and erosions• Atypical target lesions• Erosive mucous membranes

• 10-30 % of BSAinvolved

• Clinically as in SJS

• > 30 % of BSAinvolved

• Clinically as inSJS

• > 10 % of BSA involved• Extensive erythema with

erosion and exfoliationaccentuated on trunk

• Erosive mucous membranes

Therapy• CS• Perhaps acyclovir

• CS • CS• CS?• Otherwise as in

TEN

• IVIG (0.4–1 g/kg bodyweight)

• Infliximab (5 mg/kgbody weight)

• Pentoxifylline?• Cyclophosphamide

Figure 1: Toxic epidermal necrolysis. Confluent erythema with blistering.

Administration of cyclosporine A,thalidomide and N-acetylcysteine doesnot appear to be helpful [17]. Prudentbasic measures include elimination of theprecipitating drug, fluid substitution,perhaps analgesia as well as – in analogyto burn patients – positioning on antisep-tic foils (e. g Metalline® foil) [13]. Pro-phylactic antibiotic coverage has not beenshown to provide an advantage in termsof survival [13], but the patients arehighly in danger of developing sepsis, sothat the indications for antibiotic therapyshould generous. In addition to the cytotoxic drug reac-tions, hypersensitivity reactions occur inwhich exanthems or erythroderma areassociated with the involvement of inter-nal organs [21–23]. Here, liver involve-ment (elevation of transaminases) as wellas blood eosinophilia is dominant. Addi-tionally, fever, lymphadenopathy or renalfailure can occur. For this clinical presen-tation various, in the final analysis, syn-onymous terms exist, with the mostcommon term being “Drug Rash withEosinophilia and Systemic Symptoms”(DRESS). Typical inducers of DRESSare minocycline, ceftriaxone, van-comycin, abacavir, anticonvulsants andallopurinol [9, 22, 24]. A mortality of10 % is reported [21]. The pathogenesisis not completely clear. Metabolic defectssuch as slow acetylation may be impor-tant [21]. In some individual cases a co-infection with viruses, especially humanherpesvirus 6, appear to play a role. Typ-ically two to six weeks after the initiationof medication, the signs and symptomsdescribed appear [21]. Therapy ofDRESS consists of the administration ofcorticosteroids (1 mg/kg body weightprednisolone equivalent) or in severecases anti-IL-5 antibodies [21, 25].While there is usually a rapid improve-ment of fever and the general condition,elevated transaminases and erythemamay continue for weeks [21]. Another variant of adverse drug reactionsis acute generalized exanthematous pus-tulosis (AGEP). Clinically, widespreaderythema up to erythroderma developsstarting from the flexures (axillae, groins)upon which pinhead-sized sterile pus-tules develop (Figure 3). The pustulestend to coalesce, so that individual skinareas may exhibit the phenomenon ofepidermolysis [14]. Rarely circumscribedlocalized forms appear. Fever and generalmalaise are facultative signs and symp-

toms that can be accompanied by leuko-cytosis and a relative neutrophilia [14,26]. In 80 % causative drugs are antibi-otics (especially �-lactam antibiotics,macrolides, quinolones); more rarelyanalgesics, antifungal agents and antihy-pertensive drugs (diltiazem) have beenreported as inducers [26]. In several casesa type IV allergy can be confirmed bypatch testing [26]. Therapy consists inthe administration of glucocorticoids,while in severe cases with epidermolysis,infliximab may be helpful [27].

ErythrodermaErythema involving at least 90 % of thebody surface is termed erythroderma[28]. This is a descriptive diagnosis orsymptom that can be caused by variousfactors. The most common cause is theexacerbation of a preexisting chronic skindisease, most often psoriasis [29], less fre-quently atopic dermatitis or seborrheicdermatitis. Sézary syndrome is also a pos-sible cause of erythroderma. A share ofidiopathic erythroderma whose fre-quency is about 10 % must be taken intoconsideration [29]. In pediatric intensivecare medicine congenital immunodefi-ciency (especially Omenn syndrome) aswell as hereditary disorders of keratiniza-tion must be considered [30]. The acutecourses seen in intensive care medicineare mostly adverse drug reactions in thesense of DRESS. Reports on mortality oferythroderma range between 3.75 % and64 % [29], with mortality being generallyelevated even without consideration ofmalignancies as basic illness [29, 31].Reasons for this may be drastically in-creased transepidermal water loss as wellas altered volume distribution with an in-creased cardiac output. For correct diagnostic classification a de-tailed history and often a biopsy arehelpful. Adequate fluid replacementmust be provided. Glucocorticoids aretreatment of choice for inflammatorycauses of erythroderma. As a result oftheir vasoconstrictive effects, they alsohave an additional favorable effect onvascular tone and the chills patients fre-quently complain about.

Decubitus ulcersDecubitus or pressure ulcers are a com-mon problem in intensive care medicineand represent a typical complication oflong-term treatment. Reports of preva-lence range between 3 % and 29 % [32].

Decubitus ulcers are clinically classifiedinto four grades [33]: erythema (I°), ero-sion and/or blister (II°), ulcer into thesubcutis (III°), ulcer with damage tobone/musculature (IV°). Risk factors forthe development of decubitus ulcers in-clude shearing forces in positioning,moist environment, immobility, defi-ciency states and poor tissue perfusiondue to edema or shock [33, 34]. Furtherintensive care measures such as intuba-tion, drainage and catheterization can re-sult in localized pressure to skin andcause necroses on the trunk, neck or face[33]. The frequent combination of thesefactors in patients treated in intensivecare medicine explains why despite allpreventive measures the probability of adecubitus ulcer increases significantlywith the duration of intensive care [34].An assessment of the individual risk fordeveloping pressure ulcers is made usingvarious score systems such as the Bradenscale. The central point in treatment ispressure reduction, for which a variety oftechnical possibilities and positioningrecommendations are available [32].

Cutaneous infectionsCutaneous infections are the most com-mon skin diseases in intensive care med-icine [3], with candidal intertrigo beingof special significance. At first patientsdevelop an irritant contact dermatitisdue to friction, heat and moisture in thebody folds [35]. This damaged skin ispredisposed to super-infection withCandida albicans playing a prominentrole [36]. Clinically, red-brown weeping,eroded areas with a collarette scale at theborder are present, often with satellitepustules and papules just beyond theborder. Diagnosis can be made clinicallyand confirmed by culture. For treatmenta soft zinc paste is quite suitable for ini-tial stages (intertrigo without candidalsuper-infection), while for manifest can-didal infection the use of nystatin in anastringent base is a common approach[35]. Should this therapy be unsuccessfuldifferential diagnosis includes allergiccontact dermatitis, atopic dermatitis,erythrasma, zinc deficiency or psoriasisinversa (clinically sharp border, no satel-lite lesions). When in doubt biopsy issensible. Among bacterial skin infections in theintensive care setting necrotizing soft tis-sue infections such as necrotizing fasciitisare significant. Necrotizing fasciitis is



usually the result of an infection withstreptococci (occasionally even �-he-molytic group A streptococci) often incombination with Staphylococcus aureus,Gram-negative or anaerobic bacteria [37].Transferred by way of contaminated saltwater Vibrio vulnificus can also causenecrotizing fasciitis [38]. Varicella inchildhood is a verified predisposing factorwhile previous therapy with nonsteroidalanti-inflammatory drugs is discussed con-troversially [38]. Clinically a fulminantdisease occurs that initially can resembleerysipelas. Clinically, often a relativelypale erythema with a wrinkled skin sur-face exists, that without treatment can

progress to cutaneous necrosis with blis-tering (Figure 4). Extreme pain is typical(“pain out of proportion”). The diagnosisis made clinically and supported by im-aging (CT or MRI) as well as by detec-tion of leukocytosis as well as elevatedmuscle enzymes. An additional drop inthe serum sodium level below 135mmol/l is typical [39]. A deep skinbiopsy as well as bacterial cultures can betaken in the course of the inevitable sur-gical intervention with generousdébridement. Antibiosis is provided ac-cording to identified pathogens, with aninitial regimen of penicillin (3 � 10 mil-lion units) and clindamycin (3 � 600 mg)

being particularly advisable based on thegood effects against streptococci [40].Hyperbaric oxygen therapy can be usedas adjunct. In addition to bacterial infections per-sistent herpes simplex infections are sig-nificant in the intensive care setting, aspatients have a predisposition due to la-tent immunosuppression [41, 42]. Clin-ically they present as erosions and easilybleeding shallow ulcerations periorallyand sometimes in the anogenital region[42]. In the usually unconscious patientsit is difficult to assess pain, which is animportant clinical symptom in consciouspatients. Diagnosis is made by identify-ing the pathogen by PCR or a fluores-cence technique. Therapy consists ofhigh-dose acyclovir and topical antisep-tic therapy. Despite these treatment pos-sibilities, the patients are at danger dueto organ involvement such as pneumo-nia or encephalitis [43] and frequentfungal or bacterial co-infections [44].

Bacterial exotoxin reactionsBesides direct infection, extracutaneousbacterial foci can cause dermatologicsigns and symptoms of relevance in in-tensive care medicine through the actionof toxins. A typical example is staphylo-coccal scalded skin syndrome (SSSS; for-merly termed staphylococcal Lyell syn-drome or Ritter von Rittershain diseaseor Ritter disease). Predominantly chil-dren are affected, who in comparison toadults have a better prognosis in terms of



Figure 2: Involvement of the vermilion border of the lips in TEN.

Figure 3: Acute generalized exanthematous pustulosis (AGEP) with multiple pustules on an erythe-matous base.

Figure 4: Necrotizing fasciitis with bright rederythema and hemorrhagic blisters.

mortality [45, 46]. The early signs andsymptoms are often non-specific but in-clude fever and fatigue, followed by pale-red erythema with extensive blistering[45, 46]. Blisters rupture after minimal

mechanical stress, so that exfoliation pre-dominates. Responsible for the loss ofcontinuity are four different staphylo-coccal exfoliative exotoxins ETA-D [45].By binding to desmoglein 1 they lead toan intraepidermal separation at the levelof the stratum granulosum [45, 46]. Asthese structural proteins are not ex-pressed in mucous membranes mucosalerosions are atypical in SSSS. This is animportant clinical criterion to make abedside differentiation from TEN. Onthe basis of animal studies, renal insuffi-ciency has until now been considered anessential factor for developing SSSS, asthe inducing exfoliative exotoxins un-dergo renal elimination and redistributeinto the skin in advanced renal failure

[45]. In contrast, recent epidemiologicalstudies emphasize the role of underlyingor iatrogenic immunodeficiency [45].Therapy consists of the administrationof antibiotics effective against staphy-lococci and perhaps forced diuresis or dialysis. Another bacterial toxin reaction with cu-taneous involvement relevant in inten-sive care medicine is toxic shock syn-drome caused by staphylococci and lessfrequently by streptococci. Often thedisease presents in women during men-struation (so-called “tampon disease”).In the intensive care setting attention hasto be paid especially to non-menstrualtoxic shock syndrome that can originatefrom infected surgical wounds or burninjuries [47]. Toxins produced in thecourse of the infection (in 75 % of cases:TSST-1) cause fever and drop in bloodpressure up to multiple organ failure[47]. On the skin, despite the fact that itis usually staphylococcal in nature, thedisease presents with features resemblingscarlet fever with a macular-papular ex-anthems as well as erythematous facialedema with perioral paleness. After reso-lution a glove-like desquamation ofpalms and soles is typical. Besides symp-tom-oriented intensive medical care, an-tibiotic therapy targeted against staphy-lococci or streptococci is essential.

Vascular cutaneous damageDiseases primarily associated with dam-age to cutaneous blood vessels can mani-fest with hemorrhage, necrosis or livedo.Allergic vasculitis, caused by immunecomplexes, is a common cause of pur-pura. Clinically, palpable purpura devel-ops on dependent body parts. Histologyreveals features of vasculitis with disinte-gration of neutrophilic granulocytes(leukocytoclastic vasculitis). Importanttriggers include microbial foci, drugs andtumors. An important differential diag-nosis of allergic vasculitis with palpablepurpura is purpura due to thrombocy-topenia or thrombocytopathy, which incontrast is usually not palpable. The clin-ical presentation of purpura fulminanswhich begins with small maculae thatrapidly expand to extensive, bizarrelyconfigured skin hemorrhages, often withhemorrhagic blisters as an expression ofnecrosis, must be differentiated [48](Figure 5). Features resemble disseminatedintravascular thrombosis, characterizedhistologically by thromboses of dermal



Figure 5: Disseminated intravascular coagulation with purpura fulminans. Bizarrely configurednecrosis with hemorrhagic blister.

Figure 6: Acral necroses in disseminated intravascular coagulation.

Table 3: Frequent bacterialcauses of purpura fulminans[according to 48].

• Meningococci• Staphylococci• ß-hemolytic streptococci• Pneumococci• Haemophilus influencae• Rickettsia rickettsii

blood vessels [48]. Causes are numerous,with viral and especially bacterial infec-tions (Table 3) being of particular signif-icance in the intensive care setting. In thefurther course of the disease, acralnecroses frequently occur (Figure 6) withtheir development possibly being favoredby the simultaneous administration ofcatecholamines. Therapy is provided ac-cording to intensive care medicineguidelines [1]. Another group of skin diseases relevantin the intensive care setting and takingtheir origin form the vascular system arethe livedo disorders. Here net- or tendril-like livid macular discoloration of theskin exists which reflects reduced arterialperfusion [49]. While the regular net-like livedo reticularis represents a tem-perature-dependent, functional phe-nomenon of cold-induced cyanosis, thetendril-like livedo racemosa is based onstructural damage to the arterial vascula-ture [49, 50]. In a localized form thesefeatures are found as a result of cuta-neous embolism of cholesterol crystals,artificial intra-arterial injections of drugsor – in the intensive care units – distallyfrom arterial access points. Here, as theresult of embolism, necrosis can develop.Such necroses are often the predominantclinical features of occlusive vascu-lopathies and are often located on thelegs. Here the livedo pattern can be ob-served in the vicinity of the ulcers.Causes of this can include various formsof vasculitides (ANCA-positive vasculi-tides, anti-phospholipid syndrome, idio-pathic variants) but also hyperhomocys-teinemia or calciphylaxis in terminalrenal insufficiency [51]. In Wegenergranulomatosis simultaneous feverfalsely suggesting an infectious causemay make the correct evaluation moredifficult. In every case, a histology is im-portant for the correct differential diag-nostic classification with multiple biop-sies (in our own experience at least n = 3)significantly increasing informativevalue. This compilation of frequent and im-portant skin diseases in intensive carepatients underscores the significanceof interdisciplinary management ofintensive care patients, in which der-matology should prudently be inte-grated. <<<

Conflicts of interestNone.

Correspondence toPriv.-Doz. Dr. Matthias FischerDepartment of Dermatology andVenereologyHELIOS-Clinic AueGartenstraße 6D-08280 Aue, Germany Tel.: +49-3771-581-416Fax: +49-3771-581-646E-mail: [email protected]

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