| Background:APDS is a rare autosomal dominant immune deficiency with recurrent respiratory tract infection,hepato-splenic lymphadenopathy,persistent Epstein-Barr virus and/or cytomegaloviremia as the main clinical manifestations.According to different mutated genes,it can be divided into APDS1(PIK3CD gene mutation)and APDS2(PIK3R1 gene mutation).APDS was first reported in 2013 and included in the classification of primary immunodeficiency diseases for the first time in 2015 by the International Federation of Immunological Societies.Objective:Improve the understanding of this kind of disease,early recognition,early diagnosis and intervention,reduce misdiagnosis,missed diagnosis,improve long-term prognosis Methods:Two cases of children with recurrent respiratory tract infection and hepato-splenic lymph node enlargement suspected of immunodeficiency were selected,and the clinical data of these two cases were retrospectively summarized and analyzed.Meanwhile,gene sequencing was conducted on the children and their immediate family members using second-generation sequencing technology to find out the possible pathogenic genes consistent with the clinical manifestations,and the first-generation sequencing method was used for verification.According to the clinical data and genetic test results of the children and their immediate relatives,the relevant literatures were searched and reviewed in China journal full-text database with the keywords "PI3K-δ overactivation syndrome" or "P13K-δ activation syndrome" or "PIK3CD gene" or "PIK3R1 gene"."Pi3kδhyperactivation syndrome" or "APDS" or "PIK3CD" or "PIK3R1" were used to search the relevant literature in Pub Med database,and the clinical characteristics,genetic characteristics and treatment methods of patients with APDS were summarized.Results:1.Case report:(1)Case 1,a 10-year-old male,was admitted to our hospital for the first time on April28,2022 due to repeated fever for more than 3 months,aggravation and cough for more than 10 days.Parotid gland enlargement at the beginning of the disease,after many times accompanied by neck lymph node enlargement,anti-infection treatment is effective.More than 20 days ago,the patient was discharged from hospital for improvement due to severe pneumonia,Epstein-Barr virus infection and hypogammaglobulinemia.The patient had a history of recurrent respiratory tract infections,5-7 times per year.Admission to the hospital for physical examination: body thin,neck can reach 2 peanut size lymph nodes,toughness,tenderness.Pharyngeal congestion.Rough breathing sounds in both lungs,wet rales can be heard in the left.The abdomen is soft,1cm below the liver and ribs,soft without tenderness,2cm below the spleen and ribs,soft without tenderness.Auxiliary test: Epstein-Barr virus antibody Ig M,Ig G positive;Blood Ig G < 1.53g/L;Fine lymphocyte classification: CD4+T cells decreased,CD8+T cells increased,CD4+/CD8 +T cell ratio 0.57,memory B cells decreased,immature B cells increased.Piperacillin sodium tazobactam sodium,ganciclovir anti-infection,intravenous supplementation of gamma globulin improved discharge.After discharge,gene results showed that PIK3 CD gene had A heterozygous mutation c.3061G>A(AD).Combined with the mother’s history of repeated respiratory tract infection and bronchiectasis,the final diagnosis was PI3K-δ hyperactivation syndrome type1(APDS1).The patient was treated with rapamycin by oral administration.The general condition of the patient was OK,the enlarged liver and spleen retreated to normal,and no severe infection has been found.The Ig G level fluctuated between 5 and 6g/L.(2)Case 2,male,12 years old in October,was admitted to our department on August1,2021 due to "repeated respiratory tract infection,neck mass,hepatosplenomegaly for more than 9 years".The patient suffered from repeated respiratory tract infection since childhood and intermittent thrombocytopenia(2012-2015),which was obvious during fever,and the platelets could recover slowly after the body temperature was normal.In April 2015,he was hospitalized in the pediatric hematology Department of our hospital for "thrombocytopenia and Epstein-Barr virus infection".In May 2015,tonsil and adenoid extraction was performed in the otolaryngology department of our hospital due to "tonsil and adenoid hypertrophy".In January 2018,he received electronic fiberbronchoscopy in the children’s respiratory Department of our hospital for "lobar pneumonia".Admitted to hospital for physical examination: emaciated body,old rash scattered all over the body,several crater-like skin lesions in both lower limbs.There are several enlarged lymph nodes in the bilateral neck and axilla.The mucosa of the pharynx is congested,and the tonsils are absent.The breathing sounds in both lungs are rough.The abdomen is soft,1cm below the liver and ribs,soft without tenderness,2cm below the spleen and ribs,soft without tenderness.Laboratory examination: Epstein-Barr virus antibody Ig M,Ig G positive;Blood Ig G 22.5g/L,blood Ig M 5.24g/L,blood Ig E > 2500.0IU/m L;Antinuclear antibody(granular 1:10000,homogeneity 1:3200),antinucleosome antibody 2+,anti-SSA antibody+,anti-neutrophil cytoplasmic antibody +;Coombs test +;Fine lymphocyte classification:CD4+T cells decreased,initial CD4+T cells decreased,CD8+T cells increased,CD4+T/CD8+T ratio 0.76,immature B lymphocytes increased;Auxiliary examination:Neck CT showed multiple enlarged lymph nodes,abdominal ultrasound showed large liver and spleen,and the chest film showed patches of increased density in the right lower lung field.The characteristics of the patients were summarized as follows: repeated infection,lymphoid hyperplasia,autoimmune phenomenon(history of ITP,multiple positive autoantibodies),repeated rash,significant increase of multiple EBV antibodies,and multisite biopsy(tonsil,adenoid,lung tissue)indicating T-cell lymphoproliferative disease.The clinical diagnosis of immunodeficiency was highly suspected.Genetic tests were performed,and piperacillin sodium tazobactam sodium,ganciclovir anti-infection and gamma globulin immunosupportive treatment improved and the patient was discharged.The results showed that PIK3 CD gene had A spontaneous heterozygous mutation c.3061G>A(AD).The final diagnosis was APDS1 type,chronic active EBV infection,EBV-associated lymphoproliferative disease,and pneumonia.Allogeneic bone marrow hematopoietic stem cell transplantation and oral rapamycin therapy are recommended.Due to family economic reasons,the patient did not receive hematopoietic stem cell transplantation or oral rapamycin,and did not go to the clinic for follow-up after discharge.In October 2022,she was hospitalized for severe pneumonia,pulmonary fungal infection,and otitis media,and was discharged after 10 days of improvement.It is now lost to followup.2.Literature review:A total of 45 literatures with complete clinical data and genetic information were detected,including 15 Chinese literatures and 30 English literatures,including 156 patients.The clinical data of these patients were systematically summarized.(1)Clinically relevant data: the median age of onset was 2 years,the median age of diagnosis was 10 years;The most common clinical manifestations of APDS were repeated respiratory tract infection(94%),bronchiectasis was complicated in 38.8% of patients,Haemophilus influenzae and Streptococcus pneumoniae(50.1%)were the most common pathogens,Epstein-Barr virus infection accounted for 53.9%.Other common clinical manifestations included enlargement of the liver and spleen(36.6%),enlargement of lymph nodes(40.3%),recurrent diarrhea,hematochezia(30%),rash,etc.About 45% of patients would develop autoimmune related diseases(immune thrombocytopenia,hypothyroidism,systemic lupus erythematosus,arthritis,Kawasaki disease,etc.).(2)Immunological phenotype: serum Ig M level was elevated in most children with APDS,and serum Ig G level was lower than normal.CD4+ T cells decreased,CD8+T cells increased,CD4+/CD8+T cell ratio was inverted,terminal differentiation effector T cells increased,total B cells and memory B cells decreased,initial B cells,immature B cells and transitional B cells increased.(3)Genetic data: At present,there are two mutations in APDS:(1)PIK3CD gene mutation(about 80%)was the most common mutation,including 20 PIK3 CD gene mutation sites,among which c.3061G>A(p.E1021K)was the most common mutation site,with an incidence of about 81%.Other mutation sites were c.1574A>G(p.E525G),c.241G>A(p.E81K),c.371G>A(p.G124D),c.1002C>A(p.N334K),c.1213C>T(p.R405C),etc.(2)PIK3R1 gene mutation(about 20%),79% of the mutation sites were C.1425+1 G >(A,c,T)(p.434-475del),A few other mutation sites include c.1425+2 T >(A,G),c.1425+2＿1425+3del TG,c.13-1 G > C,etc.(4)Treatment: The main treatment methods for APDS include anti-infective symptomatic therapy,immunoglobulin replacement therapy,and hematopoietic stem cell transplantation for some patients.Other immunosuppressants such as hormones and rituximab are also used in the treatment of APDS.In addition,the m TOR inhibitor rapamycin acting on PI3 K signaling pathway can partially restore the function of T lymphocytes in APDS patients,and improve the liver,spleen and lymph node enlargeement in the children.Other selective PI3Kδ inhibitors are currently under clinical investigation.Conclusion:1.APDS is a rare autosomal dominant immune deficiency disease with clinical manifestations of repeated respiratory tract infection,hepato-splenic lymphadenopathy,viral infection/sepsis(Epstein-Barr virus,CMV),and autoimmune phenomena.The main mutant gene is PIK3 CD gene.2.In this paper,the diagnosis of APDS in two cases was clear according to clinical manifestations and genetic test results.For patients with repeated clinical manifestations of respiratory tract infection,hepato-splenic lymphadenopathy,Epstein-Barr virus infection,and abnormal immunological indexes,attention should be paid to early genetic test,which is helpful for definite diagnosis.3.The main treatments for APDS include anti-infective symptomatic therapy,immunoglobulin replacement therapy,immunosuppressive agents and hematopoietic stem cell transplantation.Rapamycin,a m TOR inhibitor targeting the PI3 K signaling pathway,can partially relieve severe lymphoid hyperplasia.Other selective PI3kδ inhibitors are currently in clinical studies. |
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