- Email: [email protected]
Food allergies can persist after myeloablative hematopoietic stem cell transplantation in dedicator of cytokinesis 8–deficient patients
Letter to the Editor Food allergies can persist after myeloablative hematopoietic stem cell transplantation in dedicator of cytokinesis 8–deficient patients To the Editor: Dedicator of cytokinesis 8 (DOCK8) deficiency is a highly morbid combined immunodeficiency that features recurrent sinopulmonary infections, viral skin infections, and severe food allergies.1,2 Hematopoietic stem cell transplantation (HSCT) cures infection susceptibility in patients with DOCK8 deficiency.3-7 Whether HSCT also cures food allergy has not been systematically examined in human subjects.8 To gain insight into the etiopathogenesis of food allergy and its potential treatment, we studied food allergy in 12 DOCK8-deficient patients who underwent HSCT at the National Institutes of Health (NIH) Clinical Center. First, we retrospectively evaluated 6 patients who had received either matched related or unrelated donor cells after myeloablative conditioning (patients 1-6 in Table I and see the Methods section in this article’s Online Repository at www. jacionline.org).7 Of these, patients 2 and 4 reported histories of food-induced anaphylaxis before transplantation, and patient 5 reported a new food allergy after transplantation. After transplantation, skin prick testing to 8 common food allergens and specific IgE by using ImmunoCAP (Phadia, Uppsala, Sweden) confirmed sensitization to foods precipitating the reactions. Food challenges were not performed. A fourth patient (patient 1) reported oral pruritus to lentils before transplantation and again when re-exposed more than 1 year after transplantation. Donors in these cases were confirmed to have no history of food allergy. Our observations of persisting or new food allergies were unexpected given anecdotal reports suggesting that HSCT cured food allergies and could have reflected a selection bias.4,5,9 Thus we prospectively studied food allergies in the next 6 DOCK8deficient patients undergoing transplantation at the NIH (patients 7-12 in Table I). This second group included 2 patients (patients 9 and 12) who had undergone related donor haploidentical transplantations and had systemic allergic reactions to foods to which they were already allergic before transplantation. Donors were confirmed to have no history of food allergy. Patient 9 was more than 8 months after HSCT and more than 2 months off tacrolimus when she had acute oral and facial angioedema, diffuse urticaria, vomiting, and difficulty breathing within minutes of eating oatmeal fortified with egg and milk. Her symptoms resolved after receiving epinephrine, diphenhydramine, and methylprednisolone. Before transplantation, she had had anaphylactic reactions to egg and milk. However, 2 months before her last reaction, her skin prick test responses were positive to egg but not milk, suggesting egg as the culprit (see Table E1 in this article’s Online Repository at www.jacionline.org). Similarly, patient 12 was 45 days out after HSCT when she had oral and periorbital angioedema and diffuse urticaria and pruritus within 10 minutes of eating a kiwi fruit, with sensitization confirmed by means of skin prick testing (Table I and see Table E1). Years before transplantation, she too had had oral pruritus and lip angioedema after eating kiwi and had subsequently avoided it entirely.
Among the patients studied prospectively, a third patient who underwent matched unrelated donor transplantation reported that a previously resolved food allergy had returned. Patient 7 was 3 months out of HSCT when he had cramping abdominal pain, vomiting, diarrhea, and headache within 15 minutes of eating scrambled eggs. His symptoms occurred on 2 more occasions following concentrated egg ingestion but never when he ate baked goods that contained eggs. He had had similar symptoms in his early school age years but had been eating eggs freely for the decade before transplantation. Skin prick testing confirmed that he had reacquired reactivity to egg after transplantation (Table I and see Table E1). The donor was confirmed to have no history of food allergy. Patient 7 also had a history of anaphylaxis to walnut as recently as 3 years before HSCT. Because of persisting positive skin prick tests, he continued to strictly avoid tree nuts after transplantation. We observed that while total serum IgE levels plummeted after HSCT, they remained elevated in most patients (Fig 1). Food-specific IgE levels also remained high for months after transplantation in several patients, even at levels having greater than a 95% positive predictive value for clinical food reactivity for some (see Table E2 in this article’s Online Repository at www.jacionline.org). Moreover, skin prick testing revealed persisting mast cell reactivity to food allergens, which seemed to correlate best with the anaphylactic episode described after transplantation in patient 9 (see Table E1). Persistence of allergen sensitization occurred regardless of donor type. The possibility of long-lived, host-derived, IgE-producing plasma cells in the bone marrow could explain allergy persistence. Indeed, we observed that bone marrow chimerism approached but did not reach 100% (see Table E3 in this article’s Online Repository at www. jacionline.org). Although HSCT in DOCK8-deficient patients is now considered the standard of care, its outcome for food allergy remains less clear. In 2 DOCK8-deficient patients who had full donor chimerism after HSCT, food allergies were only mentioned as having resolved.4,5 In another DOCK8-deficient patient with full donor chimerism after HSCT, multiple undescribed food allergies resolved, whereas lentil allergy (the only one to cause anaphylaxis in this patient) persisted and total IgE levels remained abnormally high.6 In a fourth patient who had mixed donor peripheral blood chimerism (53% mononuclear cells, 6% granulocytes, 98% T cells, and 35% B cells), multiple food allergies persisted, although they were less severe after transplantation.3 By contrast, all of our patients who had food allergy reactions after transplantation had 100% peripheral blood donor chimerism (see Table E3). Our study is limited in that we did not perform double-blind, placebo-controlled food challenges before and after HSCT. However, the 2 systemic reactions (patients 9 and 12) and 1 local reaction (patient 1) to foods that had previously caused reactions before transplantation strongly support persistence of food allergy in these 3 patients. Tacrolimus has been associated with new-onset food allergy after solid organ transplantation.10 Although its use in our patient cohort could have contributed to some of the allergy we observed, this seemed unlikely in 2 patients. Patient 1 received only cyclosporine for graft-versushost disease prophylaxis. Patient 5 received tacrolimus for only 1
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TABLE I. Pre- and post-HSCT clinical food allergies, skin prick test responses, and total serum IgE levels in the studied DOCK8-deficient patients Months after HSCT at most Transrecent Age at plant allergy Patient HSCT (y)/sex evaluation type no.
Patients studied retrospectively
Patients studied prospectively
GVHD prophylaxis type and duration of therapy after transplantation
Clinical food allergies
Gut GVHD
Foods causing reaction before HSCT
Foods causing reaction after HSCT
Symptoms with most severe reaction before HSCT
Skin prick testing
Before HSCT, positive*
Total serum IgE (IU/mL)
After HSCT, positive
Peak before HSCT
Most recent after HSCT
ND
8,031
870
1,058
1
18/F
18
MRD Cyclosporine: 12 mo
Yes Lentils
Lentils
Oral pruritus only
ND
2
10/F
23
MRD Tacrolimus: 8.5 mo
No Egg, milk, wheat, soy, sesame, tree nuts
Not Anaphylaxis challenged
ND
3
23/M
21
No None
None
ND
4
27/M
37
No Peanut
Peanut
25/F
24
No None
Not Anaphylaxis challenged Shrimp Gastrointestinal symptoms only
ND
5
ND
Shrimp
6
16/F
18
No None
None
None
ND
ND
7
19/M
12
MRD Tacrolimus: 14 mo URD Tacrolimus: 11 mo URD Tacrolimus: 3 wk then, cyclosporine: 14 mo URD Cyclosporine: 11 mo URD Tacrolimus: 9 mo
Egg, milk, 6,690 wheat, soy, cashew (ND: sesame) ND 51,010
Egg, no tree nut exposure
Anaphylaxis
8
21/M
Died
URD Tacrolimus: ongoing
No Egg: resolved in early childhood, tree nuts persisted Yes Milk, egg, peanut
9
20/F
12
Haplo Tacrolimus: 6 mo
10
13/M
10
MRD Tacrolimus: 7 mo
11
9/F
6
12
19/F
3
URD Tacrolimus: ongoing Haplo Tacrolimus: ongoing
None
Not Anaphylaxis challenged
Egg/milk, no Anaphylaxis No Egg, milk, exposure wheat, to others peanut, cashew No Egg, wheat, Not Anaphylaxis peanut, challenged kiwi, banana Yes None None None No Kiwi, Kiwi, no concentrated exposure milk, to others concentrated egg
Walnut, Egg, cashew walnut
1,162 38.5
180 6,398
Milk, egg, ND 31,403 peanut, shrimp 6,905 Egg, Egg, wheat, wheat, peanut, peanut, cashew cashew Egg, Egg, >6,000 wheat, wheat, peanut peanut None None 2.0
Egg, Oral Milk, angioedema egg, kiwi and pruritus cashew (kiwi not done)
>6,000
153 17.4 6.1
9.4 1,224
627
67.8
915
2.9 594
F, Female; GVHD, graft-versus-host disease; Haplo, haploidentical; M, male; MRD, matched related donor; ND, not done; URD, unrelated donor. *Skin prick tests were performed for the common food allergens milk, egg, soy, wheat, peanut, walnut, cashew, and shrimp for each patient before and after HSCT unless otherwise indicated. All positive results are listed. The patient died less than 3 months after transplantation; no follow-up skin prick tests were performed.
3 weeks before the switch to cyclosporine. Furthermore, in no previous reports of persisting allergies did DOCK8-deficient patients receive tacrolimus.3,6 Our case series describes what is to our knowledge the first systematic study of food allergy in patients undergoing HSCT, which might have implications for understanding food allergy more broadly in those without DOCK8 deficiency. We have observed that food allergy is not always cured after HSCT, at least not initially, even when 100% peripheral blood donor
chimerism is achieved. Therefore, strict food avoidance diets should continue to be followed until appropriate allergy testing and medically supervised food challenges can be performed. The overall trends toward decreasing total IgE levels, decreasing food-specific IgE levels, and decreasing skin wheal sizes together suggest that these patients may be more likely to eventually outgrow their food allergies than peers with food allergy who have not undergone transplantation. Long-term follow-up of these patients will be informative.
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Patient #: 100000
Total IgE (IU/mL)
10000
1000
100
Cancer Institute (1ZIABC011374). This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract no. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest.
1 2 3 4 5 6 7 8 9 10 11 12
Normal Total IgE 90 IU/mL
10
1 0
10
20
30
40
Months post-HSCT FIG 1. Total serum IgE in DOCK8-deficient patients after HSCT.
We thank Avanti Desai for technical assistance; Huie Jing and Julie Niemela for DNA sequencing; Thomas Dimaggio, Stephanie Cotton, Cindy Delbrook, Sherri DePollar, and Terri Moore for clinical support; Qian Zhang and Ahmet Ozen for critically reading the manuscript and helpful discussions; and the patients for participating in this research study. Corinne S. Happel, MDa Kelly D. Stone, MD, PhDb Alexandra F. Freeman, MDc Nirali N. Shah, MDd Angela Wang, BSNe Jonathan J. Lyons, MDb Pamela A. Guerrerio, MD, PhDb Dennis D. Hickstein, MDf Helen C. Su, MD, PhDa From athe Laboratory of Host Defenses, bthe Laboratory of Allergic Diseases, and c the Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md; dthe Pediatric Oncology Branch and fthe Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Md; and ethe Clinical Research Directorate/Clinical Monitoring Research Program, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, Md. E-mail: [email protected]. Supported by the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases (1ZIAAI001193), and National
REFERENCES 1. Zhang Q, Davis JC, Lamborn IT, Freeman AF, Jing H, Favreau AJ, et al. Combined immunodeficiency associated with DOCK8 mutations. N Engl J Med 2009;361: 2046-55. 2. Aydin SE, Kilic SS, Aytekin C, Kumar A, Porras O, Kainulainen L, et al. DOCK8 deficiency: clinical and immunological phenotype and treatment options—a review of 136 patients. J Clin Immunol 2015;35:189-98. 3. Bittner TC, Pannicke U, Renner ED, Notheis G, Hoffmann F, Belohradsky BH, et al. Successful long-term correction of autosomal recessive hyper-IgE syndrome due to DOCK8 deficiency by hematopoietic stem cell transplantation. Klin Padiatr 2010;222:351-5. 4. Barlogis V, Galambrun C, Chambost H, Lamoureux-Toth S, Petit P, Stephan JL, et al. Successful allogeneic hematopoietic stem cell transplantation for DOCK8 deficiency. J Allergy Clin Immunol 2011;128:420-2.e2. 5. Boztug H, Karitnig-Weiss C, Ausserer B, Renner ED, Albert MH, SawalleBelohradsky J, et al. Clinical and immunological correction of DOCK8 deficiency by allogeneic hematopoietic stem cell transplantation following a reduced toxicity conditioning regimen. Pediatr Hematol Oncol 2012;29: 585-94. 6. Metin A, Tavil B, Azik F, Azkur D, Ok-Bozkaya I, Kocabas C, et al. Successful bone marrow transplantation for DOCK8 deficient hyper IgE syndrome. Pediatr Transplant 2012;16:398-9. 7. Cuellar-Rodriguez J, Freeman AF, Grossman J, Su H, Parta M, Murdock H, et al. Matched related and unrelated donor hematopoietic stem cell transplantation for DOCK8 deficiency. Biol Blood Marrow Transplant 2015;21:1037-45. 8. Khan F, Hallstrand TS, Geddes MN, Henderson WR Jr, Storek J. Is allergic disease curable or transferable with allogeneic hematopoietic cell transplantation? Blood 2009;113:279-90. 9. Hourihane JO, Rhodes HL, Jones AM, Veys P, Connett GJ. Resolution of peanut allergy following bone marrow transplantation for primary immunodeficiency. Allergy 2005;60:536-7. 10. Frischmeyer-Guerrerio PA, Wisniewski J, Wood RA, Nowak-Wegrzyn A. Manifestations and long-term outcome of food allergy in children after solid organ transplantation. J Allergy Clin Immunol 2008;122:1031-3.e1. http://dx.doi.org/10.1016/j.jaci.2015.11.017
3.e1 LETTER TO THE EDITOR
METHODS Patients provided written informed consent and were investigated under National Institute of Allergy and Infectious Diseases and National Cancer Institute Institutional Review Board–approved research protocols. Patients 1 to 9 have been previously reported as patients 19, 6, 3, 10, 11, 15, 13, 2, and 5, respectively.E1 Patient 12 has been previously reported as patient Arh009.E2 Patients 1 to 6 underwent conditioning regimens with busulfan and fludarabine and received graft-versus-host disease prophylaxis, as previously described, with identical numbering.E3 The transplantation protocol for patients 7 to 12 was similar, with the exception that posttransplantation cyclophosphamide was added in the 2 haploidentical transplant recipients. All donors were confirmed to have no history of food allergy. DOCK8 mutation analysis has been previously published for all patients, except patients 10 and 11. Patient 10 has a homozygous NM_001193536.1: c.50191G>A, p.1626_1673del mutation detected by using Sanger dideoxy sequencing. Patient 11 has a large homozygous deletion of exons 5 to 14 detected by means of targeted exon-focused array comparative genomic hybridization analysis (GeneDx, Gaithersburg, Md). Allergy history was obtained for each patient either after transplantation (patients 1-6) or both before and after transplantation (patients 7-12). Patients with known clinical food allergy were counseled to continue strict avoidance of known food allergens. Skin prick testing was performed to 8 common food allergens at posttransplantation follow-up visits for 3 retrospectively studied patients (Table E1). In the prospectively studied patients, skin prick testing to the same panel was performed both before transplantation and at posttransplantation follow-up visits. Additionally, prick-to-prick testing with fresh kiwi was performed in patient 12 after transplantation. The largest and orthogonal wheal-and-flare diameters were measured in millimeters after 15 minutes for respective allergen skin prick tests performed by using skin picks and allergen extracts from Greer Laboratories (Lenoir, NC). A histamine positive control and a glycerin negative control were applied during each skin prick test encounter. Results were considered positive if mean wheal diameter was 3 mm
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greater than that elicited by the negative control. Mean wheal value was calculated as follows: D1d/2 (Table E1). Plasma or sera were prepared from venous blood and stored at 2808C until analyzed for allergen-specific IgE antibodies by using Phadia’s ImmunoCAP System, per the manufacturer’s instructions. Specific IgE levels to the following food allergens were quantitated: egg white, milk, wheat, peanut, and walnut. Where indicated, kiwi-, lentil-, or shrimp-specific IgE levels were also measured. Patients who approached the 50% positive predictive value of food-specific IgE testing were advised to seek the care of a local allergist for further evaluation with possible food challenge, which was unavailable at the NIH Clinical Center. No patients have done this to date. The Department of Laboratory Medicine at the National Institutes of Health Clinical Center is certified under the Clinical Laboratory Improvement Amendments of 1988 and performed total serum IgE and donor chimerism assays. Total IgE levels were measured by using a chemiluminescent immunometric assay on the Siemens IMMULITE 2000 XPI (Siemens Healthcare Diagnostics, Flanders, NJ). Donor chimerism was measured by using predetermined differences in short tandem repeats to quantitate the proportion of donor nucleated cells in samples obtained from transplant recipients. The assay can consistently measure 5% to 95% donor chimerism with an SD of 65%. REFERENCES E1. Jing H, Zhang Q, Zhang Y, Hill BJ, Dove CG, Gelfand EW, et al. Somatic reversion in dedicator of cytokinesis 8 immunodeficiency modulates disease phenotype. J Allergy Clin Immunol 2014;133:1667-75. E2. Engelhardt KR, McGhee S, Winkler S, Sassi A, Woellner C, Lopez-Herrera G, et al. Large deletions and point mutations involving the dedicator of cytokinesis 8 (DOCK8) in the autosomal-recessive form of hyper-IgE syndrome. J Allergy Clin Immunol 2009;124:1289-302.e4. E3. Cuellar-Rodriguez J, Freeman AF, Grossman J, Su H, Parta M, Murdock H, et al. Matched related and unrelated donor hematopoietic stem cell transplantation for DOCK8 deficiency. Biol Blood Marrow Transplant 2015;21:1037-45.
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TABLE E1. Skin prick testing to selected food allergens in DOCK8-deficient patients before and after HSCT Egg white Patient no. 2 4 5 Pre-HSCT ND ND ND Post-HSCT evaluation 1 15.5 (6) Negative (25) Negative (15) (months after HSCT) Post-HSCT evaluation 2 Negative (37) (months after HSCT) Milk Patient no. 2 4 5 Pre-HSCT ND ND ND Post-HSCT evaluation 1 19.5 (6) Negative (25) Negative (15) (months after HSCT) Post-HSCT evaluation 2 Negative (37) (months after HSCT) Soy Patient no. 2 4 5 Pre-HSCT ND ND ND Post-HSCT evaluation 1 5 (6) Negative (25) Negative (15) (months after HSCT) Post-HSCT evaluation 2 Negative (37) (months after HSCT) Wheat Patient no. 2 4 5 Pre-HSCT ND ND ND Post-HSCT evaluation 1 9 (6) Negative (25) Negative (15) (months after HSCT) Post-HSCT evaluation 2 Negative (37) (months after HSCT) Peanut Patient no. 2 4 5 Pre-HSCT ND ND ND Post-HSCT evaluation 1 Negative (6) 11 (25) Negative (15) (months after HSCT) Post-HSCT evaluation 2 8 (37) (months after HSCT) Walnut Patient no. 2 4 5 Pre-HSCT ND ND ND Post-HSCT evaluation 1 Negative (6) Negative (25) Negative (15) (months after HSCT) Post-HSCT evaluation 2 Negative (37) (months after HSCT) Cashew Patient no. 2 4 5 Pre-HSCT ND ND ND Post-HSCT evaluation 1 18.5 (6) Negative (25) Negative (15) (months after HSCT) Post-HSCT evaluation 2 Negative (37) (months after HSCT) Shrimp Patient no. 2 4 5 Pre-HSCT ND ND ND Post-HSCT evaluation 1 Negative (6) Negative (25) 7 (15) (months after HSCT) Post-HSCT evaluation 2 Negative (37) Negative (24) (months after HSCT) Kiwi, green pulp Patient no. 12 Pre-HSCT ND Post-HSCT 7.5 (3) (months after HSCT)
7 Negative 10 (6)
8* 21
12 (11)
7 Negative Negative (6)
8* 21.5
Negative (11)
7 Negative Negative (6)
8* Negative
Negative (11)
7 Negative Negative (6)
8* 16.5
Negative (11)
7 4.5 3 (6)
Negative (11)
5 (10)
9 6 Negative (6)
10 Negative Negative (7)
6 (12)
Negative (10)
10 Negative Negative (7)
4 (12)
Negative (10)
9 12 5 (6)
10 8.5 6 (7)
4.5 (12)
Negative (10)
9 6 5 (6)
10 9.5 6 (7)
4 (12)
Negative (10)
10 Negative Negative (7)
11 Negative Negative (6)
12 3 8 (3)
11 12 Negative 3.5 Negative (6) Negative (3)
11 12 Negative Negative Negative (6) Negative (3)
11 12 Negative Negative Negative (6) Negative (3)
11 12 Negative Negative Negative (6) Negative (3)
11 12 Negative Negative Negative (6) Negative (3)
Negative (12) Negative (10)
8* Negative
Negative (11)
7 Negative Negative (6)
5 (12)
8* 9 Negative Negative Negative (6)
3 (11)
7 9.5 Negative (6)
10 9.5 15 (7)
8* 9 Negative Negative Negative (6)
Negative (11)
7 Negative Negative (6)
9 12.5 7 (6)
9 15 9 (6)
10 Negative 3 (7)
11 12 Negative 3 Negative (6) Negative (3)
Negative (12) Negative (10)
8* 9
9 Negative Negative (6)
10 Negative Negative (7)
11 12 Negative Negative Negative (6) Negative (3)
Negative (12) Negative (10)
(Continued)
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TABLE E1. (Continued ) Kiwi, white pulp Patient no. Pre-HSCT Post-HSCT (months after HSCT)
12 ND 12.5 (3)
Mean wheal diameters are listed in millimeters. Parentheses contain the number of months after HSCT, when measured. Boldface indicates sensitization. *The patient died less than 3 months after HSCT, and no repeat skin prick tests were performed.
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TABLE E2. Food-specific IgE levels in DOCK8-deficient patients before and after HSCT Egg-specific IgE (IU/mL) Patient no. 1 Pre-HSCT 5.76 Post-HSCT evaluation 1 <0.1 (12) (months after HSCT) Post-HSCT evaluation 2 (months after HSCT) Milk-specific IgE (IU/mL) Patient no. 1 Pre-HSCT 38 Post-HSCT evaluation 1 2.99 (12) (months after HSCT) Post-HSCT evaluation 2 (months after HSCT) Wheat-specific IgE (IU/mL) Patient no. 1 Pre-HSCT 5.38 Post-HSCT evaluation 1 0.36 (12) (months after HSCT) Post-HSCT evaluation 2 (months after HSCT) Peanut-specific IgE (IU/mL) Patient no. 1 Pre-HSCT 0.3 Post-HSCT evaluation 1 <0.1 (12) (months after HSCT) Post-HSCT evaluation 2 (months after HSCT) Walnut-specific IgE (IU/mL) Patient no. 1 Pre-HSCT 0.18 Post-HSCT evaluation 1 <0.1 (12) (months after HSCT) Post-HSCT evaluation 2 (months after HSCT) Lentil-specific IgE (IU/mL) Patient no. 1 Pre-HSCT 13.6 Post-HSCT 2.06 (12) (months after HSCT) Shrimp-specific IgE (IU/mL) Patient no. 5 Pre-HSCT <0.1 <0.1 (15) Post-HSCT (months after HSCT) Kiwi-specific IgE (IU/mL) Patient no. 12 Pre-HSCT 22.3 Post-HSCT 2.74 (3) (months after HSCT)
2 3 4 5 6 7 52.5 21.7 3.39 <0.1 <0.1 5.08 9.49 (12) <0.1 (7) 0.35 (25) <0.1 (15) <0.1 (14) 5.65 (6) 8.63 (23)
9.18 (23)
0.89 (23)
8* 17
0.93 (11)
11 12 <0.1 8.82 <0.1 (6) 0.37 (3)
9 12.8 0.88 (6)
10 25.4 6.92 (7)
11 12 <0.1 28.5 <0.1 (6) 1.64 (3)
9 15.3 0.53 (6)
10 18.6 5.18 (7)
11 12 <0.1 0.78 <0.1 (6) 0.18 (3)
<0.1 (12) 1.5 (10)
8* 36
9 0.58 0.62 (6)
10 22.8 5.12 (7)
11 12 <0.1 1.09 <0.1 (6) <0.1 (3)
0.33 (12) 1.38 (10)
2.01 (11)
2 3 4 5 6 7 3.79 0.51 <0.1 <0.1 <0.1 5.95 1.05 (12) <0.1 (7) <0.1 (25) <0.1 (15) <0.1 (14) 1.3 (6)
10 46.6 17.4 (7)
<0.1 (12) 4.43 (10)
1.19 (11)
2 3 4 5 6 7 >100 9.09 21.5 <0.1 <0.1 5.01 35.4 (12) <0.1 (7) 1.07 (25) <0.1 (15) <0.1 (14) 2.37 (6) 21.7 (23)
8* 99.1
5.13 (11)
2 3 4 5 6 7 31.3 3.85 5.68 <0.1 <0.1 5.72 11.2 (12) <0.1 (7) 0.37 (25) <0.1 (15) <0.1 (14) 1.72 (6)
9 14.7 0.39 (6)
<0.1 (12) 5.45 (10)
3.58 (11)
2 3 4 5 6 7 >100 29.2 0.16 <0.1 <0.1 6.95 72.6 (12) <0.1 (7) <0.1 (25) <0.1 (15) <0.1 (14) 6.22 (6) 51 (23)
8* >100
8* 1.45
9 <0.1 0.3 (6)
10 3.06 0.81 (7)
0.21 (12) 0.19 (10)
Parentheses contain the number of months after HSCT, when measured. Boldface indicates sensitization at levels of 0.35 IU/mL or greater. *Patient 8 died less than 3 months after HSCT, and no follow-up serum IgE testing was performed.
11 12 <0.1 0.37 <0.1 (6) <0.1 (3)
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TABLE E3. Donor chimerism in peripheral whole blood and bone marrow of DOCK8-deficient patients after HSCT
Patient no.
1 2 3 4 5 6 7 8* 9 10 11 12
Peripheral whole blood donor chimerism (months after HSCT at most recent test)
100% 100% 100% 100% 100% 100% 100% 100% 100% 100% 100% 100%
(24) (23) (12) (24) (24) (23) (11) (1) (12) (10) (6) (3)
*Patient died less than 3 months after HSCT.
Bone marrow donor chimerism (months after HSCT at most recent test)
98% (12) 96% (12) 94% (12) 97% (25) 94% (24) 95% (23) 97% (11) Not done 91% (12) 96% (10) Not yet performed Not yet performed
Among the patients studied prospectively, a third patient who underwent matched unrelated donor transplantation reported that a previously resolved food allergy had returned. Patient 7 was 3 months out of HSCT when he had cramping abdominal pain, vomiting, diarrhea, and headache within 15 minutes of eating scrambled eggs. His symptoms occurred on 2 more occasions following concentrated egg ingestion but never when he ate baked goods that contained eggs. He had had similar symptoms in his early school age years but had been eating eggs freely for the decade before transplantation. Skin prick testing confirmed that he had reacquired reactivity to egg after transplantation (Table I and see Table E1). The donor was confirmed to have no history of food allergy. Patient 7 also had a history of anaphylaxis to walnut as recently as 3 years before HSCT. Because of persisting positive skin prick tests, he continued to strictly avoid tree nuts after transplantation. We observed that while total serum IgE levels plummeted after HSCT, they remained elevated in most patients (Fig 1). Food-specific IgE levels also remained high for months after transplantation in several patients, even at levels having greater than a 95% positive predictive value for clinical food reactivity for some (see Table E2 in this article’s Online Repository at www.jacionline.org). Moreover, skin prick testing revealed persisting mast cell reactivity to food allergens, which seemed to correlate best with the anaphylactic episode described after transplantation in patient 9 (see Table E1). Persistence of allergen sensitization occurred regardless of donor type. The possibility of long-lived, host-derived, IgE-producing plasma cells in the bone marrow could explain allergy persistence. Indeed, we observed that bone marrow chimerism approached but did not reach 100% (see Table E3 in this article’s Online Repository at www. jacionline.org). Although HSCT in DOCK8-deficient patients is now considered the standard of care, its outcome for food allergy remains less clear. In 2 DOCK8-deficient patients who had full donor chimerism after HSCT, food allergies were only mentioned as having resolved.4,5 In another DOCK8-deficient patient with full donor chimerism after HSCT, multiple undescribed food allergies resolved, whereas lentil allergy (the only one to cause anaphylaxis in this patient) persisted and total IgE levels remained abnormally high.6 In a fourth patient who had mixed donor peripheral blood chimerism (53% mononuclear cells, 6% granulocytes, 98% T cells, and 35% B cells), multiple food allergies persisted, although they were less severe after transplantation.3 By contrast, all of our patients who had food allergy reactions after transplantation had 100% peripheral blood donor chimerism (see Table E3). Our study is limited in that we did not perform double-blind, placebo-controlled food challenges before and after HSCT. However, the 2 systemic reactions (patients 9 and 12) and 1 local reaction (patient 1) to foods that had previously caused reactions before transplantation strongly support persistence of food allergy in these 3 patients. Tacrolimus has been associated with new-onset food allergy after solid organ transplantation.10 Although its use in our patient cohort could have contributed to some of the allergy we observed, this seemed unlikely in 2 patients. Patient 1 received only cyclosporine for graft-versushost disease prophylaxis. Patient 5 received tacrolimus for only 1
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TABLE I. Pre- and post-HSCT clinical food allergies, skin prick test responses, and total serum IgE levels in the studied DOCK8-deficient patients Months after HSCT at most Transrecent Age at plant allergy Patient HSCT (y)/sex evaluation type no.
Patients studied retrospectively
Patients studied prospectively
GVHD prophylaxis type and duration of therapy after transplantation
Clinical food allergies
Gut GVHD
Foods causing reaction before HSCT
Foods causing reaction after HSCT
Symptoms with most severe reaction before HSCT
Skin prick testing
Before HSCT, positive*
Total serum IgE (IU/mL)
After HSCT, positive
Peak before HSCT
Most recent after HSCT
ND
8,031
870
1,058
1
18/F
18
MRD Cyclosporine: 12 mo
Yes Lentils
Lentils
Oral pruritus only
ND
2
10/F
23
MRD Tacrolimus: 8.5 mo
No Egg, milk, wheat, soy, sesame, tree nuts
Not Anaphylaxis challenged
ND
3
23/M
21
No None
None
ND
4
27/M
37
No Peanut
Peanut
25/F
24
No None
Not Anaphylaxis challenged Shrimp Gastrointestinal symptoms only
ND
5
ND
Shrimp
6
16/F
18
No None
None
None
ND
ND
7
19/M
12
MRD Tacrolimus: 14 mo URD Tacrolimus: 11 mo URD Tacrolimus: 3 wk then, cyclosporine: 14 mo URD Cyclosporine: 11 mo URD Tacrolimus: 9 mo
Egg, milk, 6,690 wheat, soy, cashew (ND: sesame) ND 51,010
Egg, no tree nut exposure
Anaphylaxis
8
21/M
Died
URD Tacrolimus: ongoing
No Egg: resolved in early childhood, tree nuts persisted Yes Milk, egg, peanut
9
20/F
12
Haplo Tacrolimus: 6 mo
10
13/M
10
MRD Tacrolimus: 7 mo
11
9/F
6
12
19/F
3
URD Tacrolimus: ongoing Haplo Tacrolimus: ongoing
None
Not Anaphylaxis challenged
Egg/milk, no Anaphylaxis No Egg, milk, exposure wheat, to others peanut, cashew No Egg, wheat, Not Anaphylaxis peanut, challenged kiwi, banana Yes None None None No Kiwi, Kiwi, no concentrated exposure milk, to others concentrated egg
Walnut, Egg, cashew walnut
1,162 38.5
180 6,398
Milk, egg, ND 31,403 peanut, shrimp 6,905 Egg, Egg, wheat, wheat, peanut, peanut, cashew cashew Egg, Egg, >6,000 wheat, wheat, peanut peanut None None 2.0
Egg, Oral Milk, angioedema egg, kiwi and pruritus cashew (kiwi not done)
>6,000
153 17.4 6.1
9.4 1,224
627
67.8
915
2.9 594
F, Female; GVHD, graft-versus-host disease; Haplo, haploidentical; M, male; MRD, matched related donor; ND, not done; URD, unrelated donor. *Skin prick tests were performed for the common food allergens milk, egg, soy, wheat, peanut, walnut, cashew, and shrimp for each patient before and after HSCT unless otherwise indicated. All positive results are listed. The patient died less than 3 months after transplantation; no follow-up skin prick tests were performed.
3 weeks before the switch to cyclosporine. Furthermore, in no previous reports of persisting allergies did DOCK8-deficient patients receive tacrolimus.3,6 Our case series describes what is to our knowledge the first systematic study of food allergy in patients undergoing HSCT, which might have implications for understanding food allergy more broadly in those without DOCK8 deficiency. We have observed that food allergy is not always cured after HSCT, at least not initially, even when 100% peripheral blood donor
chimerism is achieved. Therefore, strict food avoidance diets should continue to be followed until appropriate allergy testing and medically supervised food challenges can be performed. The overall trends toward decreasing total IgE levels, decreasing food-specific IgE levels, and decreasing skin wheal sizes together suggest that these patients may be more likely to eventually outgrow their food allergies than peers with food allergy who have not undergone transplantation. Long-term follow-up of these patients will be informative.
LETTER TO THE EDITOR 3
J ALLERGY CLIN IMMUNOL VOLUME nnn, NUMBER nn
Patient #: 100000
Total IgE (IU/mL)
10000
1000
100
Cancer Institute (1ZIABC011374). This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract no. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest.
1 2 3 4 5 6 7 8 9 10 11 12
Normal Total IgE 90 IU/mL
10
1 0
10
20
30
40
Months post-HSCT FIG 1. Total serum IgE in DOCK8-deficient patients after HSCT.
We thank Avanti Desai for technical assistance; Huie Jing and Julie Niemela for DNA sequencing; Thomas Dimaggio, Stephanie Cotton, Cindy Delbrook, Sherri DePollar, and Terri Moore for clinical support; Qian Zhang and Ahmet Ozen for critically reading the manuscript and helpful discussions; and the patients for participating in this research study. Corinne S. Happel, MDa Kelly D. Stone, MD, PhDb Alexandra F. Freeman, MDc Nirali N. Shah, MDd Angela Wang, BSNe Jonathan J. Lyons, MDb Pamela A. Guerrerio, MD, PhDb Dennis D. Hickstein, MDf Helen C. Su, MD, PhDa From athe Laboratory of Host Defenses, bthe Laboratory of Allergic Diseases, and c the Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md; dthe Pediatric Oncology Branch and fthe Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Md; and ethe Clinical Research Directorate/Clinical Monitoring Research Program, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, Md. E-mail: [email protected]. Supported by the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases (1ZIAAI001193), and National
REFERENCES 1. Zhang Q, Davis JC, Lamborn IT, Freeman AF, Jing H, Favreau AJ, et al. Combined immunodeficiency associated with DOCK8 mutations. N Engl J Med 2009;361: 2046-55. 2. Aydin SE, Kilic SS, Aytekin C, Kumar A, Porras O, Kainulainen L, et al. DOCK8 deficiency: clinical and immunological phenotype and treatment options—a review of 136 patients. J Clin Immunol 2015;35:189-98. 3. Bittner TC, Pannicke U, Renner ED, Notheis G, Hoffmann F, Belohradsky BH, et al. Successful long-term correction of autosomal recessive hyper-IgE syndrome due to DOCK8 deficiency by hematopoietic stem cell transplantation. Klin Padiatr 2010;222:351-5. 4. Barlogis V, Galambrun C, Chambost H, Lamoureux-Toth S, Petit P, Stephan JL, et al. Successful allogeneic hematopoietic stem cell transplantation for DOCK8 deficiency. J Allergy Clin Immunol 2011;128:420-2.e2. 5. Boztug H, Karitnig-Weiss C, Ausserer B, Renner ED, Albert MH, SawalleBelohradsky J, et al. Clinical and immunological correction of DOCK8 deficiency by allogeneic hematopoietic stem cell transplantation following a reduced toxicity conditioning regimen. Pediatr Hematol Oncol 2012;29: 585-94. 6. Metin A, Tavil B, Azik F, Azkur D, Ok-Bozkaya I, Kocabas C, et al. Successful bone marrow transplantation for DOCK8 deficient hyper IgE syndrome. Pediatr Transplant 2012;16:398-9. 7. Cuellar-Rodriguez J, Freeman AF, Grossman J, Su H, Parta M, Murdock H, et al. Matched related and unrelated donor hematopoietic stem cell transplantation for DOCK8 deficiency. Biol Blood Marrow Transplant 2015;21:1037-45. 8. Khan F, Hallstrand TS, Geddes MN, Henderson WR Jr, Storek J. Is allergic disease curable or transferable with allogeneic hematopoietic cell transplantation? Blood 2009;113:279-90. 9. Hourihane JO, Rhodes HL, Jones AM, Veys P, Connett GJ. Resolution of peanut allergy following bone marrow transplantation for primary immunodeficiency. Allergy 2005;60:536-7. 10. Frischmeyer-Guerrerio PA, Wisniewski J, Wood RA, Nowak-Wegrzyn A. Manifestations and long-term outcome of food allergy in children after solid organ transplantation. J Allergy Clin Immunol 2008;122:1031-3.e1. http://dx.doi.org/10.1016/j.jaci.2015.11.017
3.e1 LETTER TO THE EDITOR
METHODS Patients provided written informed consent and were investigated under National Institute of Allergy and Infectious Diseases and National Cancer Institute Institutional Review Board–approved research protocols. Patients 1 to 9 have been previously reported as patients 19, 6, 3, 10, 11, 15, 13, 2, and 5, respectively.E1 Patient 12 has been previously reported as patient Arh009.E2 Patients 1 to 6 underwent conditioning regimens with busulfan and fludarabine and received graft-versus-host disease prophylaxis, as previously described, with identical numbering.E3 The transplantation protocol for patients 7 to 12 was similar, with the exception that posttransplantation cyclophosphamide was added in the 2 haploidentical transplant recipients. All donors were confirmed to have no history of food allergy. DOCK8 mutation analysis has been previously published for all patients, except patients 10 and 11. Patient 10 has a homozygous NM_001193536.1: c.50191G>A, p.1626_1673del mutation detected by using Sanger dideoxy sequencing. Patient 11 has a large homozygous deletion of exons 5 to 14 detected by means of targeted exon-focused array comparative genomic hybridization analysis (GeneDx, Gaithersburg, Md). Allergy history was obtained for each patient either after transplantation (patients 1-6) or both before and after transplantation (patients 7-12). Patients with known clinical food allergy were counseled to continue strict avoidance of known food allergens. Skin prick testing was performed to 8 common food allergens at posttransplantation follow-up visits for 3 retrospectively studied patients (Table E1). In the prospectively studied patients, skin prick testing to the same panel was performed both before transplantation and at posttransplantation follow-up visits. Additionally, prick-to-prick testing with fresh kiwi was performed in patient 12 after transplantation. The largest and orthogonal wheal-and-flare diameters were measured in millimeters after 15 minutes for respective allergen skin prick tests performed by using skin picks and allergen extracts from Greer Laboratories (Lenoir, NC). A histamine positive control and a glycerin negative control were applied during each skin prick test encounter. Results were considered positive if mean wheal diameter was 3 mm
J ALLERGY CLIN IMMUNOL nnn 2015
greater than that elicited by the negative control. Mean wheal value was calculated as follows: D1d/2 (Table E1). Plasma or sera were prepared from venous blood and stored at 2808C until analyzed for allergen-specific IgE antibodies by using Phadia’s ImmunoCAP System, per the manufacturer’s instructions. Specific IgE levels to the following food allergens were quantitated: egg white, milk, wheat, peanut, and walnut. Where indicated, kiwi-, lentil-, or shrimp-specific IgE levels were also measured. Patients who approached the 50% positive predictive value of food-specific IgE testing were advised to seek the care of a local allergist for further evaluation with possible food challenge, which was unavailable at the NIH Clinical Center. No patients have done this to date. The Department of Laboratory Medicine at the National Institutes of Health Clinical Center is certified under the Clinical Laboratory Improvement Amendments of 1988 and performed total serum IgE and donor chimerism assays. Total IgE levels were measured by using a chemiluminescent immunometric assay on the Siemens IMMULITE 2000 XPI (Siemens Healthcare Diagnostics, Flanders, NJ). Donor chimerism was measured by using predetermined differences in short tandem repeats to quantitate the proportion of donor nucleated cells in samples obtained from transplant recipients. The assay can consistently measure 5% to 95% donor chimerism with an SD of 65%. REFERENCES E1. Jing H, Zhang Q, Zhang Y, Hill BJ, Dove CG, Gelfand EW, et al. Somatic reversion in dedicator of cytokinesis 8 immunodeficiency modulates disease phenotype. J Allergy Clin Immunol 2014;133:1667-75. E2. Engelhardt KR, McGhee S, Winkler S, Sassi A, Woellner C, Lopez-Herrera G, et al. Large deletions and point mutations involving the dedicator of cytokinesis 8 (DOCK8) in the autosomal-recessive form of hyper-IgE syndrome. J Allergy Clin Immunol 2009;124:1289-302.e4. E3. Cuellar-Rodriguez J, Freeman AF, Grossman J, Su H, Parta M, Murdock H, et al. Matched related and unrelated donor hematopoietic stem cell transplantation for DOCK8 deficiency. Biol Blood Marrow Transplant 2015;21:1037-45.
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TABLE E1. Skin prick testing to selected food allergens in DOCK8-deficient patients before and after HSCT Egg white Patient no. 2 4 5 Pre-HSCT ND ND ND Post-HSCT evaluation 1 15.5 (6) Negative (25) Negative (15) (months after HSCT) Post-HSCT evaluation 2 Negative (37) (months after HSCT) Milk Patient no. 2 4 5 Pre-HSCT ND ND ND Post-HSCT evaluation 1 19.5 (6) Negative (25) Negative (15) (months after HSCT) Post-HSCT evaluation 2 Negative (37) (months after HSCT) Soy Patient no. 2 4 5 Pre-HSCT ND ND ND Post-HSCT evaluation 1 5 (6) Negative (25) Negative (15) (months after HSCT) Post-HSCT evaluation 2 Negative (37) (months after HSCT) Wheat Patient no. 2 4 5 Pre-HSCT ND ND ND Post-HSCT evaluation 1 9 (6) Negative (25) Negative (15) (months after HSCT) Post-HSCT evaluation 2 Negative (37) (months after HSCT) Peanut Patient no. 2 4 5 Pre-HSCT ND ND ND Post-HSCT evaluation 1 Negative (6) 11 (25) Negative (15) (months after HSCT) Post-HSCT evaluation 2 8 (37) (months after HSCT) Walnut Patient no. 2 4 5 Pre-HSCT ND ND ND Post-HSCT evaluation 1 Negative (6) Negative (25) Negative (15) (months after HSCT) Post-HSCT evaluation 2 Negative (37) (months after HSCT) Cashew Patient no. 2 4 5 Pre-HSCT ND ND ND Post-HSCT evaluation 1 18.5 (6) Negative (25) Negative (15) (months after HSCT) Post-HSCT evaluation 2 Negative (37) (months after HSCT) Shrimp Patient no. 2 4 5 Pre-HSCT ND ND ND Post-HSCT evaluation 1 Negative (6) Negative (25) 7 (15) (months after HSCT) Post-HSCT evaluation 2 Negative (37) Negative (24) (months after HSCT) Kiwi, green pulp Patient no. 12 Pre-HSCT ND Post-HSCT 7.5 (3) (months after HSCT)
7 Negative 10 (6)
8* 21
12 (11)
7 Negative Negative (6)
8* 21.5
Negative (11)
7 Negative Negative (6)
8* Negative
Negative (11)
7 Negative Negative (6)
8* 16.5
Negative (11)
7 4.5 3 (6)
Negative (11)
5 (10)
9 6 Negative (6)
10 Negative Negative (7)
6 (12)
Negative (10)
10 Negative Negative (7)
4 (12)
Negative (10)
9 12 5 (6)
10 8.5 6 (7)
4.5 (12)
Negative (10)
9 6 5 (6)
10 9.5 6 (7)
4 (12)
Negative (10)
10 Negative Negative (7)
11 Negative Negative (6)
12 3 8 (3)
11 12 Negative 3.5 Negative (6) Negative (3)
11 12 Negative Negative Negative (6) Negative (3)
11 12 Negative Negative Negative (6) Negative (3)
11 12 Negative Negative Negative (6) Negative (3)
11 12 Negative Negative Negative (6) Negative (3)
Negative (12) Negative (10)
8* Negative
Negative (11)
7 Negative Negative (6)
5 (12)
8* 9 Negative Negative Negative (6)
3 (11)
7 9.5 Negative (6)
10 9.5 15 (7)
8* 9 Negative Negative Negative (6)
Negative (11)
7 Negative Negative (6)
9 12.5 7 (6)
9 15 9 (6)
10 Negative 3 (7)
11 12 Negative 3 Negative (6) Negative (3)
Negative (12) Negative (10)
8* 9
9 Negative Negative (6)
10 Negative Negative (7)
11 12 Negative Negative Negative (6) Negative (3)
Negative (12) Negative (10)
(Continued)
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TABLE E1. (Continued ) Kiwi, white pulp Patient no. Pre-HSCT Post-HSCT (months after HSCT)
12 ND 12.5 (3)
Mean wheal diameters are listed in millimeters. Parentheses contain the number of months after HSCT, when measured. Boldface indicates sensitization. *The patient died less than 3 months after HSCT, and no repeat skin prick tests were performed.
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TABLE E2. Food-specific IgE levels in DOCK8-deficient patients before and after HSCT Egg-specific IgE (IU/mL) Patient no. 1 Pre-HSCT 5.76 Post-HSCT evaluation 1 <0.1 (12) (months after HSCT) Post-HSCT evaluation 2 (months after HSCT) Milk-specific IgE (IU/mL) Patient no. 1 Pre-HSCT 38 Post-HSCT evaluation 1 2.99 (12) (months after HSCT) Post-HSCT evaluation 2 (months after HSCT) Wheat-specific IgE (IU/mL) Patient no. 1 Pre-HSCT 5.38 Post-HSCT evaluation 1 0.36 (12) (months after HSCT) Post-HSCT evaluation 2 (months after HSCT) Peanut-specific IgE (IU/mL) Patient no. 1 Pre-HSCT 0.3 Post-HSCT evaluation 1 <0.1 (12) (months after HSCT) Post-HSCT evaluation 2 (months after HSCT) Walnut-specific IgE (IU/mL) Patient no. 1 Pre-HSCT 0.18 Post-HSCT evaluation 1 <0.1 (12) (months after HSCT) Post-HSCT evaluation 2 (months after HSCT) Lentil-specific IgE (IU/mL) Patient no. 1 Pre-HSCT 13.6 Post-HSCT 2.06 (12) (months after HSCT) Shrimp-specific IgE (IU/mL) Patient no. 5 Pre-HSCT <0.1 <0.1 (15) Post-HSCT (months after HSCT) Kiwi-specific IgE (IU/mL) Patient no. 12 Pre-HSCT 22.3 Post-HSCT 2.74 (3) (months after HSCT)
2 3 4 5 6 7 52.5 21.7 3.39 <0.1 <0.1 5.08 9.49 (12) <0.1 (7) 0.35 (25) <0.1 (15) <0.1 (14) 5.65 (6) 8.63 (23)
9.18 (23)
0.89 (23)
8* 17
0.93 (11)
11 12 <0.1 8.82 <0.1 (6) 0.37 (3)
9 12.8 0.88 (6)
10 25.4 6.92 (7)
11 12 <0.1 28.5 <0.1 (6) 1.64 (3)
9 15.3 0.53 (6)
10 18.6 5.18 (7)
11 12 <0.1 0.78 <0.1 (6) 0.18 (3)
<0.1 (12) 1.5 (10)
8* 36
9 0.58 0.62 (6)
10 22.8 5.12 (7)
11 12 <0.1 1.09 <0.1 (6) <0.1 (3)
0.33 (12) 1.38 (10)
2.01 (11)
2 3 4 5 6 7 3.79 0.51 <0.1 <0.1 <0.1 5.95 1.05 (12) <0.1 (7) <0.1 (25) <0.1 (15) <0.1 (14) 1.3 (6)
10 46.6 17.4 (7)
<0.1 (12) 4.43 (10)
1.19 (11)
2 3 4 5 6 7 >100 9.09 21.5 <0.1 <0.1 5.01 35.4 (12) <0.1 (7) 1.07 (25) <0.1 (15) <0.1 (14) 2.37 (6) 21.7 (23)
8* 99.1
5.13 (11)
2 3 4 5 6 7 31.3 3.85 5.68 <0.1 <0.1 5.72 11.2 (12) <0.1 (7) 0.37 (25) <0.1 (15) <0.1 (14) 1.72 (6)
9 14.7 0.39 (6)
<0.1 (12) 5.45 (10)
3.58 (11)
2 3 4 5 6 7 >100 29.2 0.16 <0.1 <0.1 6.95 72.6 (12) <0.1 (7) <0.1 (25) <0.1 (15) <0.1 (14) 6.22 (6) 51 (23)
8* >100
8* 1.45
9 <0.1 0.3 (6)
10 3.06 0.81 (7)
0.21 (12) 0.19 (10)
Parentheses contain the number of months after HSCT, when measured. Boldface indicates sensitization at levels of 0.35 IU/mL or greater. *Patient 8 died less than 3 months after HSCT, and no follow-up serum IgE testing was performed.
11 12 <0.1 0.37 <0.1 (6) <0.1 (3)
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TABLE E3. Donor chimerism in peripheral whole blood and bone marrow of DOCK8-deficient patients after HSCT
Patient no.
1 2 3 4 5 6 7 8* 9 10 11 12
Peripheral whole blood donor chimerism (months after HSCT at most recent test)
100% 100% 100% 100% 100% 100% 100% 100% 100% 100% 100% 100%
(24) (23) (12) (24) (24) (23) (11) (1) (12) (10) (6) (3)
*Patient died less than 3 months after HSCT.
Bone marrow donor chimerism (months after HSCT at most recent test)
98% (12) 96% (12) 94% (12) 97% (25) 94% (24) 95% (23) 97% (11) Not done 91% (12) 96% (10) Not yet performed Not yet performed