Epidemiology, Management, and Treatment Access of Hereditary Angioedema in the Asia Pacific Region: Outcomes From an International Survey.

BACKGROUND: Hereditary angioedema (HAE) is a rare genetic disease with significant morbidity and mortality for which early diagnosis and effective therapy are critical. Many Asia Pacific (AP) countries still lack access to diagnostic tests and evidence-based therapies. Epidemiologic data from the AP is needed to formulate regional guidelines to improve standards of care for HAE. OBJECTIVE: To investigate the estimated minimal prevalence, needs, and potential interventions for the diagnosis and management of HAE in the AP. METHODS: A structured questionnaire was distributed to representative experts from member societies of the Asia Pacific Association of Allergy, Asthma and Clinical Immunology. Patient profiles and the presence of diagnostic facilities or tests, regional and national HAE guidelines, and patient support groups were reported and compared. RESULTS: Completed questionnaires were received from 14 representatives of 12 member countries and territories, representing 46% of the world population. Overall minimal prevalence of HAE in the AP region was 0.02/100,000 population, with significant heterogeneity across different centers. Only one-half and one-third had registered on-demand and prophylactic medications, respectively. Few had patient support groups (58%) or regional guidelines (33%), and their existence was associated with the availability of HAE-specific medications. Availability of C1-inhibitor level testing was associated with a lower age at HAE diagnosis (P = .017). CONCLUSIONS: Hereditary angioedema in the AP differs from that in Western countries. Hereditary angioedema-specific medications were registered in only a minority of countries and territories, but those with patient support groups or regional guidelines were more likely to have better access. Asia Pacific-specific consensus and guidelines are lacking and urgently needed.

Cytomegalovirus Pneumonia in a Patient with X-Linked Agammaglobulinemia: A Case Report.

X-linked agammaglobulinemia (XLA) is a hereditary immune disorder that predisposes patients to frequent and severe bacterial infections caused by encapsulated bacteria (such as Streptococcus pneumoniae, Staphylococcus aureus, and Haemophilus influenzae). Otitis media, sinusitis, and pneumonia are common complications of XLA that require prompt diagnosis and treatment. Cytomegaloviruses (CMV) cause widespread and severe infections in immunocompromised individuals, affecting the respiratory tract, and consequently, leading to pneumonia, which is associated with a high mortality rate. However, CMV-induced pneumonia is rarely reported in patients with XLA. This case study details a 37-year-old male patient with XLA presenting with fever, productive cough, and dyspnea. The patient was diagnosed with CMV pneumonia and recovered after treatment. To the best of our knowledge, this is the first reported case of CMV pneumonia in a patient with XLA in Taiwan. This case study emphasizes that CMV pneumonia in patients with XLA is a treatable condition if diagnosed promptly, and that a shorter duration of treatment with the antiviral agent, in combination with immunoglobulin replacement therapy, can resolve symptoms.

Unusual presentation of linear wrist blisters associated with hereditary angioedema: The first case report in Taiwan.

Hereditary angioedema (HAE) is an autosomal dominant disease characterized clinically by recurrent episodes of swelling in the tissues of the extremities, face, abdomen, and respiratory tract. It is most often caused by C1 esterase inhibitor (C1 INH) gene mutation. This swelling may lead to bradykinin release, resulting in recurrent, paroxysmal, painful angioedema. Blister formation is an uncommon cutaneous manifestation of HAE. Herein, we report a case of a patient with HAE who developed linear wrist blisters on her skin, with swelling, as a rare complication of HAE. She was treated with attenuated androgens (Danazol) for two weeks at our clinic, after which the blisters showed dramatic improvement. To date, only a few HAE cases have been reported across the world. Therefore, it is important to focus on and recognize the development of edema blisters as a flare of HAE, which could consequently avoid unnecessary dermatological diagnostic workup and treatment.

Unilateral generalized morphea: First case report in Taiwan.

Generalised morphea (GM) is a subtype of localised scleroderma that usually manifests with bilateral involvement. Unilateral generalised morphea (UGM) is a rare variant of GM. This is a case report of a Taiwanese girl with UGM over the left side of her body. She presented with hyperpigmentation, tightness, and skin atrophy over the left extremities and trunk. Mild range of motion (ROM) limitation over the left knee was also noted. At the clinic, the patient was given oral prednisolone, oral methotrexate (MTX), and oral D-penicillamine. topical emollient and topical glucocorticoids were also given. The dose of oral prednisolone was tapered gradually. All symptoms were improved under the treatment and regular rehabilitation program. To date, there is very little evidence to form the basis for treatment recommendations. This case report provides a treatment option for UGM in the paediatric group without the use of intravenous methylprednisolone pulse therapy.

Incidence and risk factors for recurrent Henoch-Schönlein purpura in children from a 16-year nationwide database.

BACKGROUND: The recurrence rate of Henoch-Schönlein purpura (HSP) is 2.7%-30%, with varied average intervals between the first and second episodes. Few studies have explored the incidence and risk factors for recurrent HSP. METHODS: We used a 16-year nationwide database to analyze the incidence of recurrent HSP. Patients with HSP were identified, and risk factors for recurrent HSP were explored. Kaplan-Meier and Cox regression model analyses were performed, and covariates were adjusted in the multivariate model. RESULTS: From January 1, 1997 to December 31, 2012, among 2,886,836 individuals in the National Health Insurance Research Database, 1002 HSP patients aged < 18 years were identified. Among them, 164 had ≥2 HSP episodes (recurrence rate, 16.4%; incidence of recurrent HSP, 7.05 per 100 person-years); 83.6% patients with one HSP episode remained free of secondary HSP. The average time intervals between the first and second and second and third HSP episodes were 9.2 and 6.4 months, respectively. After adjusting for demographic parameters, comorbidities, and socioeconomic status, recurrent HSP was found to occur more frequently in patients who had renal involvement (adjusted hazard ratio, 2.41; 95% confidence interval [CI], 1.64-3.54; p < 0.001), were receiving steroid therapy for > 10 days (adjusted hazard ratio, 8.13; 95%CI, 2.51-26.36; p < 0.001), and had allergic rhinitis (adjusted hazard ratio, 1.63; 95%CI, 1.06-2.50; p = 0.026). CONCLUSIONS: The annual incidence of recurrent HSP was low. However, children who had underlying allergic rhinitis, presented with renal involvement, and received steroid treatment for > 10 days should be notified regarding the possibility of recurrence.

Biphasic buckwheat anaphylaxis:Case report and systematic review.

Buckwheat anaphylaxis is commonly recognized in Europe and Asia, and there is only one case reported in Taiwan so far. Here, we report a case of biphasic buckwheat anaphylaxis in a 57 year-old male patient who lost consciousness twice in the same day after having buckwheat noodles. The serum test shows that Dermatophagoides pteronyssinus (Dp)immunoglobulin E (IgE) (42.4 kU/L) and buckwheat-specific IgE (81.5 kU/L) are unusually high. Although biphasic buckwheat anaphylaxis is rare, we should still be aware the second episode could be life-threatening and happen within a day after the exposure to the buckwheat antigen.

The risk of hospitalization for respiratory tract infection (RTI) in children who are treated with high-dose IVIG in Kawasaki Disease: a nationwide population-based matched cohort study.

BACKGROUND: Kawasaki disease (KD) is an immune-mediated systemic vasculitis, and infection plays an important role in the pathophysiology of KD. The susceptibility to infectious disease in patients with KD remains largely unclear. This study aimed to investigate the risk of respiratory tract infection (RTI)-related hospitalizations in children with KD. METHODS: Data from the Taiwanese National Health Insurance Research Database was analyzed. We excluded patients with history of congenital abnormality, allergic diseases, or hospitalization history. Children with KD were selected as KD group and age- and sex-matched non-KD patients were selected as control group with 1:4 ratio. Both cohorts were tracked for one year to investigate the incidences of RTI-related hospitalizations. Cox regression hazard model was used to adjust for confounding factors and calculate the adjusted hazard ratio (aHR). RESULTS: Between January 1996 and December 2012, 4,973 patients with KD were identified as the KD group and 19,683 patients were enrolled as the control group. An obviously reduced risk of RTI-related hospitalizations was observed in KD patients (aHR: 0.75, 95% CI [0.66-0.85]). The decreased risk persisted through the first six-months follow-up period with a peak protection in 3-6 months (aHR: 0.49, 95% CI [0.37-0.64]). CONCLUSIONS: KD patients had approximately half reduction of risk for RTI-related hospitalizations. The protective effects persisted for at least six months. Further studies are warranted to elucidate the entire mechanism and investigate the influences of intravenous immunoglobulin.

Exhaled nitric oxide helps discriminating asthmatic children with and without positive specific IgE to aeroallergens.

BACKGROUND: Aeroallergen sensitization may predict higher fractional exhaled nitric oxide (FeNO) levels. OBJECTIVE: We evaluate cut-off values of FeNO in asthmatic children with and without positive specific immunoglobulin E (IgE) to at least one of 5 aeroallergens (Dermatophagoides pteronyssinus, Dermatophagoides farinae, cat, dog, and cockroach). METHODS: 564 patients with asthma and allergic rhinitis (AR) aged 5 to 18 years were enrolled into two groups. Sensitized group included 378 children with positive IgE to at least one of 5 inhaled allergens. Non-sensitized group included 186 children. Pulmonary function tests, FeNO, eosinophil counts, and IgE levels were examined. Patients were divided into preschool age (5~6 years old), elementary school children (7~11 years old) and adolescents (12~18 years old). RESULTS: In preschool children, FeNO≥15.5 ppb differentiates between non-sensitized and sensitized groups. (sensitivity 54.3%; specificity 87.5%; positive predictive value (PPV) 86.2%; negative predictive value (NPV) 57.1%; area under receiver operating characteristic curve (AUC) 0.72) Among elementary school children, the cut-off value of FeNO≥19.5 ppb showed sensitivity 66.4%; specificity 85.8%; PPV 90.5%; NPV 55.7%; AUC 0.81. In adolescents, FeNO≥27.5 ppb showed sensitivity 60.2%; specificity 85.4%; PPV 91.2%; NPV 46.1%; AUC 0.76. CONCLUSION: In asthmatic children, aeroallergen sensitization appears to contribute to higher FeNO levels than those not sensitized. Cut-off values of FeNO which well discriminate asthmatic children with and without aeroallergen sensitization should be chose according to different ages.

Polymorphisms of EHF-ELF5 genomic region and its association with pediatric asthma in the Taiwanese population.

BACKGROUND: The EHF and ELF5 genes, located on chromosome 11p and linked to asthma phenotypes, are high-potential candidate genes conferring asthma susceptibility. The purpose of this study was to investigate the genetic association among single nucleotide polymorphisms (SNPs) of EHF and ELF5, and their relationship with asthma in the Taiwanese population. METHODS: We selected and performed genotyping on 16 SNPs that encompass the genomic region of EHF and ELF5 in Taiwanese children with or without asthma. A total of 1983 children, 523 in the test group and 619 and 842 in two validation groups, were recruited for this study. RESULTS: The SNP rs3910901, located in the 5' upstream region of ELF5, was found to have a weak association (p = 0.043) with asthma in the odds ratio analysis. The genotype distribution was similar in all comparison groups, but the CC genotype was more frequent in asthma patients. Logistic regression adjusted allergy comorbidity showed obviously diluted association. CONCLUSION: The results indicated that SNP rs3910901 may have a minor impact on pediatric asthma in the Taiwanese population.

Pachydermodactyly: Three new cases in Taiwan.

Pachydermodactyly (PDD), Greek for thick-skin-finger, is an infrequently recognized benign disorder characterized by painless fusiform swelling of the soft tissues around the proximal interphalangeal joints of the hands. Histopathologic features include increased dermal accumulation of collagen fibers. Young males are predominantly affected. PDD is quite rare with approximately 90 cumulative cases reported worldwide. We report three new cases of PDD in Taiwan, including two female patients. Except for patient 1 having the habit of cracking the knuckles, and patient 2 having a history of patent ductus ateriosus post catheterization, the histories of all three patients were unremarkable. X-ray of bilateral hands revealed no abnormal finding except for soft tissue swelling around proximal interphalangeal joints. Laboratory examinations all showed negative results. No local or systemic treatment was given to these patients to treat PDD, with the exception of non-steroidal anti-inflammatory drugs prescribed to one patient for a short period. Skin care with local irritation avoidance was explained to all three patients. The long-term outcome of PDD was benign.

Transitional cell carcinoma in a patient with X-linked hyperimmunoglobulin M syndrome.

Patients with X-linked hyperimmunoglobulin M syndrome (XHIGM) have a defective CD40-CD40 ligand system and further immunoglobulin class-switching. They may present with recurrent infection and malignancy involving the liver, pancreas or biliary tract. We report here a case of poorly differentiated transitional cell carcinoma in a young man with XHIGM even on regular treatment and discuss the possible pathogenesis. Given that the triggering of the CD40-CD40 ligand system has been found to improve tumor immunogenicity in recent studies, future immunotherapy targeting the CD40 ligand for these patients may be feasible to prolong their survival.

Unusual manifestations of Kawasaki disease with retropharyngeal edema and shock syndrome in a Taiwanese child.

We report a 3-year-old girl with Kawasaki disease who presented with retropharyngeal edema and shock syndrome. This is the first reported case in Taiwan. The patient initially presented with fever, cough, and pyuria followed by rapidly progressive enlarged bilateral cervical lymphadenopathy. On the third day of the fever, computed tomography for airway compression sign found widening of the retropharyngeal space mimicking a retropharyngeal abscess. Later, an endotracheal tube was inserted for respiratory distress. A skin rash over her trunk was also noted. On the fifth day of the fever, the clinical course progressed to hypotension and shock syndrome. Because of more swelling of bilateral neck lymph nodes, computed tomography was arranged again and revealed partial resolution of the edematous changes in the retropharyngeal space. Edema of the hands and feet, bilateral bulbar conjunctivitis, and fissured lips were subsequently found. The diagnosis of Kawasaki disease was confirmed on the eighth day of fever. There was no evidence of bacterial infection. She was administered intravenous immunoglobulin (2 mg/kg) and high dose aspirin (100 mg/kg/day). One day later, the fever subsided, and her blood pressure gradually became stable. Heart echocardiography on the Day 13 revealed dilated left coronary artery and mitral regurgitation. Follow-up echocardiography six months later showed normal coronary arteries. To date, the patient has not experienced any complications. This case illustrates that retropharyngeal edema and shock syndrome can be present in the same clinical course of Kawasaki disease. Clinicians and those who work in intensive care units should be aware of unusual presentations of Kawasaki disease to decrease rates of cardiovascular complications.

Cystic fibrosis: experience in one institution.

Cystic fibrosis (CF) is one of the most common autosomal recessive inherited disorders among Caucasians. Comparatively, it is considered to be a rare disease among Asians. To date, only a few cases of Taiwanese CF have been published. We report four CF cases from three families. Case 1 was the first report of CF associated with a homozygosity for the CF transmembrane conductance regulator gene (CFTR gene) mutation 3849+10kb C->T in a Taiwanese patient. Cases 2 and 3 had heterozygous c. 1898+5 G->T and heterozygous p. I1023R (novel mutation) for the CFTR gene mutation. Case 4 was homozygous for the CFTR gene mutation R553X being reported in 2005 and complicated with cor pulmonale. These four patients had received 300 mg bid aerosolized tobramycin treatment every other month.

Clinical features and genetic analysis of Taiwanese patients with the hyper IgM syndrome phenotype.

OBJECTIVES: Hyper IgM syndrome (HIGM), characterized by recurrent infections, low serum IgG and IgA, normal or elevated IgM, defective class switch recombination and somatic hypermutation, are heterogeneous disorders with at least 6 distinct molecular defects, including the CD40 ligand (CD40L) and the nuclear factor κB essential modulator (NEMO, also known as IKKγ) genes (both X-linked), the CD40, activation-induced cytidine deaminase (AICDA or AID), uracil-DNA glycosylase genes (autosomal recessive) and IκBα (IKBA) (autosomal dominant). Our objective was to determine the molecular basis and clinical features of Taiwanese patients with the HIGM phenotype. METHODS: Clinical manifestations and candidate genes were analyzed in a nationwide population-based study. RESULTS: Among 14 patients (12 unrelated families) since 2003, 10 patents were identified (8 families) with CD40L mutations, including 2 novel deletions of "A" nucleotide (Del 347A and Del 366A), both frameshift and stop at the 127th location; 1 novel AID deletion mutation lack of the 37thAsp and 38th Ser; 1 ataxia-telangiectasia mutation; and 1 deletion of chromosome 1q42. An adult-onset patient with mutant (Thr254Met)CD40L had approximately 30% detectable affinity and therefore less severity. Memory B cells decreased in patients with CD40L and activation-induced cytidine deaminase mutations. Three mortalities encompassed renal cell carcinoma in 1 patient with (Tyr169Asn)CD40L, pneumothorax in 1 with (Tyr140Stop)CD40L and pneumonia after chemotherapy in an ataxia-telangiectasia patient. One patient without detectable genetic defects but normal lymphocyte proliferation resembled the mild form of common variable immune deficiency phenotype. CONCLUSIONS: In contrast to those with AICDA mutation, small chromosome 1 q42 deletion and unknown genetic defect, the majority (10/14; 71.4%) with CD40L mutations except (Thr254Met) and an ataxia-telangiectasia patient had the severe form of HIGM phenotype.

Clinical manifestations and BTK gene defect in 4 unrelated Taiwanese families with Bruton's disease.

BACKGROUND AND OBJECTIVE: X-linked agammaglobulinemia (XLA, also called Bruton's disease) is is an X-linked recessive disorder characterized by recurrent bacterial infections, usually occurring in the first few years of life. Here, we report the results of a BTK gene mutation screening study that was performed in Taiwanese families with the BTK gene defect to further understand the inheritance patterns of XLA patients in Taiwan and to avoid new cases of XLA within families. MATERIALS AND METHODS: In this study, 52 members of 4 unrelated Taiwanese families with the BTK gene defect were enrolled. We studied the immunologic reports of 6 symptomatic living male patients with confirmed BTK gene defects and correlated the findings with their clinical symptoms. The genomic DNA of the subjects was subjected to direct sequencing mutation analysis. RESULTS: We screened 52 members of 4 unrelated Taiwanese families with the BTK gene defect for BTK gene mutation and found that there were 6 symptomatic living patients with a confirmed defect, 7 symptomatic deceased patients highly suspected to have had the defect and 11 asymptomatic female carriers. CONCLUSIONS: This is the first report in a series of the thorough screening for the BTK mutation and its carrier status in 4 unrelated Taiwanese families. One pedigree of our study comprises 4 generations. A complete BTK gene mutation study for the patient's family members is strongly suggested.

Distribution, clinical features and treatment in Taiwanese patients with symptomatic primary immunodeficiency diseases (PIDs) in a nationwide population-based study during 1985-2010.

Primary immunodeficiency diseases (PIDs) are a group of rare diseases with wide geographic and ethnic variations in incidence, prevalence, and distribution patterns. The aim of this study was to examine the distribution pattern and clinical spectrum of PIDs in Taiwan at a national referral institute. From 1985 to 2010, 215 patients from 183 families were diagnosed and grouped according to the updated classification of PIDs. Eighty-one (37.7%) patients had "other well-defined immunodeficiency syndromes", followed by "predominantly antibody deficiencies" (54 patients; 25.1%), "T- and B-cell immunodeficiencies" (34; 15.8%), "congenital defects of phagocytes" (25; 20.2%), "complement deficiencies" (15; 7.0%), and "disease in immune dysregulation" (5; 2.3%). The last category included two patients with Chediak-Higashi syndrome, and one each with familial hemophagocytosis, IPEX, and hypogammaglobulinemia and albinism. One female had cold-induced auto-inflammatory disease. There were no cases of "defects in innate immunity". Pseudomonas and Streptococcus pneumoniae were the two most identified microorganisms in septicemia (42.7%; 44/103 episodes). Stem cell transplantation was successful in 13 of 22 patients, while 34 patients (15.8%) died. Molecular defects were identified in 109 individuals (from 90 families). There were relatively fewer cases of "predominantly antibody deficiencies" due to there being only a few patients with adult-onset PIDs, implying certainty bias rather than ethnic variation. Awareness of under-diagnosis among physicians rather than pediatricians is vital for timely diagnosis and consequently adequate treatment.