Hypoproteinemia in severe childhood atopicdermatitis: A serious complication

Nomura I, Katsunuma T, Tomikawa M, Shibata A, Kawahara H, OhyaY, Abe J, Saito H, Akasawa A. Hypoproteinemia in severe childhoodatopic dermatitis: A serious complication.PediatrAllergyImmunol2002:13:287–294.#2002BlackwellMunksgaard

As a complication of atopic dermatitis (AD), the frequency ofhypoproteinemia is increasing among infants with severe AD in Japan.It can be a life-threatening condition owing to hypovolemic shock as aresult of hypoproteinemia and vascular infarction as a result ofthrombocythemia. However, the pathophysiology of this conditionremains unclear. The present study consisted of 2 objectives. The firstobjective was to determine the main route of protein loss, i.e. throughthe damaged skin or the gastrointestinal tract, or as a result ofinsufficient food intake. The second objective was to identify whetherallergy or infection was the cause of severe skin inflammation. Fifteenpatients with AD were enrolled who had serum protein levels of 3.2–5.8 g/dl. Specific immunoglobulin E (IgE) and skin test to allergens,stool eosinophils, a1-antitrypsin clearance, skin Staphylococcus aureuscolonization and superantigens (SAgs) produced by the organism, serumSAg-specific IgE antibodies, serum interleukin (IL)-5, IL-6, IL-12, andinterferon-c (IFN-c) were evaluated. Prominent serous skin dischargewas seen in all of the patients and was found to have almost the sameprotein concentration as serum. Marked thrombocytosis, with amaximum of 1,0603103/ml, was seen. Skin culture revealed S. aureuscolonization in all patients. SAg-producing S. aureus were found in84.6% of the patients. The concentration of serum IL-5 was significantlyincreased and correlated well with the blood eosinophil count. Hence,the main route of protein loss was believed to be through damaged skin.The cause of severe inflammation was thought to be a combination ofallergic inflammation and skin colonization by SAg-producing S. aureus.Serum cytokines showed a T helper 2 (Th2) T-cell-mediated pattern. Toprevent hypovolemic shock, vascular occlusion, and growth retardation,it is of vital importance to diagnose hypoproteinemia at an early stageand start appropriate therapy.

Ichiro Nomura1, Toshio Katsunuma1,Morimitsu Tomikawa1,Atsushi Shibata1,Hidetoshi Kawahara1,Yukihiro Ohya1, Jun Abe2,Hirohisa Saito3 and Akira Akasawa11Department of Allergy, National Children’sHospital, Taishido, Setagayaku, Tokyo, Japan,Departments of 2Child Ecology and 3Allergyand Immunology, National Children’s MedicalResearch Center, Taishido, Setagayaku, Tokyo,Japan

Key words: atopic dermatitis;hypoproteinemia; Staphylococcus aureus;

superantigens; IL-5; thrombocytosis

Akira Akasawa, MD, PhD,Department of Interdisciplinary Medicine,

National Center for Child Health and

Development (former National Children’s

Hospital),2-10-1 Okura Setagaya-ku,

Tokyo 157-8535, Japan

Tel.: 81-3-3416-0181Fax: 81-3-3416-2222

E-mail: akasawa-a@ncchd.go.jp

Accepted 15 November 2001

Atopic dermatitis (AD) is a chronic inflammatoryskin disease caused mainly by allergy (1). Theincidence of AD has increased in recent years (2)and, simultaneously, incidence of complicationsof the disease has been increasing. There arecertain complications of AD that need carefulattention. As ophthalmic complications, there arecataract and retinal detachment. Increased sus-ceptibility to infections such as herpes simplexvirus, Staphylococcus aureus, and fungi are alsoseen. However, hypoproteinemia in AD is themost serious complication. It has been observed

that children with AD who have hypoproteine-mia, have serum protein of 3-5 g/dl compared to aormal range of 6-7 g/dl in the similar age range. Insevere cases, this concentration may fall below3 g/dl. If appropriate therapies are not adminis-tered, hypoproteinemia may become a life-threatening condition.Three reports of hypoproteinemia have been

published to date in English. All are single-patient case reports. The first publication, byAbrahamov et al. in 1986 (3), reported a10-month-old-boy with AD and hypoproteine-

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Printed in UK. All rights reservedCopyright # 2002 Blackwell Munksgaard

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mia. The route of protein loss was considered tobe from the damaged skin. Goodyear et al. (4)and Capulong et al. (5) also reported a patient ina similar condition. However, in Japan there havebeen an increasing number of reports of severeAD with hypoproteinemia. (The manuscriptswere written in Japanese.) To date, there havebeen 20 published case reports of a total of 50 ADpatients with hypoproteinemia in Japan. Thefrequency of the condition has been increasingover the last 10 years (Fig. 1). Terada et al. (6).reported six infants with AD who also hadhypoproteinemia. They concluded that thecause of condition might be mainly protein lossthrough the skin and partly poor intake of food.Ohashi et al. (7). reported that a 5-month girlwith AD and hypoproteinemia (serum totalprotein: 4.6 g/dl) suffered from cerebralinfarction. Thrombocytosis (9103103/ml) anddecreased anticoagulant factors were suspectedto be the cause of infarction.Regarding this serious complication of AD, its

pathophysiology has not been investigated. Weidentified 15 patients with hypoproteinemia in thepast 3 years, and successfully treated them. Here,we attempt to unravel the route of protein loss,the cause of the dermatitis, and patterns of pro-inflammatory cytokines.

Subjects and methods

Patients

Fifteen patients (11 male, four female) with AD,who also had severe skin discharge and hypo-proteinemia less than –2 standard deviations(SD) of age-matched controls, were enrolled inthis study. The severity of AD was scored on thebasis of the modified Leicester system (8,9). This

gave a disease activity score with a maximum of90 points.

Alpha-1-antitrypsin clearance

The total amount of 1-day excretion of a1-antitrypsin into stool was determined as follows:

Total amount of 1 day excretion

of a1 antitrypsin into stool ¼ F|W ð1Þwhere F represents the a1-antitrypsin concentra-tion of the stool (in mg/g) and W the stool weightof the day (in g/day).The a1-antitrypsin clearance (in ml/day) was

calculated as follows:

a1 antitrypsin clearance ¼F|W

a1 antitrypsin concentration of bloodð2Þ;

where the a1-antitrypsin concentration of bloodis given in mg/ml. F and W are described above.

Calculation of corrected serum protein fraction

The absolute value (in g/dl) of each proteinfraction of the serum was calculated as follows:

Absolute value5

total protein|percentage of each fraction ð3Þ:The corrected serum protein fraction was deter-mined as follows:

Corrected serum protein fraction ¼

absolute value of each protein fractionabsolute value of the same protein fraction

of age matched control

|100 ð4Þ:Skin bacterial culture and detection of superantigen (SAg)genes by the polymerase chain reaction (PCR)

In patients 3–5, 10 and 15, SAg-producing S.aureus was detected as described previously (9).In patients 7–9 and 11–14, it was examined asfollows. Swabs of S. aureus were taken from thenasal cavity and three separate areas of theaffected skin. The swabs were spread onto sheep-blood agar plates and then immersed in 2 ml ofBrain Heart Infusion broth (Difco Laboratories,Detroit, MI, USA). After incubation for 16 h at378C, the broth was centrifuged at 18 000 g for1 min. Bacterial DNA was extracted from thepellets using the QIAamp DNA extraction kit(QIAGEN K.K., Tokyo, Japan). The eightsuperantigen genes (sea, b, c, d, g, h, I, and tsst-1), staphylococcal coagulase gene, and protein Agene were amplified by PCR. PCR products were

Year

Fig. 1. Reported number of patients with hypoproteinemiain Japan from 1991 to 1999. The number at the top of eachbar indicates the number of reports for each year. Patientnumbers have been increasing dramatically.

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288

resolved by 2% agarose-gel electrophoresis andphotographed.In patients 1, 8, 12, 14 and 15, exfoliative toxins

A and B (ETA, ETB) were also determined byusing the same method.

Assay of specific immunoglobulin E (IgE) antibody to SAg

Evaluation of specific IgE to SAg was performedas reported previously (9). Anti-SAg IgE anti-bodies of control sera were as follows: straphy-lococcal enterotoxin A (SEA), 0.15 units 6 0.46(mean 6 SD); SEB, 4.2 units 6 4.1; SEC, 2.0units 6 2.9; and toxic shock syndrome toxin(TSST)-1, 1.7 units 6 3.3. Cut-off points weredefined as mean values +2SD of controls, andthey were: SEA, 1.07 units; SEB, 12.6 units; SEC,7.4 units; and TSST-1, 8.3 units.

Determination of serum inflammatory cytokines, IL-5, IL-6, IL-12, and interferon-c (IFN-c) by enzyme-linked immunosorbentassay (ELISA)

IL-5 was determined by using the IL-5 EnzymeImmuno-assay kit (Immunotech, Marseille,France). IL-6 was measured by using theQuantikine kit (R & D Systems, Minneapolis,MN, USA), IL-12 was determined by using theIL-12 Enzyme Immuno-assay kit (Pharmingen,San Diego, CA, USA). IFN-c was determined byusing the IFN-c Enzyme Immuno-assay Kit(Immunotech).

Therapy

Patients were hospitalized and treated by sys-tematic washing of the skin using soap andapplication of steroid ointment three times everyday. Antihistamines were used for the preventionof itching. In some patients, oral or intravenousantibiotics were administered for elimination ofS. aureus. To avoid scratching of the skin, the

fingernails were covered with mittens which werefastened to the pyjama arm openings. Inaccordance with the patient’s history, results ofradioallergosorbent testing (RAST), and skin-prick tests, food-allergen avoidance was carriedout in 13 patients.

Statistical analysis

Statistical analysis of the protein fraction and theplatelet count was performed using the unpairedt-test. Analysis of the results of cytokine deter-mination was first performed with one-factoranalysis of variance (anova). When significantdeviation was observed, the Scheffe F-test wasperformed as a post hoc test. Analysis ofcolonization of SAg-producing S. aureus, andthat of positivity of serum IL-6 with and withouthypoproteinemia, were performed using the chi-square test. All were performed using theprogram statview iv. A p-value of ,0.05% wasaccepted as significant.

Results

Reports in Japan

Figure 1 shows the number of reports ofhypoproteinemia in patients with AD and thenumber of patients who were described in thesereports (whole reports were written in Japanese).From this information the number of patientsseems to be increasing.

Age distribution of the patients

The age distribution of patients with hypopro-teinemia is shown in Fig. 2. One-hundred andeighteen patients (69 males and 49 females) werediagnosed with severe AD and admitted to ourdepartment between 1997 and 2000. Fifteen ofthese patients were also diagnosed with hypo-

Fig. 2. Age distribution of patientswith hypoproteinemia. The opencolumn represents the total numberof patients with atopic dermatitis(AD) who were admitted to ourdepartment between April 1997 andMarch 2000. The closed columnrepresents the number of patientswith hypoproteinemia. Eleven of 13infants with AD who needed in-patient care also hadhypoproteinemia.

Hypoproteinemia in atopic dermatitis

289

proteinemia. Eleven of the 15 patients withhypoproteinemia were 3–12-month-old infants.There was a male predominance (11 patients,73.3%) in the patients with hypoproteinemia.

Clinical data

Clinical data of the patients with hypoprotei-nemia are shown in Table 1. The lowest valueof serum total protein was 3.2 g/dl. All thepatients had marked serous skin discharge fromAD lesions. Eleven patients showed severedermatitis, which extended over most of thebody. In the remaining four patients (3, 5, 9,and 11), dermatitis was primarily locatedaround the face and neck. Edema was seen in12 patients. Oliguria and tachycardia weresuspected in patients 7 and 4, respectively. Inthree patients, peripheral cyanosis (especiallyon the feet) was recognized. There were nopatients with low blood pressure. Diarrhea wasreported in five patients (2, 4, 8, 10, and 13).Photographs of patient 10 are shown on thefront cover of the current issue of PediatricAllergy and Immunology.

Laboratory data

All the patients showed increased peripheralblood eosinophil counts (mean: 18.8610.0%).Total IgE antibody titers were also high (mean:5,186610,415 IU/ml). Specific IgE antibody tofood allergen showed high titers. Mean serumsodium concentration was 135.763.4 mEq/l.Zinc concentrations were examined in fourpatients and were within normal limits.Table 2 summarizes results obtained from the

gastrointestinal system in these patients. Stooleosinophils were not detected. A positive SudanIII stain was suggestive of impaired lipidabsorption in patient 8. Results of a1-antitrypsinclearance were normal in all three patientsexamined.The concentration of total protein and the

percentage of protein fractions of both serum andskin discharge are shown in Table 3. In the skindischarge, a total protein concentration of 9.0 g/dl was detected and showed almost the sameconcentration of fractions as serum.Corrected values of serum protein fractions

from the patients with and without hypoprotei-

Table 1. Clinical data profile of the patients on admission

Patient no. AgeTP(g/dl)

WeightSD Edema Diarrhea

Eosinophil(%)

Total IgE(IU/ml)

Specific IgE

House dust mite Egg white Milk

1 3 months 4.3 –1.60 ++ – 45 7.4 0 0 1.962 3 months 4.4 –0.48 + + 24 441 2.07 100 03 4 months 5.2 –0.50 – – 8 54.6 0 8.48 04 5 months 3.2 –3.60 +++ +/– 11 1,996 1.16 95.4 10.35 6 months 5.3 –0.73 + – 18 160 0 85.9 06 6 months 4.7 +0.28 + – 9 51.3 0 0 07 6 months 5.1 +0.25 + + 22 839 0 95.5 1008 6 months 4.5 –1.30 ++ + 8 671 0.62 26 30.39 6 months 4.9 –0.50 – – 19 25.6 0 4.53 1.4910 8 months 3.6 –1.90 ++ + 27 410 5.53 40.7 73.711 10 months 5.4 –1.17 – – 22 20,136 45.8 100 37.812 1 year 4.4 –3.55 +++ – 14 2,731 100 100 92.513 1 year 5.3 –1.64 + + 26 14,082 18.9 100 10014 2 years 5.8 –0.61 + – 8 58 0 0 015 13 years 5.3 –0.10 +++ +/– 22 36,128 100 5.02 4.44

IgE, immunoglobulin E; SD, standard deviation; TP, total protein.

Table 2. Examination of the gastrointestinal system in patients with diarrhea

Patient no.Stool

eosinophilSudan IIIstaining

Seruma1-AT*

Stoola1-AT{

a1-ATclearance{

2 – ND ND ND ND4 – – 199 17.3 8.78 – + 184 0.73 0.410 – – ND ND ND13 – – 331 3.6 1.1

*mg/dl.{mg/day.{ml/day.a1-AT, a1-antitrypsin; ND, not done.

Nomura et al.

290

nemia are shown in Fig. 3. The corrected a1-globulin fraction was significantly higher inpatients with hypoproteinemia than in thosewithout hypoproteinemia. Corrected fractionsof albumin, b-globulin, and c-globulin weresignificantly lower in patients with hypoprotei-nemia.C-reactive protein (CRP) was positive only in

patient 14. Cytology of skin discharge wasobserved in three patients and inflammatorycells were not seen.

S. aureus, production of SAg, and SAg-specific IgEantibodies

S. aureus was isolated from all patients.Methicillin-resistant S. aureus (MRSA) wereseen in three patients. Among 13 patients whowere examined for staphylococcal SAg produc-tion, 11 (83.3%) were found to have SAg-producing S. aureus on their skin (Table 4).Five patients were examined for ETA and ETBproduction. Only one patient (patient 15) hadETB-producing S. aureus. ETA-producing S.aureus was not detected in any of these patients.

Platelet count

Comparison of peak platelet counts betweenpatients with or without hypoproteinemia isshown in Fig. 4. Peak platelet counts in patientswith hypoproteinemia were significantly higherthan in those without hypoproteinemia. Diseaseactivity scores did not show a statistically

significant difference between these groups ofpatients. Peak platelet counts were observed13.4615.0 days after admission.

Serum IL-5, IL-6, IL-12, and IFN-c

Figure 5 shows results of serum IL-5, IL-12, andIFN-c. Patients with hypoproteinemia had sig-nificantly higher IL-5 concentrations than didpatients with mild AD. Serum IL-5 concentra-tions and peripheral blood eosinophil countscorrelated well (R50.707, p ,0.05) withinpatients with hypoproteinemia. The serum IL-12 concentration of patients with severe AD, withor without hypoproteinemia, was significantlylower than that of patients without AD. Therewas no significant difference in the serum IFN-clevel between these patients. We also examined(by using ELISA) the serum IL-6 level of thepatients with and without hypoproteinemia. Fiftyper cent of patients with hypoproteinemia werepositive for IL-6 (i.e. had an IL-6 value greaterthan the cut-off point of 2 pg/ml) whereas only10% of patients without hypoproteinemia werepositive for IL-6. This result was statisticallysignificant (p 5 0.013).

Therapy

After starting our standard therapy for AD, 13patients responded promptly. It required lessthan 1 week to stop the skin discharge experi-enced by the patients. Two patients (13 and 15)had difficulty in recovering. It took longer than

Table 3. Comparison of protein fractions between serum and the skin discharge of patient 11 on the same day

TP(g/dl)

Albumin(%)

a1-globulin(%)

a2-globulin(%)

b-globulin(%)

c-globulin(%)

Serum 5.4 60.5 5.4 12.9 9.8 5.5Skin discharge 9.0 54.7 6.3 11.9 13.0 14.1

TP, total protein.

Fig. 3. Corrected serum proteinfraction values of patients with andwithout hypoproteinemia. Serumprotein fractions were corrected withreference to an age-matched healthycontrol according to formula (4).The corrected a1-globulin fraction issignificantly higher in patients withhypoproteinemia than in thosewithout hypoproteinemia. Correctedfractions of albumin, b-globulin,and c-globulin were significantlylower in patients withhypoproteinemia. Disease activityscores of these two groups ofpatients did not show a statisticallysignificant difference.

pp

Hypoproteinemia in atopic dermatitis

291

several months to bring their skin inflammationunder control.Twelve patients had food-specific IgE anti-

bodies. Food allergen elimination had alreadybeen undertaken in nine patients before admis-sion. These patients continued the same degree offood elimination, even after admission. Fourpatients started food elimination after admission.With few exceptions, patients had a good

appetite before and after admission. They hadbeen taking sufficient calories and proteins. Abody weight mean of –1.5 SD61.3 on admissionincreased to –0.8 SD61.0, 1 year later.

Discussion

In Japan, the number of patients with ADwho also have hypoproteinemia, is increasingeach year. Even cerebral infarction, as a con-sequence of hypoproteinemia, has been reported(7). In our hospital, 11 out of 13 infants,12 months of age, with severe AD and whoneeded admission, had hypoproteinemia.Prominent serous skin discharge was seen inall of the patients. Skin edema, peripheralcyanosis, oliguria, and diarrhea were observedin some of the patients. No patient developedhypovolemic shock or vascular infarction inour series. Peripheral blood eosinophilia anda high IgE antibody titer were observed.Thrombocythemia, on and after admission,was seen.There are three possible mechanisms to

explain the hypoproteinemia: loss of proteinfrom the gastrointestinal tract; loss of proteinfrom the skin lesions; or insufficient foodintake. Five patients had diarrhea on admis-sion. Eosinophils were not found in stoolsamples from these patients. Sudan III-positivestaining, which suggests a defect in lipidabsorption, was positive in one patient.Alpha-1 antitrypsin clearance was normal inall three patients examined. Thus, protein-losingenteropathy and mal-absorption were thoughtnot to be the main reason for hypoproteinemia.Almost all patients had a good appetite onadmission. Intake of calories and proteinsbefore admission were estimated as sufficientfor each patient. All the patients had markedskin discharge, which had almost the same

Table 4. Clinical data of the patients

Patient no. WBC/ml Platelet count* CRP Skin SAg-producing S. aureus Positive serum SAg-specific IgE{

1 16,500 1,016 0.16 ND ND2 22,500 940 0.06 ND ND3 11,700 342 0.15 – –4 22,200 530 0.06 SEA, SEC ND5 13,100 473 0.06 SEA, SEB SEA{6 13,500 370 0.13 ND ND7 9,890 663 ND SEB –8 19,700 737 0.09 TSS, SEB, SEC, SEG, SEI –9 10,400 432 0.09 SEA, SEC –10 22,200 602 0.06 – –11 25,800 659 0.09 TSS, SEB, SEC, SEG TSS{12 15,700 711 0.19 SEC SEC{13 7,930 1,062 0.18 SEA SEA{14 11,400 582 1.76 SEA –15 16,400 373 0.36 SEB, ETB SEA, SEB,{ SEC, TSS

*Peak platelet count 3 103/ml.{Serum superantigen (SAg)-specific immunoglobulin E (IgE) antibody levels higher than the cut-off points.{Agreement between IgE specificity and SAg produced by the isolated Staphylococcus aureus.CRP, C-reactive protein; ETB, exfoliative toxin B, ND, not done; SEA, SEB, SEC, SEG, SEI, staphylococcal enterotoxin A,B, C, G and I, respectively; TSS, toxic shock syndrome;WBC, white blood cell count

p

Fig. 4. Comparison of peak platelet counts between patientswith or without hypoproteinemia. Peak platelet counts ofpatients with hypoproteinemia were significantly higher thanthose of patients without hypoproteinemia. Disease activityscores of both groups of patients did not show a statisticallysignificant difference. Platelet counts peaked, on average,13.4615.0 days after admission.

Nomura et al.

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protein concentration as serum. For thesereasons, the main route of protein loss wasspeculated to be via discharge from thedamaged skin.Next, we evaluated the potential cause of

severe dermatitis in these patients. As values ofCRP were within normal limits in almost allpatients, and as polymorphonuclear cells werenot found in the skin discharge of some patients,overt bacterial skin infection, such as impetigo,was eliminated. Specific IgE antibodies andpositive skin-prick tests to some food allergenswere seen in 13 patients. However, beforeadmission, nine of 13 patients were placed onthe same recipe of food elimination as onadmission. Careful elimination of causative

food was needed, but food elimination did notcause significant change in skin inflammation ofthese patients.Colonization of S. aureus was observed among

all the patients. S. aureus colonization exacer-bates AD by various mechanisms. SAgs producedby the organism activate skin-infiltrating T cells,as well as Langerhans’ cells and keratinocytes, toproduce pro-inflammatory cytokines and che-moattractant proteins (10–13). Many cellularcomponent proteins (14), as well as SAgs(9,15,16) of S. aureus, act as allergens and causeinflammation through type I allergy. Of 13patients examined, 11 (84.6%) were found tohave SAg-producing S. aureus on their skin. Thispercentage is significantly higher (p5 0.044) thanfound in patients with severe AD withouthypoproteinemia (54%). Lee et al. reported thatTSST-1 affects endothelial cells and may lead tocapillary leak (17). SAgs may affect capillaries inthe dermis, leading to skin discharge and proteinloss. Pairing of skin SAg-producing S. aureus andserum-specific IgE antibody to the same SAgwas found in five patients. These serum IgEantibodies specific to SAg might promote allergicinflammation of the skin.The serum IL-5 concentration was significantly

elevated in AD patients with hypoproteinemia.IL-5 is a cytokine that promotes the differentia-tion and function of eosinophils. There was asignificant correlation between peripheral bloodeosinophil counts and serum IL-5. The serum IL-12 concentration of patients with and withouthypoproteinemia was significantly lower than inthe patients without AD. Thus, severe dermatitisof patients with hypoproteinemia may be theresult of T helper 2 (Th2) T-cell-mediated allergicinflammation.Increased platelet counts were seen in patients

with hypoproteinemia and were significantlyhigher than found in AD patients withouthypoproteinemia. Thrombopoiesis is modulatedby several cytokines. Thrombopoietin, IL-3, IL-6, IL-11, and others are known to be able tosupport megakaryopoiesis and platelet produc-tion (18). Thrombocytosis is seen in severalinflammatory diseases such as rheumatoid arthri-tis, nephrotic syndrome, and Kawasaki disease.In these diseases, over-production of pro-inflam-matory cytokines is known to occur and is thecause of thrombocytosis. Thrombocytosis is alsoseen in burns patients. Nijsten et al. reported thatplatelet counts increased to supra-normal levels2 weeks after a burn occurred (19). High levels ofserum IL-6 and other acute-phase proteins inburns patients might be a cause of thrombocy-tosis. If the patients with AD and hypoproteine-

p

p

p

Fig. 5. Levels of serum interleukin (IL)-5, IL-12, andinterferon-c (IFN-c). (a) Patients with atopic dermatitis(AD) and hypoproteinemia; (b) patients with severe AD butwithout hypoproteinemia; (c) patients with mild AD; (d)patients without AD. The patients with hypoproteinemiahad significantly higher IL-5 concentrations than patientswith mild AD. Serum IL-5 concentration and peripheralblood eosinophil counts correlated well (R50.707, p ,0.05)within patients with hypoproteinemia. The serum IL-12concentration of patients with severe AD, with or withouthypoproteinemia, was significantly lower than that ofpatients without AD. There was no significant differencein serum levels of IFN-c between these patients. Diseaseactivity scores of severe AD without hypoproteinemia were.40 and did not show a statistically significant differencefrom patients with hypoproteinemia. Disease activity scoresof mild AD were ,20.

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293

mia had deeper or more severe skin damage thanthe AD patients without hypoproteinemia, pro-duction of cytokines with thrombopoietic activitymight occur in patients with hypoproteinemia.We examined serum IL-6 levels of the patientswith and without hypoproteinemia by usingELISA. Fifty per cent of patients with hypopro-teinemia had serum IL-6 level of greater than 2pg/ml, whereas only 10% of patients withouthypoproteinemia had serum IL-6 greater thanthis level. This difference was statistically sig-nificant (p 5 0.013). Disease severity scoresbetween the two groups were not significantlydifferent. Therefore, an increased level of IL-6 inpatients with hypoproteinemia might be onereason for thrombocytosis.Thirteen patients responded promptly to our

standard therapy for AD. Two patients needed alonger period of treatment (several months) toenter remission of their AD.In general, AD patients with hypoproteinemia

should be admitted to the hospital for treatment.Careful treatment is needed, such as washing theskin with soap and water, proper use of steroidointment, preventing scratching of the skin,allergen avoidance, and parental education.Although we have not seen a patient with aserum protein level of,3.0 g/dl until now, such aprotein level is associated with the risk ofhypovolemic shock. Treatment with plasmaexpanders (albumin, fresh-frozen plasma) willbe required.To prevent hypovolemic shock, vascular occlu-

sion, and growth retardation, it is crucial toidentify hypoproteinemia at an early stage and tostart appropriate therapy as soon as possible.

Acknowledgments

We thank all staff in the Department of Allergy andnursing staff of the National Children’s Hospital for theirsupport and assistance. We thank Miss Hiroko Nogami,Miss Atsuko Nakajima, Miss Naoko Wakaki and DrNorikazu Ikeda for their technical assistance. We alsothank Dr Donald Y. M. Leung at the National JewishMedical and Research Center in Denver for his kindadvice and correction of English grammar.

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