To the Editor :

Autoimmune lymphoproliferative syndrome (ALPS) is characterized by defective apoptotic mechanisms and altered lymphocyte homeostasis.1, 2 We report a pediatric patient who was diagnosed with probable ALPS, but his symptoms did not improve despite 2 years of immunosuppressive therapy. He was ultimately diagnosed with and treated for Bartonella henselae endocarditis after which his ALPS‐like features resolved.

An 8‐year‐old Caucasian male with history of pulmonary atresia repaired in infancy was hospitalized for atypical pneumonia, splenomegaly, and pancytopenia (Figure 1A,B). His pneumonia resolved with antibiotics, but he continued to have intermittent fevers, persistent fatigue, splenomegaly, and pancytopenia. Subsequent bone marrow evaluation was normal, and he was found to have elevated total serum IgG of 3038 mg/dL (normal 660–1530 mg/dL) and low CD3⁺, CD4⁺, and CD8⁺ T‐cell counts (490, 359, and 147 cell/mcL, respectively). Antiplatelet and antineutrophil antibodies were detected, so he was started on prednisone for a diagnosis of the Evan syndrome. One week later, he developed posterior reversible encephalopathy syndrome and acute renal failure. Complement levels were low, and renal biopsy revealed diffuse sclerosing and crescentic immune complex glomerulonephritis (Figure S1). He was started on mycophenolate mofetil and weaned off steroids. ALPS immunophenotypic evaluation sent prior to initiation of immunosuppression showed elevated α/β double negative T cells (DNTs) at 2.2% of total lymphocytes (nml < 1.5%). Chromosomal microarray, next‐generation sequencing, and deletion/duplication panel for ALPS and ALPS‐like mutations, and whole exome sequencing did not identify a genetic etiology. Clinical and laboratory evaluation led to a diagnosis of probable ALPS. His kidney function and complement levels normalized on mycophenolate mofetil but he continued with fatigue, intermittent fevers, splenomegaly, and pancytopenia.

By age 10, the patient had gained no weight for 2 years, dropping from 37th to <3rd percentile of weight (Figure 1C). With persistent cytopenias, he was bridged from mycophenolate mofetil to sirolimus. Seven days later, he was admitted for fever and worsening fatigue and cytopenias. Echocardiogram revealed vegetation in the bilateral branch pulmonary arteries (Figure S1). Retrospective review of routine echocardiograms performed at ages 8 and 9 demonstrated antecedent but previously unappreciated changes including "redundant tissue" in the pulmonary conduit and conduit valve thickening. Multiple blood cultures were negative. Further history revealed that the patient had frequent contact with his grandmother's kittens. Bartonella henselae serum IgG titers were markedly elevated at a dilution of >1:1024 and blood B. henselae polymerase chain reaction (PCR) test was positive. The patient was treated with parenteral ceftriaxone and gentamicin followed by prolonged oral therapy with doxycycline and rifabutin. His energy, appetite, weight, splenomegaly, and pancytopenia subsequently improved (Figure 1A‐C). Repeat blood Bartonella PCR tests at 4‐ and 10‐week posttreatment initiation were negative. Repeat ALPS panel sent 5 months after initiation of antibiotic treatment showed normalization of DNT percentage to 0.7% of total lymphocytes, and FAS‐mediated apoptosis assay was normal. At age 11, after 12 months of antibiotics, the patient underwent pulmonary artery conduit replacement. PCR testing of tissue adherent to the pulmonary conduit was positive for Bartonella . His weight and cell counts remain improved and splenomegaly has not recurred despite discontinuation of antibiotics and immunosuppression.

This case illustrates that chronic Bartonella endocarditis can mimic clinical and immunologic findings of ALPS. Clinical features of ALPS include lymphadenopathy, splenomegaly, hepatomegaly, autoimmune hemolytic anemia, immune‐mediated thrombocytopenia, neutropenia, and glomerulonephritis.2 Diagnosis is challenging given that features may overlap with many other conditions including chronic infections.2 Bartonella endocarditis, first described in 1993, has been recognized as the second leading cause of blood culture–negative endocarditis in France.3 The clinical presentation is typically subacute to chronic with prolonged fatigue, fever, and weight loss. Associated findings can include splenomegaly, hepatomegaly, digital clubbing, thromboembolic phenomena, cytopenia, and glomerulonephritis.4, 5 Diagnosis is achieved by detection of extremely high serum Bartonella IgG antibody titers and positive PCR from valve/vegetation tissue.

Our patient's clinical course was defined by a protracted 2‐year period of fatigue, failure to gain weight, splenomegaly, immune‐mediated cytopenia, and glomerulonephritis. He met criteria for probable ALPS diagnosis by the presence of both required criteria (chronic splenomegaly and elevated DNT cells) and one of the secondary accessory criteria (autoimmune cytopenias with elevated serum IgG levels).2, 6 While his renal disease improved following initiation of mycophenolate mofetil, the remainder of his clinical features persisted until sirolimus was initiated, at which time he experienced a clinical worsening that led to the discovery of his pulmonary conduit vegetations and ultimate diagnosis of Bartonella endocarditis by both serology and PCR. Following initiation of treatment for Bartonella endocarditis, his weight, pancytopenia, and splenomegaly rapidly resolved. In addition, his DNT cell elevation resolved and his ALPS‐like illness features have remained absent following discontinuation of both antimicrobial and immunosuppressive therapy.

Because of the rapidity of his clinical improvement and resolution of his ALPS symptoms, signs, and laboratory findings, we conclude that the entirety of his presentation was due to a prolonged disease course with Bartonella endocarditis. To our knowledge, this is the first reported case of Bartonella endocarditis mimicking the immunophenotypic manifestations of ALPS. Physicians and caregivers of patients with ALPS and other immune dysregulatory disorders should consider Bartonella endocarditis in the differential diagnosis of new‐onset or exacerbations of existing immune dysregulation.

致编辑：

自身免疫性淋巴组织增生综合征（ALPS）的特征是凋亡机制缺陷和淋巴细胞稳态改变。1，2我们报道了一名儿科患者，其被诊断为可能患有ALPS，但尽管进行了2年的免疫抑制治疗，其症状仍未改善。最终他被诊断出患有汉氏巴尔通体心内膜炎并接受了治疗，此后他的ALPS样特征得以解决。

一名8岁的白人婴儿，其肺部闭锁史在婴儿期得到修复，因非典型肺炎，脾肿大和全血细胞减少而住院（图1A，B）。他的肺炎通过抗生素解决，但他继续出现间歇性发烧，持续疲劳，脾肿大和全血细胞减少症。随后的骨髓评估正常，发现他的总血清IgG升高了3038 mg / dL（正常660–1530 mg / dL），而CD3 ⁺，CD4 ⁺和CD8 ⁺较低T细胞计数（分别为490、359和147细胞/ mcL）。由于检测到抗血小板和抗中性粒细胞抗体，因此他开始使用泼尼松来诊断埃文氏综合症。一周后，他患上了后可逆性脑病综合征和急性肾衰竭。补体水平低，肾活检显示硬化性弥漫性硬化和新月型免疫复合物肾小球肾炎（图S1）。他开始服用霉酚酸酯，并断掉了类固醇激素。在开始免疫抑制之前进行的ALPS免疫表型评估显示，总淋巴细胞的2.2％（nml <1.5％）的α/β双阴性T细胞（DNT）升高。染色体微阵列，下一代测序以及针对ALPS和ALPS样突变的缺失/重复面板以及整个外显子组测序均未发现遗传病因。临床和实验室评估导致可能的ALPS的诊断。他的肾功能和补体水平在霉酚酸酯上恢复正常，但继续出现疲劳，间歇性发烧，脾肿大和全血细胞减少。

到10岁时，该患者在2年内没有体重增加，从体重的37％下降到<3％（图1C）。患有持续的血细胞减少症，他从霉酚酸酯桥接到西罗莫司。7天后，他因发烧，疲劳加剧和血细胞减少而入院。超声心动图显示双侧分支肺动脉中有植被（图S1）。回顾性回顾了在8岁和9岁时进行的常规超声心动图检查，发现之前但未曾意识到的变化包括肺导管中的“冗余组织”和导管瓣膜增厚。多次血培养均为阴性。进一步的历史表明，该患者经常与祖母的小猫接触。亨氏巴尔通体稀释度> 1：1024时，血清IgG滴度显着升高，并且血B. henselae聚合酶链反应（PCR）测试呈阳性。该患者接受了胃肠外头孢曲松和庆大霉素的治疗，随后接受了强力霉素和利福布汀的长期口服治疗。随后，他的精力，食欲，体重，脾肿大和全血细胞减少症得到改善（图1A-C）。重复抽血巴尔通体治疗开始后4周和10周的PCR测试均为阴性。抗生素治疗开始后5个月发送的ALPS复查组显示DNT百分比正常化至总淋巴细胞的0.7％，FAS介导的凋亡测定正常。在抗生素使用12个月后，患者11岁时接受了肺动脉导管置换。肺导管粘连组织的PCR检测为巴尔通体阳性。尽管停止使用抗生素和免疫抑制，他的体重和细胞计数仍保持改善，脾肿大并未复发。

该病例说明慢性巴尔通体心内膜炎可以模仿ALPS的临床和免疫学发现。ALPS的临床特征包括淋巴结病，脾肿大，肝肿大，自身免疫性溶血性贫血，免疫介导的血小板减少症，中性粒细胞减少和肾小球肾炎。2由于特征可能与许多其他情况（包括慢性感染）重叠，因此诊断具有挑战性。2 巴尔通体心内膜炎最早于1993年描述，在法国已被认为是血液培养的第二大主要原因-阴性心内膜炎。3临床表现通常是亚急性的，伴有长期的疲劳，发烧和体重减轻。相关的发现可能包括脾肿大，肝肿大，指状棍，血栓栓塞现象，血细胞减少和肾小球肾炎。4，5通过检测极高的血清Bartonella IgG抗体滴度和来自瓣膜/植物组织的阳性PCR来进行诊断。

我们患者的临床病程由长期的2年疲劳，体重减轻，脾肿大，免疫介导的血细胞减少和肾小球肾炎定义。通过同时存在必需的标准（慢性脾肿大和DNT细胞升高）和次要的辅助标准之一（血清IgG水平升高的自身免疫性血细胞减少症），他达到了可能的ALPS诊断标准。2，6虽然他的霉酚酸酯引起的肾脏疾病有所改善，但他的其余临床特征一直持续到西罗莫司开始使用，这时他经历了临床恶化，导致发现了他的肺导管赘生物并最终诊断为巴尔通体通过血清学和PCR检测心内膜炎。开始治疗巴尔通体心内膜炎后，他的体重，全血细胞减少症和脾肿大迅速消失。此外，在停用抗微生物和免疫抑制治疗后，他的DNT细胞升高得以缓解，ALPS样疾病特征仍然消失。

由于他的临床改善迅速并且他的ALPS症状，体征和实验室检查结果得以解决，因此我们得出的结论是，他的整个报告归因于Bartonella心内膜炎的病程延长。据我们所知，这是第一例报道的巴尔通体心内膜炎，其模仿了ALPS的免疫表型。ALPS和其他免疫失调性疾病患者的医师和护理人员在新发或现有免疫失调加剧的鉴别诊断中应考虑Bartonella心内膜炎。