Typhoid fever is a systemic infection caused by Salmonella enterica subsp. enterica serovar Typhi and occasionally Salmonella Paratyphi. Thrombocytopenia is relatively common in typhoid fever, with a reported incidence up to 26% in children. It has been classified as a marker of severity in typhoid fever and indicates a high risk for development of complications. Despite this, its pathophysiology and management in typhoid fever is not well established. We present a case of severe thrombocytopenia in a child with typhoid fever and we discuss the published literature.

伤寒是由沙门氏菌亚种、伤寒沙门菌、偶有甲型副伤寒沙门（氏）菌引起的全身性感染。血小板减少症常见于伤寒，据报道儿童发生率高达26%，是伤寒病情严重的指征之一，提示并发症高风险。虽然如此，血小板减少症在伤寒中的病理生理学和管理尚不完全明确。下述为伤寒儿童患者重度血小板较少症一例，并对已发表的文献予以讨论。

病例呈现

A 4-year-old Asian boy presented to the emergency department at a tertiary children’s hospital in Sydney, Australia, 1 day after returning from travel to Bangladesh with a persistent fever for 10 days. He had visited Bangladesh with his parents and stayed for 8 weeks. He had vomiting, diarrhea, and fever 3 weeks after arriving in Bangladesh, for which he was given oral ciprofloxacin for 3 days. The vomiting and diarrhea resolved after 1 week, but he continued to have intermittent fevers up to 38 °C (100.4 °F) for an additional 2 weeks. During the last 10 days of his stay in Bangladesh, his fever became persistent, with peaks of 40 °C (104 °F). He had reduced oral intake and constipation, but no vomiting. His mother reported that she had developed self-limited vomiting and diarrhea for a few days after the onset of his symptoms. The family denied eating street food or drinking tap water in Bangladesh. There was no history of contact with patients with tuberculosis. The child had been born in Australia to Bangladeshi parents, and his immunizations were up to date, according to the Australian schedule. He did not receive any travel vaccines prior to travel or malaria prophylaxis. His medical history was unremarkable apart from mild asthma.

患者，4岁，亚籍男孩。在孟加拉旅行返回1天后开始出现持续性高烧，症状持续10天，到悉尼的一家三级医院急诊科就诊。患者曾与父母在孟加拉旅行8周，到达孟加拉3周后出现呕吐、腹泻等症状，用药口服环丙沙星3天。1周后呕吐和腹泻缓解，但间歇性发烧38 °C又持续了2周。在孟加拉的最后10天，出现持续性发烧，最高时体温达40 °C。饮食减少，便秘，无呕吐症状。患者母亲称孩子出现症状几天后自己也出现自限性呕吐和腹泻。否认食用街边食物和饮水。未与肺结核患者接触。患者出生在澳大利亚，父母是孟加拉人，一直进行免疫接种。旅行前未接种任何疫苗和预防疟疾。病史：轻度哮喘，其他不明显。

In the emergency department he appeared unwell and moderately dehydrated. He was febrile at 39.8 °C (103.6 °F), tachycardic with a heart rate of 160 beats per minute, and his respiratory rate was 32 breaths per minute. There was no icterus, pallor, or lymphadenopathy. A skin examination did not reveal any rash, petechiae, or bruising. A chest and cardiovascular examination revealed no abnormalities. His abdomen was soft, mildly tender, and distended with no organomegaly. There was no clinical ascites and his bowel sounds were present. He was alert and oriented, with a normal neurological examination. He had no bone or joint pains or swelling. Initial investigations showed anemia, leukopenia, and thrombocytopenia. His hemoglobin concentration was 102 g/L and reached a nadir of 89 g/L on day 11 of admission. He had a nadir white cell count of 4.30 × 109/L (neutrophils 2.6 × 109/L and lymphocytes 0.9 × 109/L) on presentation, which gradually improved to 11 × 109/L by day 11. His initial platelet count was 97 × 109/L. His renal function was normal apart from mild hyponatremia, while his liver function tests showed hypoalbuminemia and mild transaminitis with normal bilirubin concentrations. His C-reactive protein level was elevated at 92 mg/L. Considering his clinical presentation, travel history, and the initial investigation results, the differential diagnoses included typhoid fever, malaria, and dengue fever. We ordered a blood culture, and thick and thin blood films for malaria parasites and dengue IgM, IgG, and NS1 antigen. He was then commenced on ceftriaxone intravenously and admitted to our hospital. There were no malaria parasites seen in two films and dengue serology was also negative. The following day his stool and blood cultures grew Salmonella Typhi. The organism was reported to be susceptible to ceftriaxone and azithromycin, with decreased susceptibility to ciprofloxacin. It was reported to be resistant to ampicillin, chloramphenicol, and trimethoprim.

在急诊室时，患者表现不适，中度脱水，发烧39.8 °C，心动过速，心率160次/分，呼吸频率32次/分。无黄疸、面色苍白、或淋巴结肿大。皮肤检查未发现皮疹、瘀点或青紫。胸部和心血管检查未发现异常。腹部质软，轻微压痛，扩张，无脏器肿大。无腹水，有肠鸣音。患者清醒，定向良好，神经检查正常。无骨或关节疼痛、肿胀。最初检查显示贫血，白细胞减少，血小板减少。血红蛋白浓度102 g/L，入院第11天达到最低89 g/L。入院时，最低白血细胞计数4.30 × 109/L（中性粒细胞2.6 × 109/L，淋巴细胞0.9 × 109/L），入院11天后，逐渐升至11 × 109/L。最初血小板计数97 × 109/L。除轻度低钠血症外肾功能正常，肝功能检查发现低蛋白血症，轻微转氨酶升高，胆红素浓度正常。C-反应蛋白水平升高92 mg/L。鉴于患者的临床表现、旅行经历及最初的检查结果，鉴别诊断包括伤寒，疟疾和登革热。安排了血培养，采用厚薄涂层以分析疟原虫和登革热IgM，IgG，和NS1抗原。之后患者开始静脉滴注头孢曲松，收入我们医院。血培养未发现疟原虫，登革热血清检查也呈阴性。第二天患者粪培养和血培养发现伤寒沙门氏菌。据报道此类有机物对头孢曲松和阿奇霉素敏感，对环丙沙星敏感度降低。有报道称其对氨苄青霉素、氯霉素、甲氧苄氨嘧啶有抗性。

Our patient continued to have fever spikes to 39–40 °C every 4 hours after admission until the fifth day, when the frequency of fever decreased to three spikes daily. Further improvement was noticed by day 9, with temperature spikes decreasing to twice daily and less than 39 °C. He required intravenous fluids for a short period to correct his dehydration until his oral intake gradually normalized over the first week in hospital. In addition, he received an albumin infusion on day 5 after he developed clinical ascites with a further drop in his albumin to 17 g/L. Thrombocytopenia was notable in our patient. His platelet count initially fell steadily and reached a nadir of 16 × 109/L on day 5 despite appropriate antibiotic therapy (Fig. 1).

自入院到第5天，患者持续发烧（每4个小时一次），达39–40 °C，第五天起每日发烧3次。第9天时情况改善，每日发烧2次，且低于39 °C。入院第一周内，患者请求静脉注射药物以治疗脱水，直至经口饮食恢复正常。此外，在入院第5天时，患者出现腹水，白蛋白水平降至17 g/L，于是接受输注白蛋白。血小板减少症较为明显，血小板计数稳定下降，虽然给予抗生素治疗，但是入院第5天血小板计数达最低16 × 109/L。

He was monitored closely for complications associated with thrombocytopenia: his sensorium remained intact and he did not develop petechiae, bruising, or rectal bleeding during admission. There was no sign of intestinal perforation, with normal bowel sounds and an absence of bloody stool. At this stage, we considered whether additional therapy for thrombocytopenia would be required, such as platelet transfusion. Upon discussion with our infectious diseases team, it was decided to treat him conservatively with close observation and not to give him a transfusion. His platelet count was monitored on a daily basis, began to improve on day 6 of admission, and finally normalized on day 11 and then climbed to supra-normal levels by day 15. Likewise, his transaminases were abnormal throughout admission, peaking on day 5 (Fig. 1), but started to improve before discharge. By day 9 of admission, his oral intake improved and oral azithromycin was added to transition to oral therapy. He completed a 12-day course of ceftriaxone in hospital and was discharged in a good condition, although he still had occasional fever spikes to 39 °C. He continued to have intermittent elevated temperatures (<38 °C) at home, but his parents reported that he returned to his previous energy level and activity. After he completed a total 7-day course of azithromycin, he was reviewed in an outpatient clinic where he was afebrile with a normal examination.

密切监视患者血小板减少症相关的并发症：感觉中枢完好，住院期间未出现瘀点、瘀斑、或直肠出血。无肠穿孔症状，肠鸣音正常，无血便。我们考虑是否需要额外治疗血小板减少症，如输注血小板。与传染病专家组讨论后，决定给予保守治疗，并密切观察，不予以输注血小板。每日监测血小板发现，入院第6天时，患者血小板计数开始改善，第11天时恢复正常，第15天时达到超正常水平。同样，住院期间患者转氨酶水平异常，第5天达到峰值（图1），出院前开始好转。入院第9天，经口饮食改善，加用口服阿奇霉素，过渡到口服治疗。住院期间患者接受头孢曲松一个疗程（12天），出院时状况良好，偶尔发烧 39 °C。出院后仍存在间歇性体温升高（<38 °C），患者父母称能量和活动方面已恢复。接受一个疗程（7天）阿奇霉素后，门诊检查时无发烧，一切正常。

图1：血小板减少和转氨酶变化过程

Discussion

讨论

Typhoid or “enteric” fever is a systemic infection caused by Salmonella enterica subsp. enterica serovar Typhi and occasionally Salmonella Paratyphi. It is characterized by severe systemic illness, often presenting with features of fever, constipation, and abdominal pain. Its incidence in endemic countries can be as high as 540 cases per 100,000 population, making it a public health challenge. In an Australian setting, it particularly affects returned travelers from the Asian subcontinent.

伤寒是一类由沙门氏菌亚种、伤寒沙门菌菌偶有甲型副伤寒沙门氏菌引发的全身性感染。特征为严重的全身性症状，常伴发烧、便秘和腹痛。疾病流行国家的发病率高达540/100000人，因而对公共健康造成了挑战。澳大利亚的一项研究表明，该病常感染亚洲次大陆的游客。

Important differential diagnoses of typhoid fever in a returned traveler from South and Southeast Asia include dengue fever and malaria. In addition, acute murine typhus can have similar presentation to typhoid fever. It is common, yet underdiagnosed, in travelers from this region. Thompson et al. found serologic evidence of acute murine typhus in 17% of patients who presented with undifferentiated febrile illnesses at a tertiary referral hospital in Nepal. All patients had sterile blood cultures with no cases of murine typhus found among those with confirmed enteric fever. We did not investigate our patient for murine typhus or other rickettsial infection because typhoid fever was confirmed promptly on day 2 of his admission.

旅行后的患者出现伤寒重要的鉴别诊断包括登革热和疟疾。此外，急性斑疹伤寒的临床表现可能与伤寒相似，可能诊断不出来。Thompson等对尼泊尔一家三级转诊医院的患者开展研究，17%的患者出现无差别发烧，从而发现了急性斑疹伤寒的血清学证据。所有受试患者均进行无菌血培养，已证实伤寒的患者中未发现斑疹伤寒。对于本文所述患者在入院第二天即确诊为伤寒，所以未进行斑疹伤寒或其他立克次体感染检查。

Thrombocytopenia is an important finding in the assessment of returned febrile travelers. It is defined as a platelet count below the lower limit of normal (i.e., <150 × 109/L). It is further subdivided into mild (100–150 × 109/L), moderate (50–99 × 109/L), and severe thrombocytopenia (<50 × 109/L). In a study conducted in an outpatient clinic in Germany, 3.8% of returned travelers had thrombocytopenia. Typhoid/paratyphoid fever was responsible for 14% of the cases, ranking fifth after malaria, acute human immunodeficiency virus (HIV) infection, dengue fever, and Epstein-Barr virus (EBV) infectious mononucleosis. The most frequent travel destination in the study was Asia (42%). Thrombocytopenia is well reported in patients with typhoid fever. Malik reported an incidence of 26% in Malaysian children with typhoid fever and Pohan found it in 61.5% of cases in one study of adults. Despite this, the pathophysiology of thrombocytopenia and its clinical course in typhoid fever are not well understood. Proposed mechanisms of the hematological manifestations of typhoid fever, including thrombocytopenia, include bone marrow suppression, peripheral destruction by the reticuloendothelial system, autoimmune-induced destruction, and Salmonella endotoxin-induced thrombocytopenia. Bone marrow examination was not performed in our patient but we note he had abnormalities in three hematological cell lines, suggesting possible bone marrow suppression.

血小板减少症在评估旅行后出现发热的患者时是一项重要发现，表现为血小板计数低于正常值下限（即 <150 × 109/L）。血小板减少症进一步分为轻度（100–150 × 109/L）、中度（50–99 × 109/L）和重度（<50 × 109/L）。德国一家门诊诊所进行的一项研究表明，3.8%的旅行后的人群出现血小板减少症。其中伤寒和副伤寒占14%，继疟疾、急性人类免疫缺陷病毒（HIV）感染、登革热、Epstein Barr病毒（EBV）传染性单核细胞增多症之后排名第五，最常见的患者旅行目的地为亚洲（42%）。伤寒患者出现血小板减少症的报道颇多：据Malik报道，马来西亚儿童伤寒的发病率为26%；Pohan在一项针对成年人的研究中发现，伤寒发病率为61.5%。尽管如此，人们对血小板减少症的病理生理学及其在伤寒时临床过程尚不完全清楚。已有的伤寒（包括血小板减少症）的血液学表现包括：骨髓抑制、网状内皮系统周围的破坏、自身免疫引发的症状、以及沙门氏菌内毒素引起的血小板减少症。该患者未进行骨髓检查，但注意到其三系血细胞异常，提示可能存在骨髓抑制。

Factors that might contribute to the severity of typhoid fever include the duration of illness before therapy, the inoculum size, the immune status of the patient, and the previous vaccination against typhoid fever. Our patient had been unwell for several weeks before presentation and thus the inoculum size at the time of commencing treatment could have been relatively high. He had no known or suspected immunodeficiency, but had not received a typhoid vaccination prior to travel to Bangladesh, which could have prevented this illness. The duration of illness and fever in patients with typhoid strains resistant to ampicillin, chloramphenicol, and trimethoprim can be more prolonged despite receiving antibiotics to which strains are susceptible.

判断伤寒严重程度的因素包括治疗前病程、接种量、患者免疫状态、之前接种的抗伤寒疫苗。该患者入院就诊前数周出现身体不适，因此开始治疗时的接种量可能相对较高。患者无已知或疑似免疫缺陷，旅行前未接种过伤寒疫苗（预防伤寒）。有伤寒菌的患者对氨苄青霉素、氯霉素、甲氧苄氨嘧啶有抗性，易感伤寒菌的患者即使接受了抗生素治疗，其病程和发烧持续时间更久。

In addition to splenomegaly and leukopenia, thrombocytopenia is considered a sign of severe disease in typhoid fever with a higher risk for development of complications. Thrombocytopenia usually develops during the course of the illness, but it can be a presenting feature of typhoid fever, as in this case. Severe complications of typhoid include intestinal perforation, intracranial hemorrhage, and multi-organ failure. Among 102 children with typhoid fever in one study, 33% developed complications, most commonly anicteric hepatitis and bone marrow suppression, but also paralytic ileus, myocarditis, psychosis, cholecystitis, osteomyelitis, peritonitis, and pneumonia. The rate of any complications among those with thrombocytopenia was 54%. Our patient had anicteric hepatitis, hypoalbuminemia with ascites, and thrombocytopenia, but he remained alert and oriented without any clinical evidence of intracranial hemorrhage despite a platelet nadir of 16 × 109/L on day 5 of admission. He also did not have any clinical evidence of intestinal perforation and his renal function remained normal throughout his admission. Considering our patient’s pancytopenia, we considered the possibility of infection-associated hemophagocytic syndrome as a complication of his typhoid fever, because this has been previously reported. Given that he was slowly improving clinically, we decided to observe him closely without performing additional invasive tests, such as bone marrow examination. Further investigation, including consideration of hemophagocytic syndrome, would have been required if he had failed to improve.

除了脾肿大和白细胞减少症，血小板减少症也被视为伤寒中的严重症状，且并发症风险高。血小板减少常出现于伤寒过程中，可视为伤寒的特征表现（如本文所述）。伤寒较为严重的并发症包括肠穿孔，颅内出血，多器官功能衰竭。一项研究纳入102例伤寒儿童患者，其中33%出现并发症，无黄疸型肝炎和骨髓抑制最为常见，还有麻痹性肠梗阻、心肌炎、精神病、胆囊炎、骨髓炎、腹膜炎、肺炎。血小板减少症患者出现上述并发症的几率为54%。该患者出现无黄疸型肝炎、低蛋白血症伴腹水和血小板减少症，清醒，定向良好，入院第5天血小板达最低值16 × 109/L，无颅内出血证据。住院期间未出现肠穿孔，肾功能检查显示正常。鉴于其全血细胞减少，我们将感染相关的噬血细胞综合征作为伤寒的一种并发症（之前曾有相关报道）。由于患者临床症状逐渐改善，我们决定密切观察，不予以额外的有创性检查，如骨髓检查。若患者情况未改善，则应进行进一步检查包括考虑噬血细胞综合征。

Because the risk of hemorrhage is increased when the platelet count falls below 20 × 109/L, this level was traditionally considered the threshold for prophylactic platelet transfusion. Later prospective studies have proved that lowering this trigger to 10 × 109/L in stable patients with cancer or blood disorders is still safe. However, platelet count should not be the only indicator for deciding transfusions. Other important elements that indicate the patient is at increased risk of bleeding, and thus likely to have an increased need for platelet transfusion, include raised body temperature, sepsis, and rapid decrease in platelet count. Like most blood products, platelet transfusions are not free of adverse effects. These include blood-borne infections, although now rare owing to good screening; bacterial contamination; febrile transfusion reactions; transfusion-related acute lung injury; and anaphylactic reactions.

由于血小板计数低于20 × 109/L时出血风险升高，传统上将这一水平作为预防性血小板输注的临界值。后续的前瞻性研究已证明，对于病情稳定的癌症患者和血液疾病患者，将这一指标降至10 × 109/L后，仍处于安全范围。但是，血小板计数不应作为判断输注的唯一因素。其他重要提示出血风险增高，因而增加了输注血小板的必要性的因素包括：体温升高，脓毒症，血小板急速下降。与大多数血液制品一样，输注血小板也存在副作用，如血源性感染（目前筛查较严格，出现较少）、细菌污染、发热性输血反应、输血相关的急性肺损伤以及过敏反应。

There are no studies or guidelines addressing the management of thrombocytopenia in typhoid fever. This poses a challenge for clinicians, especially when faced with severe thrombocytopenia, as in this case. Some case reports have described platelet normalization shortly after starting antibiotic therapy without a need for platelet transfusion. In one case, however, the platelet count fell from 154 × 109/L to 14 × 109/L despite antibiotic therapy, and this was associated with multi-organ failure; plasma exchange was given to correct the thrombocytopenia and other abnormalities. One adult patient died from severe hemolytic uremic syndrome attributed to Salmonella Typhi, with failure to respond to a platelet transfusion given along with a blood transfusion and plasmapheresis. Our patient had a relatively slow recovery with fever and hepatitis persisting for 2 weeks, despite appropriate antibiotic therapy, and a slow return to normalization of platelet count on day 11. However, he avoided a platelet transfusion and was well at last follow-up.

关于伤寒中的血小板减少症的管理尚无临床研究和指南。这为临床医师带来了挑战，尤其是重度血小板减少症患者的诊治（如本文患者所示）。一些病例报告中，作者描述了启动抗生素治疗后血小板即恢复正常，无需输注血小板。但是，有一例患者虽进行抗生素治疗，但其血小板计数从154 × 109/L降至14 × 109/L，这与多器官功能衰竭相关；进行了血浆置换以治疗血小板减少症和其他疾病。还有一例成年患者死于沙门伤寒菌引起的危重型溶血尿毒综合征，进行输注血小板、输血及血浆置换均无效。本文所述患者虽然进行适当的抗生素治疗，发烧和肝炎症状持续2周，之后才缓慢恢复，血小板计数在第11天才缓慢恢复至正常水平。不过，患者未进行血小板输注，随访检查一切正常。

Conclusions

结论

We have described a case of severe thrombocytopenia in typhoid fever with slow clinical and laboratory response but complete recovery after appropriate antibiotic therapy and supportive care alone, thus avoiding the risks associated with platelet transfusions or plasmapheresis. The optimal management of thrombocytopenia in typhoid fever merits further study to guide clinical practice.

本文描述了一例伤寒症患者出现血小板减少症。患者只进行了适当的抗生素治疗和支持性治疗，临床和实验室检查指标恢复较慢，最终完全恢复，因而避免了血小板输注或血浆置换相关的风险。为指导临床实践，伤寒症中的血小板减少症的管控仍有待进一步研究。

（此文为转载）