组织胞浆菌病

译者：张上珠博士

北京协和医院内科

Email：pearl-aquarius@hotmail.com

审阅者：罗玲博士

北京协和医院内科

Email：luolingnk@yahoo.com.cn

Histoplasmosis is the most common endemic mycosis and a major cause of morbidity in patients who live in endemic areas. It has emerged as an important opportunistic infection in immunocompromised patients including those with AIDS or who are taking medications that impair cellular immunity. Exposure to bird or bat guano are important epidemiological clues to the diagnosis. Unique clinical manifestations may alert the clinician to consider the diagnosis of histoplasmosis. Serologic tests measuring the antibody response and tests for antigen complement cultural methods for diagnosis. Newer treatment options have improved the outcome of therapy and offered effective and well-tolerated alternatives to amphotericin B.

　　在流行地区，组织胞浆菌病不但是最常见的地方性真菌病，也是当地居民患病的主要原因。它主要见于免疫力低下患者的机会感染，这些患者包括艾滋病患者和因应用药物而造成细胞免疫受损的患者。鸟或蝙蝠排泄物的接触史可为诊断提供重要的流行病学线索。其独特的临床表现可使临床医生考虑到组织胞浆菌病的诊断。血清学检测抗体、检测抗原的方法与培养的方法对于诊断起到相互补充的作用。新的治疗方法提高了疗效，并且提供了有效的、耐受性好的两性霉素B替代方案。

The mold form of Histoplasma capsulatum grows in soil containing rotted bird or bat guano. Microconidia are the infectious particles of the mold, while the macroconidia are characteristic of the organism and provide a clue to its identification. H. capsulatum grows as a yeast above 35°C. The yeast is the pathogenic form of the organism found in the tissues of infected individuals. Complete identification requires conversion of the mold to the yeast, identification of specific antigens by immunologic tests, or genetic verification using nucleic acid probes.

　　夹膜组织胞浆菌的霉菌形式在含有腐烂的鸟或蝙蝠排泄物的土壤中增长。小分生孢子是霉菌的感染颗粒，而小分生孢子是此种微生物的特征，并提供了鉴定的线索。在35°C以上的温度，夹膜组织胞浆菌以酵母形式生长。酵母是受感染亇体的組織中夹膜组织胞浆菌的致病形式。明确的鉴定需要将霉菌转换为酵母菌的形式，通过免疫学检测发现特异性抗原，或者用核酸探针基因來鉴定。

Histoplasmosis, although worldwide in distribution, is more prevalent in certain parts of North and Latin America (1,2) (Figure 1). Bird and bat excrement enhance the growth of the organism in soil by accelerating sporulation. Birds, because of their higher body temperature, are not susceptible to histoplasmosis and do not acquire the infection; while bats, however, may be infected with H. capsulatum, and spread the organisms to different locations in the environment (3). Several outbreaks have resulted from exploration of caves inhabited by bats (4-6). Other animal species also may be infected with H. capsulatum var capsulatum, including sea mammals (3). Factors accounting for its geographic distribution are poorly understood but include high humidity, moderate climate, and acidic soil characteristics. Activities that disturb environments containing the H. capsulatum cause airborne spread of the microconidia, infecting those who are exposed during the disturbance. These environmental sites typically are visibly contaminated by heavy accumulations of bat or bird droppings, but patients often are unaware of any such exposure.

　　组织胞浆菌病，虽然在全世界广泛分布，它在北美洲和拉丁美洲(1,2)的某些地区尤为流行(图1)。鸟和蝙蝠的排泄物通过加速孢子形成从而加速微生物在土壤中的生长。由于鸟类较高的体温，不适合组织胞浆菌生长，因而不会被感染；然而，蝙蝠有可能感染夹膜组织胞浆菌，并将微生物传播到不同的地点(3)。几次爆发性感染均与人们对蝙蝠憩息洞穴的探险有关(4-6)。其他动物，包括海洋哺乳动物也可能感染夹膜组织胞浆菌(3)。影响其地理分布的因素尚未完全了解，但它们包括高湿度、适度气候和酸性土壤特征。人类行为可能导致孢子在空气中的传播，感染在那些地区的人群。这些地区往往有大量的鸟类或蝙蝠的排泄物，但被感染者常并不在意。

Review Article: Singh, N., Perfect, J. Immune Reconstitution Syndrome Associated with Opportunistic Mycoses. The LANCET Infectious Diseases 2007; Vol.7, Issue 6, 395-401.

Histoplasmosis usually is asymptomatic or non-progressive in healthy individuals (7). With low-level exposure, asymptomatic infection is most common. Such cases are detected by skin test surveys or identification of pulmonary nodules, mediastinal lymphadenopathy, or splenic calcifications on CT scan or abdominal radiogram. In endemic areas, half to more than 80% of young adults are infected with H. capsulatum, based upon skin test surveys. While fewer than 5% of individuals develop symptomatic disease after low level exposure, attack rates exceeding 75% follow heavy exposure, as might occur during work or recreation at a contaminated site (8).

　　对于健康个体而言，组织胞浆菌病感染通常没有症状或非进展性。(7)。低水平的暴露导致的无症状的感染是很常见的。这一类型的感染通常是通过皮肤试验监测以及影像学所提示的肺部结节、纵隔淋巴结肿大和脾钙化而被发现的。在流行区域，根据皮肤试验监测的结果，50%-80％以上的成人感染过夹膜组织胞浆菌，然而個体在低水平的病菌暴露之后，仅有小于5%的人会发展为有症状的疾病。而在严重的暴露之后，会有将近75%的人会发展为有症状的疾病(8)。

Acute Pulmonary Histoplasmosis: The common clinical findings of self-limited infection include acute pulmonary histoplasmosis, pericarditis (9), and rheumatologic syndromes (10). Patients present with fever, cough and chest pain; and chest radiograms show mediastinal lymphadenopathy with infiltrates. Heavy exposure causes more extensive pulmonary involvement, sometimes accompanied by respiratory insufficiency (11). Patients also may experience symptoms caused by obstruction of mediastinal structures by enlarged lymph nodes (12).

急性肺组织胞浆菌病：常见的自限性感染临床表现包括急性肺部组织胞浆菌感染、心包炎(9)和风湿病综合症表现(10)。患者可以出现发热、咳嗽和胸痛；胸部影像学可提示肺部浸润影及纵隔淋巴结肿大。個体在严重的病菌暴露之下常可导致广泛的肺部受累，有时可伴呼吸衰竭(11)。由于肿大淋巴结，患者也可出现纵隔内气管受压的临床表现(12)。

The severity of illness correlates with the intensity of exposure (13). Following heavy exposure, patients may present with diffuse pulmonary involvement (11,14,15). Symptoms of fever, chills, sweats, headache, myalgia, anorexia, cough, and chest pain characterize these illnesses (16), and respiratory failure and death may ensue (17). Chest radiograms show diffuse reticulonodular or miliary pulmonary infiltrates in 90% of cases, sometimes with mediastinal lymphadenopathy (5,14,15). Following the more typical, low-level exposure, the pulmonary illness is more commonly sub acute and mild, or even asymptomatic. Chest roentgenograms show enlarged hilar or mediastinal lymph nodes with patchy infiltrates (18), but may be normal (19). While rapid improvement in two to three weeks is characteristic (16), fatigue may linger (19).

　　疾病的严重程度与暴露的程度相关(13)。严重的暴露后，患者可以出现弥漫性肺部受累(11,14,15)。可出现包括发热、寒战、盗汗、头痛、肌痛、食欲减退、咳嗽和胸痛(16)；呼吸衰竭和死亡可相继出现。(17)。90%病例的胸部影像学提示网格结节影或粟粒样肺部浸润，有时可伴有纵隔淋巴结肿大(5,14,15)。低水平暴露后，肺部疾病常为亚急性表现、轻度甚至无临床表现。胸片提示肺门增大或纵隔淋巴结肿大伴有片状渗出(18)，但也可表现为正常(19)。特征性表现在2-3周内症状可迅速缓解，乏力可持续存在(19)。

Enlarged mediastinal lymph nodes may impinge upon the airways, pulmonary vessels or vena cava, or the esophagus, occurring in <10% of patients with acute pulmonary histoplasmosis (20-24). These findings may first present years after the initial infection, as a result of smoldering inflammation and necrosis in the involved node. Symptoms include chest pain, cough, hemoptysis, dyspnea and dysphagia (22,25,26).

小于10%的急性肺部组织胞浆菌病患者可出现肿大纵隔淋巴结压迫气道、肺部血管、上腔静脉或食道(20-24)。由于受累淋巴结内的缓慢而持续的炎症和坏死，淋巴结肿大可在初次感染后的数年后出现。其症状可包括胸痛、咳嗽、咯血、呼吸困难和吞咽困难(22,25,26)。

Chronic Pulmonary Histoplasmosis: Patients with emphysema develop chronic pulmonary histoplasmosis characterized by recurrent symptoms, progressive lung infiltrates, fibrosis and cavitation (7,34). Upper lobe infiltrates with cavities are present in most cases. While some patients recover spontaneously (34), the majority demonstrate progression with cavity enlargement, formation of new cavities, and spread to new areas of the lungs. Rarely bronchopleural fistula may develop. Care must be taken to exclude cancer in patients with nodular lesions not responding to treatment, as cigarette use is a shared risk factor for both conditions. Tuberculosis also may coexist and must be excluded (7,34). Bacterial infection, common in patients with underlying emphysema or other chronic lung diseases, may be the cause of recurrent symptoms, rather than relapse or progression of histoplasmosis. Aspergilloma, chronic invasive aspergillosis, and atypical mycobacterial infections also may complicate chronic pulmonary histoplasmosis.

慢性肺部组织胞浆菌病：患有肺气肿的患者可表现为慢性肺部组织胞浆菌病，其表征為反复出现的症状、进行性肺部浸润、纤维化和空洞。上叶受累出现空洞可见于大部分的患者中(7,34)。一部分患者可以自行好转(34)，而大多数则表现为空洞的增大、新空洞的形成和播散至肺部其它部位。少见的情况下，支气管胸膜瘘也可出现。对于患者肺部出现结节性病变並且治疗無進展者应注意排除其肿瘤的可能性。因吸烟是这两种疾病共有的危险因素。患者可同时合并结核感染，這也要注意排除(7,34)。慢性肺疾病或肺气肿的患者受细菌感染后，也可表现为反复发作的症状。然而肺曲菌球病、慢性侵袭性曲霉病和非典型分支杆菌感染也可以合并于慢性肺部组织胞浆菌病，使其鉴別診断過程複雜化。

Rheumatologic Syndromes and Pericarditis: Pericarditis is a local inflammatory or immunologic reaction to the adjacent mediastinal histoplasmosis, occurring in about 5% of symptomatic cases (9). Perhaps necrotic mediastinal nodes erode into the pericardium, releasing antigenic or inflammatory substances in some cases. Pericarditis rarely may be a complication of disseminated histoplasmosis. Hemodynamic compromise occurs in 40% of these patients (9). Patients usually respond to anti-inflammatory medications without antifungal therapy (9,10), while those with hemodynamic compromise may require corticosteroid therapy or drainage of the pericardial fluid. Outcome is excellent, with rare progression to constrictive pericarditis (9,27-29). Antifungal therapy is unnecessary (9,30) unless the patient receives corticosteroids or has disseminated disease.

风湿热综合征和心包炎：大約5％有症状的患者会出现心包炎，這是一种对邻近的纵隔组织胞浆菌病的局部炎症或免疫反应(9)。這可能为坏死的纵隔淋巴结侵蚀入心包膜，并释放抗原和炎性物质。心包炎很少是播散性组织胞浆菌病的并发症。40％的這類患者会出现血流动力学改变(9)。抗炎症治疗（而不包括抗真菌治疗）对患者常常有效(9,10)。出现血流动力学改变的患者可能需要激素治疗或心包积液引流。预后较好，并很少出现缩窄性心包炎的併發症(9,27-29)。除非患者在接受激素治疗或出现播散性疾病，抗真菌治疗不是必需要有的(9,30)。

Rheumatologic syndromes also occur in about 5% of patients with recent histoplasmosis, and appear to represent a systemic immunologic reaction to the pulmonary infection (10,31,32). Arthralgia or arthritis, usually polyarticular and symmetrical, may be the sole finding, or may be associated with pulmonary complaints. Half of patients exhibit erythema nodosum. Joint radiograms are normal, while chest radiograms may show pulmonary histoplasmosis. The joint symptoms usually resolve in response to anti-inflammatory therapy (33).

　　大约5%的新近感染的组织胞浆菌病患者出现风湿性综合征，其表现为对肺部感染的系统性自身免疫反应(10,31,32)。关节炎或关节痛多为多关节受累，为对称性，常为唯一的表现，也可伴随出现肺部症状。约50%的患者表现为结节性红斑。关节影像学可为正常，而肺部影像学可提示肺部组织胞浆菌病。抗炎治疗通常对于缓解关节症状有效(33)。

Disseminated Histoplasmosis: Hematogenous spread outside the lungs occurs in a high proportion of individuals during the acute infection but rarely is recognized clinically. These patients recover with the development of cellular immunity to H. capsulatum. Disseminated infection is progressive in about one in 2000 acute infections, however (35). Progressive disseminated histoplasmosis is seen most often in patients who are immunosuppressed or at the extremes of age. Severity varies with the degree of immune deficiency. An acute, rapidly-fatal course with diffuse reticuloendothelial involvement characterizes the infection in infants and others who are severely immunosuppressed, while a chronic course with a more focal organ distribution is more typical in non-immunocompromised children and adults (36).

播散性组织胞浆菌病：急性期，肺外的血行播散会占很大比例，不过在临床中很少被发现。这些患者随着机体对组织胞浆菌的细胞免疫的出现而康复。1/2000急性感染的患者会出现进展的播散性组织胞浆菌病。进展的播散性组织胞浆菌病常出现在免疫低下的人群或婴儿以及老人(35)。发病严重程度与免疫缺陷的程度相关。婴儿及其他严重免疫低下者出现的急性快速致死性病程表现为弥漫性网状内皮细胞受累，而对于免疫力正常的儿童或成人典型常表现为更局限的慢性病程(36)。

Clinical findings of progressive disseminated histoplasmosis are non-specific. Fever, weight loss and respiratory symptoms are the most common clinical findings. Examination often reveals hepatomegaly, splenomegaly or lymphadenopathy; and laboratory tests may show findings of bone marrow suppression and hepatitis. Shock and multi-organ failure may complicate severe cases (37). Other frequent sites of dissemination include the oral mucosa, gastrointestinal tract, skin, kidneys and adrenal glands. Skin lesions include papules, pustules, folliculitis, ulcers, subcutaneous nodules, and roseacea-like eruptions. Gastrointestinal involvement also is common, presenting as mass lesions or ulcerations, causing pain, bleeding, perforation or malabsorption. Chest roentgenograms usually show diffuse infitrates but may be normal in one third of cases.

　　播散性组织胞浆菌病的临床表现是不特异。发热、体重减轻和呼吸系统症状较为常见。查体常发现肝大、脾大或淋巴结肿大；实验室检查可提示骨髓抑制和肝炎。严重者可出现休克和多器官功能衰竭(37)。其他常见的受累部位有口腔粘膜、消化道、皮肤、肾脏和肾上腺。皮肤受累包括丘疹、脓疱、毛囊炎、溃疡、皮下结节和玫瑰疹。消化道受累常见，可表现为巨大的病变或溃疡，导致疼痛、出血、穿孔或吸收障碍。胸片通常提示弥漫性病变，不过三分之一患者可有正常的胸片。

Brain, spinal cord or meningeal involvement occurs in about 5% to 10% of cases (35,37,38). In older studies, although recognized clinically in only 4% of cases, CNS involvement was present at autopsy in one to two-thirds (15,36). About 5% of cases in recent series of disseminated histoplasmosis in patients with AIDS exhibited CNS involvement (Wheat, unpublished). Of 89 cases of CNS histoplasmosis reviewed with the author since 1991, 67% had meningitis, 27% brain lesions, and 7% cord involvement (Wheat, unpublished). Among those with meningitis, 17% had hydrocephalus, most of which had CSF shunts in place at the time of diagnosis of meningitis. In many cases, the diagnosis was overlooked for months to years before testing for histoplasmosis was performed. Clinical syndromes include sub acute or chronic meningitis, focal brain or spinal cord lesions (39), stroke syndromes caused by vascular involvement or emboli, or encephalitis (38,40) . CNS infection may occur as manifestations of widely disseminated disease or as isolated sites of dissemination, with nearly equal frequency.

5-10％患者(35,37,38)可有脑、脊髓或脑膜受累。过去的研究中，虽然临床上仅有4%的患者有临床表现，尸检结果发现有1/3-2/3(15,36)的患者有神经系统受累。大约5%的艾滋病合并近期播散性组织胞浆菌病的患者可有中枢神经系统的受累(Wheat, 未出版)。自1991年开始，人们先后对89例中枢神经系统受累的组织胞浆菌病进行综述，其中67％为脑膜炎，27％为脑受累，7%为脊髓受累。在脑膜炎的患者中，17％存在脑积水，大部分存在诊断脑膜炎时采用的外科分流术。多数病例在组织胞浆菌病检测进行之前已漏诊数月或数年。相关的临床综合征包括亚急性或慢性脑膜炎，局灶的脑或脊髓受累(39)，脑炎(38,40)以及血管受累或栓塞导致的卒中。中枢神经受累可为单独病变或全身播散的一部分，两者发生率类似。

Endocarditis is a rare complication of disseminated histoplasmosis and usually is manifested by systemic emboli in a person with other finding of disseminated disease, but may present as isolated culture-negative endocarditis (41,42). No such cases have been identified during the recurrent outbreaks in Indianapolis, although a single case of a left atrial myxoma infected with H. capsulatum was reported from our institution (43).

心内膜炎是播散性组织胞浆菌病较为少见的并发症，通常因器官栓塞而被发现。也可出现在血培养阴性的心内膜炎。印第安纳州出现的多次爆发中没有相关报道，我们研究院报道了组织胞浆菌感染的左房粘液瘤的个案(43)。

Other sites of dissemination include the kidneys, ureters, bone and joints, sinuses, eye, ears, gallbladder, cystic duct, common bile duct, prostate, breast, epididymis, urinary bladder, penis or vagina, testis or ovary, heart, pleura, and aorta. Thymus involvement is common in fatal cases in children. Cases presenting with necrotizing cellulitis, psoas abscess, myositis, and renal mass also have been seen in disseminated histoplasmosis.

　　其他播散的部位包括：肾脏、输尿管、骨和关节、鼻窦、眼、耳、胆囊、胆囊道、总胆管、前列腺、乳腺、附睾、膀胱、阴茎或阴道、睾丸或卵巢、心脏、胸膜和主动脉。胸腺受累常见于儿童中的致死性病例。坏死性蜂窝组织炎、前列腺脓肿、肌炎和肾脏肿物也可见于播散性组织胞浆菌病。

Broncholithiasis: Calcified mediastinal nodes and pulmonary granulomas may erode into adjacent bronchi (44). Patients may expectorate rock-like particles of tissue and experience hemoptysis, bronchial obstruction or tracheoesophageal fistula.

支气管结石：钙化的纵隔淋巴结和肺部肉芽肿可以侵入临近的支气管(44)。患者可咳出组织含有石头样的颗粒，咯血，支气管阻塞或支气管胸膜瘘。

Mediastinal Fibrosis: Mediastinal fibrosis is a rare manifestation of histoplasmosis which is felt to represent an abnormal host response to the infection (45) (12,46). Viable organisms cannot be found in these tissues, supporting the belief that fibrosing mediastinitis represents an exuberant fibrotic reaction to past infection rather than an active, progressive infection. The superior vena cava, airways, pulmonary arteries or veins, or esophagus are most commonly involved but any mediastinal structure can be trapped in these fibrotic masses (12,46). Chest radiograms may be normal or show only mediastinal widening, but CT scans reveal restriction and invasion of mediastinal structures. Calcification often is present. Recurrent hemoptysis is a common symptom and respiratory failure often ensues. Commonly-reported symptoms include cough, dyspnea, chest pain, hemoptysis, pleurisy caused by vascular obstruction, dyspnea or recurrent pneumonia caused by airway narrowing; facial or upper extremity swelling or congestion, varicose veins on the head, neck, arms or abdomen, dizziness, headache, and rarely syncope caused by superior vena cava obstruction (12).

纵隔纤维化：纵隔纤维化是组织胞浆菌病的一种少见表现，它表现了一种机体对感染的异常反应。在纤维化的组织中没有活的微生物存在，这支持纤维化纵隔炎是一种慢性的纤维化表现，而非活动性、进展的感染。上腔静脉、气道、肺动静脉或食道常受累，但任何纵隔内的结构都有可能受累。胸片可以正常或仅表现为纵隔增宽，不过CT可以发现被限制和受侵蚀的纵隔组织。钙化较为常见。反复发作的咯血也常见，也可继发呼吸衰竭。常被报道的症状包括：咳嗽、呼吸困难、胸痛、咯血，血管栓塞导致胸膜炎，气道狭窄可导致呼吸困难或反复出现的肺炎；上腔静脉阻塞可导致面部和上肢肿胀或瘀血，面部、颈部、臂部或腹部静脉曲张，头晕，头痛，及少见的晕厥。

Enlarging Pulmonary Histoplasmoma: Rarely patients may develop a slowly enlarging pulmonary nodule which has been called enlarging histoplasmoma (47). Histoplasmomas usually are asymptomatic but often cause concern about malignancy. They range in diameter from 8 mm to 35 mm and enlarge an average of 2 mm per year, presumably through inflammation and fibrosis in response to antigenic materials released from the central core into the surrounding tissue. Calcification occurs in the core and the periphery of the lesion. Histologically they are characterized by a necrotic center surrounded by a fibrous-like capsule. Organisms may be seen in the necrotic center but usually cannot be isolated in cultures.

扩大性肺组织浆细胞瘤：极少数患者可表现为缓慢增大的肺部结节，被称为扩大性肺组织浆细胞瘤。组织浆细胞瘤通常没有症状，不过可引起人们对恶性疾病的顾虑。结节直径在8-35mm，且以平均每年2mm的速度增大，大概由于中心释放抗原物质到周围组织而导致炎性反应和纤维化，从而使结节增大。中心和周边常见钙化。组织病理以中心坏死灶及其周围纤维样包囊为特点。中心坏死灶内可见有机生物，不过常不能在体外培养。

Presumed Ocular Histoplasmosis: Choroiditis involving the macula and causing visual loss has been attributed to histoplasmosis (48), but there is no scientific basis establishing H. capsulatum as its cause. The association has been based on high rates of skin test reactivity rather than demonstration of the fungus in the tissues (49). Identification of patients with similar findings outside the endemic area for histoplasmosis further weakens the association of histoplasmosis with this clinical syndrome (50). However, the eye may be involved in patients with disseminated histoplasmosis (51).

推测的眼部组织胞浆菌病：累及黄斑并导致失明的脉络膜炎曾报道由组织胞浆菌病引起。但目前没有科学证据证实其因果关系。相关性是基于皮肤试验，而并非在组织中发现真菌。由于在组织胞浆菌病的非流行区也发现了类似情况，因此组织胞浆菌病与这种临床综合症的相关性被质疑。然而，患者有播散性组织胞浆菌病也可累及眼睛部位。

A battery of diagnostic procedures is needed for diagnosis of histoplasmosis (52). Serologic tests for antibodies forms the basis for diagnosis in most patients with mild infections, while cultures, stains, and tests for antigens are more useful in those with more severe disease.

　　诊断组织胞浆菌病需要一系列实验室检查。血清学的抗体检查是大多数轻度感染的患者的诊断基础，而培养、染色和对抗原的检测对重度感染更为有用。

Serologic Tests: Antibodies to H. capsulatum measured by immunodiffusion or complement fixation develop in most patients. H precipitin bands can be demonstrated in less than 25% of patients and clear during the first 6 months following exposure (53,54). M bands occur in over three-quarters of cases and persist for years in some patients. Complement fixation titers of 1:8 or more are found in most patients with active histoplasmosis while those of 1:32 or higher are more suggestive of active infection. Both the immunodiffusion and complement fixation test should be performed to obtain the highest sensitivity for diagnosis. Tests for antibodies using enzyme immunoassay or radioimmunoassay methods are more difficult to interpret because of higher background positivity rates and have not been validated adequately to recommend their use in place of immunodiffusion and complement fixation (55).

血清学检查：大多数患者会出现针对夹膜组织胞浆菌的抗体，可通过免疫扩散法和补体结合法检测。H沉淀素带在小于25％的患者中出现，而且在暴露之后的6个月清除。M带可出现在超过四分之三的患者中，并在一些患者中可以持续存在多年。在多数活动性组织胞浆菌感染的患者中可见补体结合滴度测定为1:8或更大，滴度大于等于1:32更提示活动性感染。免疫扩散法和补体结合滴定法对于诊断都有较高的敏感性。由于较高的背景阳性率，酶联免疫法或放免法的结果解释比较困难，因而还没有替代免疫扩散法和补体结合滴定法(55)。

Antibodies require 4 to 8 weeks to develop following acute infection and may be negative when the patient is first seen. Furthermore, serologic tests may be falsely-negative in up to one-third of immunocompromised patients (54). Positive results caused by cross reactions occur in patients with blastomycosis, coccidioidomycosis and paracoccidioidomycosis (56).

　　抗体需等到急性感染过后的4-8周后才出现，所以患者首次就诊时抗体可为阴性。而且近三分之一的免疫抑制患者可有假阴性出现(54)。並且芽生菌病、球孢子菌病、南美芽生菌病的患者可能有交叉阳性反应。

High levels of antibodies, particularly M precipitin bands and low titers (1:8 or 1:16) of complement fixing antibodies, may require several years to clear after acute infection, occasionally causing confusion in patients with other diseases. Consequently, histoplasmosis may be diagnosed incorrectly in a patient with another illness who has high levels of antibodies to H. capsulatum persisting after an earlier episode of histoplasmosis.

高水平的抗体，尤其是M带和低滴度（1:8或1:16）的补体结合性抗体，在急性感染后的数年还能存在，有时会其他疾病相混淆，如患其他疾病而有较高水平的组织胞浆菌病抗体的患者可被误诊为组织胞浆菌病。

Culture: Cultures are most useful in patients with disseminated or chronic pulmonary histoplasmosis. The sensitivity is only l0 to 15% in patients with other forms of histoplasmosis (54). In disseminated histoplasmosis, the highest yield is from bone marrow or blood, positive in over 75% of cases (35,37). Organisms can be found in sputum or bronchoscopy specimens in 60 to 85% of cases of cavitary histoplasmosis (7).

培养：对于播散性或慢性肺部组织胞浆菌病的患者而言，培养是最有意义的。但其他形式的组织胞浆菌病的敏感性仅为10-15％(54)。播散性组织胞浆菌病的患者，骨髓或血中的培养阳性率可达75%(35,37)。60-85%的空洞型肺部组织胞浆菌病的患者可以在其痰或支气管肺泡灌洗液中找到病原体(7)。

Antigen Detection: Sensitive methods for rapid diagnosis of histoplasmosis in patients with severe manifestations are essential to allow prompt initiation of therapy. Fungal stain is rapid but insensitive. Detection of antigen offers a valuable approach to the rapid diagnosis in severe cases (54,57). Antigen is found in the blood, urine and bronchoalveolar lavage fluid of most individuals with disseminated histoplasmosis and in the urine of 75% of those with extensive pneumonitis following heavy acute exposure. Antigen may be found in CSF of 25 to 50% of patients with meningitis caused by histoplasmosis. Cross-reactions may be seen in patients with African histoplasmosis, blastomycosis, paracoccidioidomycosis, and Penicilliosis marneffii. Antigen levels decline during treatment and increase with relapse, providing a tool for monitoring therapy (58). Antigen testing is available at MiraVista Diagnostics.

抗原检测：为了及早开始治疗，敏感的检测方法进行快速诊断对于重症患者的是十分必要的。真菌染色检测快速但并不敏感。抗原检测对于严重患者提供了快速诊断的方法(54,57)。在大多数播散性患者的血液、尿液和支气管肺泡灌洗液中均可找到抗原，而且对于严重暴露后而患大面积肺炎的患者，有75％的患者尿液中可发现抗原。25-50％的组织胞浆菌脑膜炎患者的脑脊液中检出抗原。非洲组织胞浆菌病、芽生菌病、南美芽生菌病和马尼菲青霉菌可与该病存在交叉反应。抗原的水平随着治疗会降低，而病情反复时会升高，为临床治疗效果提供检测指标(58)。美国MiraVista Diagnostics公司生产這抗原检测的试剂盒。

Fungal Stains: Silver stain of tissue sections or Wright stain of peripheral blood smears permits rapid diagnosis but with a lower sensitivity than culture or antigen detection. Fungal stains of tissues are positive in about half of cases of disseminated histoplasmosis (35). Candida glabrata, Cryptococcus neoformans, Blastomyces dermatitidis, Penicillium marneffei, Pneumocystis carinii, Toxoplasma gondii, Leishmania and staining artifacts may be misidentified as H. capsulatum.

真菌染色：组织切片银染或外周血涂片瑞氏染色可以迅速诊断但较培养或抗原检测阳性率低。大约一半播散性组织胞浆菌病的患者组织真菌染色为阳性(35)。光滑念珠菌、新型隐球菌、皮炎芽生菌感染、马尼菲青霉菌、卡氏肺孢子虫、弓形虫、利什曼原虫及染色的伪差可能会被误认为是组织胞浆菌。

Histoplasmin Skin Test: Skin test reagents are no longer available, and should not be used diagnostically because of high rates of positivity (50-80%) in endemic areas and false-positive results in patients with other fungal diseases (59). Skin tests also may be falsely negative in patients with disseminated disease. Skin tests increase levels of antibody, causing confusion in the interpretation of serologic tests. In vitro methods for measurement of cellular immune response, including lymphoproliferative and induced interferon-γ production have been described (60).

组织胞浆菌皮肤试验：皮肤检测反应物已经停止生产，由于在流行地较高的阳性率（50-80%）以及其他真菌感染可导致的假阳性结果，因而该试验已被弃用(59)。在播散性组织胞浆菌病患者中，皮肤试验还可能为假阴性。皮肤试验还可增高抗体水平从而干扰血清检测。也有报道在体外测定包括淋巴细胞增殖和诱导γ干扰素产生在内的细胞免疫反应从而进行检测(60)。

Infection develops when conidia are inhaled and transform into yeasts in the lungs. may occur in non-immunosuppressed individuals (36,37).

　　当患者吸入孢子，继而孢子在肺中转变为酵母样，就导致了感染。也可以发生在非免疫低下的人群(36,37)。

Cellular immunity is the primary host defense against H. capsulatum (62-64). CD4 lymphocytes activate macrophages to assume fungicidal properties (65,66), serving to control the infection in immunocompetent individuals. Progressive disseminated disease is seen in those with underlying immunosuppression (67) or at the extremes of age (36,67). Interferon-γ and IL-12 play important roles in the development of an effective Th1 immune response to H. capsulatum. Depletion of these factors prevents the development of effective immunity in experimental histoplasmosis (66,68).

细胞免疫是机体对抗组织胞浆菌的基本机制 (62-64)。CD4淋巴细胞激活巨噬细胞可以清除真菌病原体 (65,66)，以控制免疫正常者体内的感染。进展的播散性疾病见于应用免疫抑制剂的患者或婴幼儿和年老者(36,67)。 γ干扰素和白介素12对于组织胞浆菌病产生有效的T1辅助细胞免疫反应起到非常重要的作用。这些因子的缺失会使机体無法产生有效的〝对抗组织胞浆菌〞免疫反应(66,68)。

Reactivation of quiescent infection is postulated to occur during immunosuppression (37,69,70). Such cases are suspected outside endemic areas in patients who previously lived in endemic regions. Identification of a Panamanian genotype in immigrants to New York City supports this hypothesis (71). The ability to reactivate old lesions may decline over time, however.

当免疫力低下时，潜伏的感染可能会再激活(37,69,70)。这些病例多出现于以前在流行区居住而后在非流行地发现的患者中。在纽约移民者身上鉴定出巴拿马基因型的菌株支持这一假说(71)。不过随着时间的推移，激活的可能性减小。

Reinfection also may occur, as suggested by the occurrence of acute histoplasmosis in persons with radiographic, skin test or laboratory evidence of past infection (61,72-74). Certainly persons living in endemic areas, especially those with jobs or hobbies that are likely to expose them to soil containing H. capsulatum spores, are at risk for reinfection. Reinfection histoplasmosis is postulated to be less severe than primary infection because of residual immunity induced by the initial episode (61,72-74).

在皮肤试验或实验室证据证明其既往曾有感染的基础上，出现急性感染者的影像学表现可能是再次感染(61,72-74)。居住在流行地者，尤其是工作或习惯接触泥土者再次感染的风险更大。由于最初感染所留下的剩余的免疫，所以认为其再次感染常不及初次感染严重(61,72-74)。

Review Article: Singh, N., Perfect, J. Immune Reconstitution Syndrome Associated with Opportunistic Mycoses. The LANCET Infectious Diseases 2007; Vol.7, Issue 6, 395-401.

Review Article: Gauthier G, et al. Insights into Fungal Morphogenesis and Immune Evasion. Microbe 2008;3(9):416-423.

SUSCEPTIBILITY IN VITRO AND IN VIVO Guided Medline Search In Vitro and In Vivo

Susceptibility testing shows H. capsulatum to be susceptible to a variety of drugs. Since the yeast phase is the pathogenic form of the organism found in the tissues of infected patients, testing is recommended using it rather than the mold phase of the organism. Studies comparing the susceptibility of the yeast and the mold phase have not been performed, precluding a conclusion that the mold phase could be substituted for the yeast in susceptibility testing. Since the mold phase is the form isolated by culture in the mycology laboratory, it must be converted to the yeast phase before susceptibility testing can be performed; and conversion may require several weeks. This delay reduces the usefulness of susceptibility testing in clinical practice; its main role is in research to identify agents to study in animal models (75-78) and to determine the cause for treatment failure or relapse.

　　易感性试验表明组织胞浆菌对多种药物敏感。由于酵母相为组织中病原体的致病形式，试验时常用酵母相，而不用菌丝相。目前没有比较酵母相和菌丝相对药物敏感性的研究，因此尚不肯定酵母相的数据可以完全用于菌丝相。由于在真菌实验室中培养分离得到的是菌丝相，因此在进行药敏实验前必需将其转化为酵母相；而转化常需要数周时间。这样的延迟减少了药敏指导临床用药的可用性；培养的主要作用则为在动物模型研究(75-78)中鉴别病原体以及确定治疗失败与疾病复发的原因。

Susceptibility testing on the yeast phase is available at MiraVista Diagnostics using a modified NCCLS procedure. We have reported on the potential usefulness of such information in clinical research. We have shown that resistance to fluconazole developed in 59% of AIDS patients with disseminated histoplasmosis who failed treatment, explaining why it was less effective than itraconazole. Susceptibility testing also has been used to evaluate several new antifungal agents. We have found that H. capsulatum is highly susceptible to posaconazole, and show an excellent response to that agent in experimental infection (75,79). Conversely, H. capsulatum was not susceptible to caspofungin, and caspofungin was ineffective in our murine model (77). Variable susceptibility was observed to nikkomycin, correlating with its effect in the mouse model (76). Others have shown voriconazole to be active against H. capsulatum (80), but animal studies have not been conducted.

　　MiraVista Diagnostics公司应用改良的NCCLS法对酵母相进行药敏实验。59%治疗无效的患播散性组织胞浆菌病的艾滋病患者对氟康唑耐药，这就解释了为什么它的药效比伊曲康唑要差。药敏实验也可用于评估几种新的抗真菌药物。我们发现组织胞浆菌对泊沙康唑的敏感性很高，而且该药在感染动物模型中也有很好的疗效(75,79)。相反，组织胞浆菌对卡泊芬净不敏感，而且在大鼠模型中也无效(77)。报道的对Nikkomycin的敏感性有所不同，并与小鼠模型中的疗效相关(76)。药敏实验发现伏立康唑对组织胞浆菌特别有效(80)，但动物实验还未进行。

We have explored the combination of itraconazole or fluconazole with amphotericin B in vitro and in our murine model. Although antagonism was not observed in vitro, fluconazole and amphotericin B were antagonistic in the pulmonary model of histoplasmosis (81). Recently we have extended these observations to a murine model Guided Medline Searchof Histoplasma meningitis, established through direct infection of the meninges, where, again, fluconazole antagonized the effect of amphotericin B (R. Haynes, in press, 2002).

　　我们已经对伊曲康唑或氟康唑和两性霉素B的联合使用进行体外实验和大鼠模型的探究。尽管在体外实验中没有发现药物的相互拮抗作用，但在组织胞浆菌病的肺部模型中伏立康唑对两性霉素B有拮抗作用(81)。最近我们已经将实验扩大为大鼠组织胞浆菌病脑膜炎模型（通过直接感染脑膜建立模型），发现氟康唑会拮抗两性霉素B的疗效(R. Haynes, in press, 2002)。

Acute Pulmonary Histoplasmosis: Patients with extensive acute pulmonary histoplasmosis who are dyspneic and hypoxic respond to antifungal therapy (11,82). Left untreated, recovery may be slow (15) and the outcome may be fatal (17,83). Patients with acute histoplasmosis who have less extensive disease but who remain symptomatic for a month or more also may benefit from therapy.

急性肺部组织胞浆菌病：患有急性广泛肺组织胞浆菌病并且有呼吸困难和低氧的患者对抗真菌治疗有反应(11,82)。如不进行治疗，患者的恢复可能很缓慢(15)，而且有可能導致死亡(17,83)。急性组织胞浆菌病病情较轻但症状持续大于一月的患者也可能从治疗中获益。

Amphotericin B 50 mg daily, or 0.7 to 1 mg/kg/d, given for one to two weeks, followed by itraconazole 200 mg once or twice daily for 3 months induces a rapid response and should be used in severely-ill patients. Itraconazole 200 mg twice daily for 2 weeks followed by once or twice daily for 3 months is recommended in patients with milder illnesses, and has proven to be effective in controlled trials in patients with disseminated and chronic pulmonary infection (84,85).

　　重症患者推荐用药：两性霉素B 50mg每日，或0.7-1mg/kg/d，应用1－2周，之后续贯伊曲康唑200mg 每日1次或2次，治疗三个月，可诱导快速反应。轻型患者推荐用药：伊曲康唑200mg 每日2次，应用2周，之后每日1次或2次治疗3个月。对照实验证明该方案对播散性和慢性肺部感染有效(84,85)。

Itraconazole is highly active against H. capsulatum, with MICs of <0.019 µg/ml in most cases. Drug levels of at least 1 µg/ml measured by bioassay should be effective for treatment of histoplasmosis, but higher concentrations (4 to 10 µg/ml) are preferred. Dosages of 200 mg daily achieve peak blood concentrations 2 to 4 hours after an oral dose of about 3 µg/ml while doses of 200 mg twice daily yield concentrations of about 6 µg/ml (85). Dosage could be reduced in patients with concentrations above 10 µg/ml. Itraconazole is better tolerated than ketoconazole and more active than fluconazole against H. capsulatum (86).

　　MIC小于<0.019 µg/ml时伊曲康唑对大多数患者有效。药物浓度为1 µg/ml即对治疗组织胞浆菌有效，较高的浓度(4 to 10 µg/ml)更受推荐。200mg每日一次在口服药2-4小时可以达到峰浓度3 µg/ml，而200mg每日2次则可达到6 µg/ml的浓度(85)。如患者体内药物浓度大于10 µg/ml则应该减量。伊曲康唑比酮康唑更易耐受，而且比氟康唑对组织胞浆菌更敏感(86)。

Mediastinal Granulomas: Mediastinal granuloma may produce obstructive symptoms or fistula. Occasional patients with these complications improve following antifungal therapy (87). Itraconazole 200 mg once or twice daily given for 3 to 6 months is recommended. In severe cases or those that show no response to antifungal therapy, addition of corticosteroid therapy may be helpful (88). Other patients have responded favorably to surgical resection of the granuloma (89). Antifungal treatment or resection of granuloma to prevent fibrosing mediastinitis is not indicated since progression of granulomatous mediastinitis to fibrosing mediastinitis has not been documented and must be rare (12).

纵隔肉芽肿：纵隔肉芽肿可能导致上腔静脉阻塞综合征和瘘形成等并发症。有时经过抗真菌治疗后这些并发症可有所改善(87)。推荐治疗方案：伊曲康唑200mg 每日1次或2次，治疗3-6个月。对于重症感染或通过抗真菌治疗无效者，加用激素治疗是有益的(88)。其他患者通过手术切除肉芽肿也有很好的效果(89)。由于从肉芽肿纵隔炎发展成纤维纵隔炎还未被报道，這应是罕见的，因此不需要抗真菌治疗及手术治疗来预防纤维纵隔炎(12)。

Rheumatologic Syndromes and Pericarditis: Patients with these inflammatory manifestations usually respond to aspirin or non-steroidal anti-inflammatory agents. Coriticosteroids may be required in patients with more severe manifestations or those who do not respond to less aggressive therapy (9,10). Organisms are not found in the pericardium or joints and antifungal therapy would not be expected to alter the course in patients with these manifestations of acute histoplasmosis. Nevertheless, itraconazole 200 mg once or twice daily may be appropriate in patients who receive corticosteroids for treatment of pericardial tamponade. Rarely joints or pericardium are sites of disseminated infection, in which case treatment would be necessary.

风湿热综合征和心包炎：患有这些炎症反应症状的患者通常对阿司匹林或非甾体抗炎药有效。对于较为症状严重的病例或治疗效果欠佳者，這可能需要应用激素來治疗(9,10)。在心包或关节处未发现病原体，则抗真菌治疗不能改变急性组织胞浆菌感染患者的这些症状的进程。不过，伊曲康唑200mg 每日1次或2次，可能对于心包填塞且应用激素治疗的患者比较适合。如果病況为播散性感染，则抗真菌治疗是有必要的，但关节和心包很少为播撒性感染所累及的部位。

Chronic Pulmonary Histoplasmosis: Untreated chronic pulmonary histoplasmosis usually is slowly progressive (34,90). Treatment improves survival, reduces symptoms, promotes radiographic healing and eradicates H. capsulatum from the sputum (91). Most patients with chronic pulmonary histoplasmosis respond well to treatment with itraconazole (84). Amphotericin B 50 mg daily, or 0.7 mg/kg/d, may be needed for the first few weeks of therapy in patients with more severe respiratory insufficiency to achieve a more rapid response to therapy. Itraconazole 200 mg once or twice daily should be continued for at least 18 months and until maximal clinical and radiographic benefit has been achieved. Successful treatment eliminates H. capsulatum from the sputum and causes regression of the pulmonary infiltrates in at least two-thirds of cases (92). Anti-Histoplasma antibody titers fall (92) but the significance of persistent seropositivity is unknown. Relapse is common (~ 25% of cases) after discontinuation of treatment, emphasizing the need for prolonged follow-up.

慢性肺部组织胞浆菌感染：如未经治疗，慢性肺部组织胞浆菌病通常进展缓慢(34,90)。治疗可以减少死亡率，缓解症状，改善影像学表现以及使痰中组织胞浆菌转阴(91)。多数患者对伊曲康唑反应较好(84)。对于有严重的呼吸衰竭者，需在初始数周内应用两性霉素B 50mg 每日1次，或0.7mg/kg /d。之后应续贯伊曲康唑200mg 每日1次或2次，至少18个月，直至获得最大的临床和影像学好转。成功的治疗可以使痰中的组织胞浆菌转阴，并使至少三分之二的患者的肺部渗出减少(92)。抗组织胞浆菌抗体滴度会下降，但持续血清学阳性的意义并不清楚。中途停止治疗的患者中常出现复发（约25％），因此强调续贯治疗时间应足够长。

Mediastinal Fibrosis: The course in slowly progressive in some patients, and may be fatal, supporting the urgent need for effective therapy. While most authorities believe that neither antifungal nor anti-inflammatory treatment ameliorates the outcome of this complication of histoplasmosis (12,46), one report suggested benefit from ketoconazole therapy (93). However, based upon the pathologic finding of extensive fibrosis, without inflammation or active infection, treatment would not seem likely to be beneficial.

纵隔纤维化：一些患者会缓慢发展为纵隔纤维化，而且可能是致命的，需要有效的治疗。尽管多数权威认为抗真菌治疗和抗炎治疗均不能改善纵隔纤维化患者的预后(12,46)，有个案报道酮康唑治疗有效(93)。不过根据病理所示广泛的纤维化而未见炎症和活动性感染，治疗似乎意义不大。

A three-month trial of itraconazole should be considered, particularly if complement fixation titers and the sedimentation rate are elevated. If follow-up CT scans and clinical evaluation show objective evidence for response, treatment should be continued for one year. Use of corticosteroids or other anti-inflammatory agents is not recommended. These patients may experience bacterial superinfections (12), requiring antibacterial therapy.

　　对于抗体滴度增加和血沉增快者，推荐应用3个月伊曲康唑的治疗方案。如果之后复查CT和临床症状评估发现治疗有改善，则需继续治疗1年。激素和其他抗炎药物均不推荐。如患者合并细菌感染，则应用抗细菌治疗(12)。

Surgery is controversial in management of fibrosing mediastinitis. Fewer than 40% of patients benefited and 20% died as a complication of surgery in the largest review of the surgical treatment of fibrosing mediastinitis (12,94). Intravascular stents may be helpful in selected patients with superior vena cava, pulmonary vascular or pulmonary venous obstruction (95), and embolization may relieve pulmonary hemorrhage.

目前对于外科治疗纤维化纵隔炎尚存在争议。有大规模外科治疗综述表明仅有小于40%的患者从中获益，且20％患者死于手术并发症(12,94)。对于一些上腔静脉、肺部血管和肺静脉阻塞的患者应用静脉内支架可能有效(95)，而栓塞术可能减轻肺部出血。

Disseminated Histoplasmosis: Disseminated histoplasmosis is usually fatal if untreated (35,96). Amphotericin B and itraconazole are highly effective therapy, inducing a remission in 85 to 90% of patients, including those who are immunosuppressed (35,37,84,85). Liposomal amphotericin B (AmBisome) was more effective than the deoxycholate formulation in a study in patients with AIDS (97). Resolution of fever and improvement of symptoms occurred in a higher proportion of patients treated with the liposomal formulation at a dose of 3 mg/kg/d than with the standard deoxycholate preparation at a dose of 0.7 mg/kg/d (97). Survival also was better with the lipid preparation. Thus, liposomal amphotericin B, 3 mg/kg/d is preferred in patients with severe or moderately severe disseminated histoplasmosis. Amphotericin B 50 mg daily, or 0.7 to 1 mg/kg/d, is an alternative.

播散性组织胞浆菌病：如不经治疗，播散性组织胞浆菌病往往是致命的(35,96)。两性霉素B和伊曲康唑为较为有效的治疗，85-90％患者可以有所缓解，其中包括免疫抑制的患者(35,37,84,85)。一项关于艾滋病患者的研究表明脂质体两性霉素B的效果优于胆盐形式的两性霉素B(97)。应用剂量为3mg/kg/d的脂质体形式与剂量为0.7mg/kg/d(97)胆盐形式的患者相比，发热缓解和症状恢复的比例明显增高。应用脂质体的患者生存率也增高。因此严重和危重的组织胞浆菌病患者推荐应用脂质体两性霉素B，3mg/kg/d，两性霉素B 50mg 每日或0.7－1mg/kg/d，作为备选。

Treatment can be changed to itraconazole after patients become afebrile, usually in 3 to 7 days. Longer courses of amphotericin B may be required in patients who are severely ill as indicated by the presence of shock or respiratory failure. Itraconazole 200 mg once or twice daily should be administered for 6 to 12 months in most patients and indefinitely in those with AIDS or other severe, irreversible immunosuppressive states. Improvement can be expected within one week in most patients (35,85), but relapse is common in patients who are immunosuppressed (35,37). Levels of Histoplasma antigen decline with therapy and increase with relapse, providing a useful tool for monitoring the response to therapy (58). Treatment should be continued until antigenemia and antigenuria have resolved.

　　经治疗后大约3-7日，患者体温降至正常，可更换为伊曲康唑治疗。如患者为严重感染者，例如存在休克或呼吸衰竭，可能需要更长时间两性霉素B的治疗。大多数患者需应用伊曲康唑200mg 每日1次或2次，持续6-12月，而艾滋病患者或其他严重的不可逆的免疫抑制状态者的治疗时间尚不确切。多数患者在治疗1周内好转(35,85)，但免疫抑制的患者常有复发(35,37)。组织胞浆菌抗原水平可以很好的监测治疗效果(58)。治疗需继续直到血清中和尿中抗原均转阴。

Central Nervous System: The outcome is unsatisfactory in patients with meningitis. Although most patients responded to treatment with amphotericin B, half relapsed during the next two years (38). The explanation for the poor outcome is unknown but may include the poor brain and CSF penetration of amphotericin B. The liposomal form of amphotericin B achieves higher concentrations in brain tissue, but also fails to penetrate the CSF (98). Fluconazole penetrates the CSF well, but is not highly active against H. capsulatum, and was less active than amphotericin B in an animal model of Histoplasma meningitis (R. Haynes, in press, 2002). Furthermore, fluconazole antagonized the activity of amphotericin B in the meninges when administered concurrently. Liposomal amphotericin B is recommended at a dose of 3 to 5 mg/kg/d for a total dose of 100 to 150 mg/kg, over two to three months, and until CSF cultures are negative. Itraconazole 200 mg twice or three times daily should be given for another year to prevent relapse. Careful follow-up with monitoring of CSF culture (10 ml of CSF) and antigen concentration is advised as resistance to fluconazole can develop during therapy (86). Life-long maintenance therapy may be needed in patients who relapse after appropriate therapy. Patients who fail chronic maintenance therapy may require direct injection of amphotericin B into the ventricles, an approach commonly complicated by arachnoiditis or radiculopathy (38), and one that is very rarely performed. Voriconazole is active against H. capsulatum and penetrates the CSF but has not been studied in histoplasmosis.

中枢神经系统：患有脑膜炎的组织胞浆菌病患者预后不佳。尽管大多数患者对两性霉素B有反应，一半患者会在之后的两年内会复发(38)。导致预后差的原因不明，可能由于两性霉素B在脑组织和脑脊液中的浓度较低。虽然两性霉素脂质体在脑组织中的浓度较高，但无法渗透入脑脊液(98)。氟康唑可较好的渗透入脑脊液，但它对于组织胞浆菌的作用较弱，有动物脑膜炎模型表明它比两性霉素B的作用差(R. Haynes, in press, 2002)。而且在脑膜中氟康唑还可拮抗两性霉素B的作用。两性霉素B脂质体的推荐剂量为3-5mg/kg/d，总的剂量为100-150mg/kg，至少2-3个月，直至脑脊液培养转阴。为预防复发，应再应用1年伊曲康唑200mg 每日2次或3次。由于在应用氟康唑治疗过程中可能会出现耐药，因此需严密监测脑脊液培养结果和抗原浓度(86)。如患者经治疗后出现复发，则可能需要终身维持治疗。如维持治疗无效，则需侧脑室注射两性霉素B，其并发症有蛛网膜炎或神经根病(38)，较为罕见。

Cerebritis or histoplasmomas in the brain or spinal cord usually do not require surgical excision (38). They resolve during antifungal therapy in most cases. Liposomal amphotericin B 3 mg/kg/d for two to three months, followed by itraconazole 200 mg twice daily to complete a year of therapy is recommended. Follow-up head CT or MRI is recommended to assure that the lesions have cleared before stopping therapy.

　　伏立康唑对组织胞浆菌有作用，可以渗透入脑脊液，不过目前尚无相关研究。大脑炎和/或在大脑或脊髓中的结节型组织胞浆菌病通常不需要外科切除(38)。多数会在抗真菌治疗中缓解。推荐应用两性霉素B脂质体3mg/kg/d 2-3月，之后以伊曲康唑200mg 每日2次续贯治疗1年。在停药前应复查CT或MRI以确保病变已清除。

Endocarditis: Treatment of Histoplasma endocarditis is unsatisfactory (41,42). Antifungal therapy combined with resection of the infected valve is recommended (42). In that report, 5 of 7 (71%) cases treated with antifungal therapy combined with surgery were cured compared to 4 of 9 (44%) who received antifungal therapy alone (42). These observations support a recommendation to administer amphotericin B, preferably the liposomal preparation, at maximal doses for two to three months, followed by itraconazole for another year. The valve also should be replaced, if possible. Chronic maintenance therapy may be appropriate in those who relapse or cannot undergo valve replacement.

心内膜炎：对于感染性心内膜炎的治疗效果欠佳(41,42)。推荐切除感染的瓣膜的同时予以抗真菌治疗(42)。该项研究中发现手术和抗真菌联合治疗的7例中有5例(71%)治愈，而9例单独以抗真菌治疗的患者中仅4例(44%)治愈(42)。通过这些观察结果，临床推荐予以两性霉素B，尤其是两性霉素B脂质体，以最大剂量治疗2－3个月，并以伊曲康唑治疗1年。如果条件允许，应行瓣膜置换手术。复发的病例和不能行瓣膜置换术者可能需要长期维持治疗。

Presumed Ocular Histoplasmosis: Presumed ocular histoplasmosis, if indeed caused by H. capsulatum , does not represent an active infection and would not be expected to respond to antifungal therapy ( 48) . Corticosteroids and laser therapy have been used in these patients ( 103-105) .

推测的眼部组织胞浆菌病：如果确实为眼部组织胞浆菌病，不表现为活动性感染，对抗真菌感染治疗不敏感( 48)。激素和激光治疗曾用于治疗这一类病人( 103-105)。

Maintenance Treatment: Relapse occurs in 10% to 20% of patients with disseminated histoplasmosis, and up to 80% of those with AIDS. In addition to AIDS, other immunosuppressive disorders (35,37), adrenal insufficiency (99), and inadequate therapy (7,35,36,96,100) increase the likelihood for relapse. Most experience with treatment to prevent relapse results from clinical trials in patients with AIDS.

维持治疗：10-20％的播散性组织胞浆菌病的患者会复发，而且80％的复发者为艾滋病患者。除患艾滋病以外，其他免疫抑制者、肾上限功能不全和不恰当的治疗(7,35,36,96,100)均增加复发的可能性。多数防止复发的治疗经验均源自患有艾滋病的患者。

Until recently, maintenance therapy was recommended in all patients with AIDS who recovered following treatment for histoplasmosis. Ongoing studies suggest that it is safe to stop maintenance therapy in patients with AIDS who have responded well to antifungal therapy, as evidenced by reduction of Histoplasma antigen levels to <4 units, and to antiretroviral therapy, based upon restoration of CD4 counts to >150 cells/mm³.

　　直至最近，对所有艾滋病患者均推荐维持治疗。正在进行的研究提示对于抗真菌治疗反应较好的艾滋病患者（依据组织胞浆菌抗原水平下降至4单位以下），且对抗病毒逆转录治疗反应较好，CD4细胞数恢复至大于150cells/mm³，停止维持治疗是安全的。

Several regimens have been used for maintenance therapy. Amphotericin B 50 mg weekly, although highly effective (81-97%), is inconvenient and not well tolerated in some patients (37,101). Itraconazole 200 mg given once or twice daily is over 90% effective and well tolerated (102), but may not be appropriate in some patients because of drug interaction, gastrointestinal intolerance, or inability to achieve therapeutic serum levels. A high relapse rate (31%) occurred using fluconazole 400 mg daily as maintenance therapy. These findings support use of itraconazole 200 mg daily. If fluconazole is used, doses of at least 400 mg daily are recommended, and patients should be monitored for relapse by clinical assessment and measurement of Histoplasma antigen in urine and serum.

　　几种药物被用于维持治疗。两性霉素B 50mg 每周1次，尽管有较好的效果（81-97％），然而因其不便和不易耐受，有一些患者無法使用此方案(37,101)。伊曲康唑200mg 每日1次或2次 90％以上有效，并且耐受好(102)，不过由于药物相互作用、胃肠不耐受或不能达到治疗血浆水平，一些患者也可能不适合。较高的复发率（31％）出现在应用氟康唑400mg 每日1次作为维持治疗的过程中。这样就更支持伊曲康唑200mg 每日1次的治疗。如应用氟康唑，则建议剂量至少为400mg 每日1次，并且应通过临床评估和血及尿中组织胞浆菌抗原的水平来监测患者情况。

New Therapies: Both voriconazole (80) and posaconazole (75) show activity in vitro, and posaconazole was more effective than itraconazole in vivo in a murine model of histoplasmosis (75,79). Neither has been studied in man, however. Nikkomycin Z is also active against some strains of H. capsulatum (76), while the echinocandins appear not to be effective (77).

新治疗：伏立康唑(80)和泊沙康唑(75)均有体外活性，而且在组织胞浆菌(75,79)大鼠的体内实验中泊沙康唑比伊曲康唑(75,79)更有效。不过，两者均无人体内实验。Nikkomycin Z 对部分组织胞浆菌也有效(76)，但棘白菌素类抗真菌药物无效(77)。

Review Article: Singh, N., Perfect, J. Immune Reconstitution Syndrome Associated with Opportunistic Mycoses. The LANCET Infectious Diseases 2007; Vol.7, Issue 6, 395-401.

There are two situations in which adjunctive immunomodulatory therapy should be considered. The first is in the patient with severe or relapsing disseminated disease. Animal data support a potential role of granulocyte/monocyte colony stimulating factor (107), interferon-g (110), or IL-12 (111) in such cases, but there are no studies in man, or even anecdotal reports. Of note is that our laboratory has not confirmed the benefit of interferon-g and IL-12 in experimental histoplasmosis, and the benefit seen in other studies often was very modest. Furthermore, interferon-g and IL-12 are quite toxic. Thus, these treatments cannot be endorsed until some experience in man supports their efficacy and tolerability.

　　在两种情况下需要考虑辅助治疗。第一为患者患有严重的或复发的播散性疾患时。动物试验的数据支持粒细胞集落刺激因子(107)、g干扰素(110)或白介素12(111)在该种病例中有潜在的作用，不过尚无人体实验甚至零散的报道。我们实验室并没有证实g干扰素和白介素12在组织胞浆菌病的效果，而且在其他研究中它们的作用也有限。g干扰素和白介素12毒性较大。因此在其有效性和耐受性在人体上被确定之前，这些治疗不能被认可。

The second situation is that of acute pulmonary or mediastinal histoplasmosis where the immune or inflammatory response is thought to contribute to the illness. Examples include patients with diffuse pulmonary involvement presenting with respiratory compromise following high inoculum exposure, and those with enlarged mediastinal nodes that obstruct the airways or major pulmonary vessels. There are reports of improvement with combined antifungal and corticosteroid therapy in such cases (11,82,88), supporting adjunctive corticosteroids in selected patients: diffuse acute pulmonary histoplasmosis causing respiratory compromise and mediastinal granuloma causing obstructive syndromes. The risk of promoting dissemination seems to be low if the patients receive concurrent antifungal therapy, and have no underlying immunosuppressive disorder.

第二种情况为急性肺部或纵隔组织胞浆菌病中有免疫或炎性反应的参与，例如，由于大量接触导致弥漫性肺部受累伴有呼吸衰竭者和纵隔淋巴结肿大伴有气道和大血管阻塞者。有报道指出抗真菌和激素联合治疗对上述病例有效(11, 82, 88)，因此需要考虑附加激素治疗。如果患者没有基础的免疫抑制缺陷如果同时应用抗真菌治疗，使用激素治疗時，其造成播散的风险比较小。

There have been no studies defining endpoints for monitoring therapy, but clinical experience does support some guidelines in the absence of firm data. Whether monitoring titers of complement fixing antibodies to H. capsulatum would be useful is unknown. In untreated cases, antibody titers may remain elevated for several years (53). While treatment may accelerate the decline in antibody titers, studies showing the effect of treatment on antibody titers, and the correlation of antibody titer reduction with response to therapy have not been reported. Without such data, treatment decisions based upon antibody titer clearance cannot be recommended.

目前尚无研究定义治疗监测的终点，不过临床经验确实支持一些指南的建议。监测组织胞浆菌的补体结合抗体滴度是否有用尚不清楚。在未治疗的病例中，抗体滴度可能持续升高数年(53)。治疗可以加速抗体滴度的下降，治疗对于抗体滴度的影响和治疗后抗体滴度的减弱与治疗效果的关系的研究尚未被发表。因为没有这样的数据，因此不推荐以抗体滴度清除指导治疗决策。

The effect of treatment on Histoplasma antigen levels has been investigated more fully. Treatment does cause progressive decline in antigen levels in the urine and blood (108), and relapse has been associated with rising levels (58). Recent unpublished observations indicate that antigen levels should eventually become undetectable with successful antifungal therapy, and immune reconstitution (CD4 counts increase to above 150 cells/ml) in patients with AIDS. Thus, strong consideration should be given to continuation of antifungal therapy for disseminated histoplasmosis until antigen can no longer be detected in the blood or urine.

治疗对组织胞浆菌抗原水平的效果有更全面的研究。治疗可以使血和尿(108)中的抗原水平明显下降，并且复发时伴随有抗原水平升高(58)。未发表的临床观察表明经过成功的抗真菌治疗和艾滋病患者的免疫重建（CD4计数升至150cells/ml）后抗原水平会最终无法测到。因此，较强的建議是；应一直维持抗真菌的治疗直至在血和尿中抗原消失。

Guidelines have been provided for duration of therapy in the preceding section and in other reviews (109). Unfortunately, clinical studies defining the optimal duration of therapy have not been conducted. Good clinical judgment must be used in recognition of these limitations. In patients with acute pulmonary histoplasmosis requiring therapy, treatment should be continued until the clinical findings have resolved, and the radiogram has shown resolution of the infiltrates. However, mediastinal adenopathy may persist, as may evidence of prominent interstitial markings; and these are not reasons to prolong therapy. With progressive, or cavitary pulmonary infection, treatment should be continued until the chest radiogram is stable and consistent with residual scarring rather than active inflammation. Most of these patients have underlying chronic obstructive lung disease, the clinical manifestations of which will persist after the infection has resolved. Treatment for disseminated infection should not be stopped until the clinical findings have resolved, the minimal duration of therapy has been reached, and antigen has disappeared from the blood and urine. If antigen concentrations persist at greater than 2 units in the blood or urine, consideration should be given to the use of chronic maintenance therapy.

前面的章节和其他综述中包含有关于治疗持续时间的指南(109)。但临床研究并没有最终确定出最理想的治疗持续时间。好的临床判断是很重要的。急性肺部组织胞浆菌感染的患者需要治疗，则要到临床症状均消失，而且影像学发现渗出缓解为止。不过纵隔淋巴结肿大可能存在，以及显著性间质性改变；这些表现则不是延长治疗指征。如有病情进展或空洞型肺部感染，需要持续治疗至肺部影像学稳定而且仅为陈旧疤痕而无活动性炎症。存在慢性阻塞性肺疾病的患者，感染被治愈后临床症状可能一直存在。播散性感染的治疗应一直持续到临床症状缓解为止，并且血、尿中的抗原转阴。如果抗原在血或尿中的浓度持续大于两亇单位，则应考虑应用长期维持抗真菌的治疗治疗。

Review Article: Wheat LJ, Freifeld AG, Kleiman MB, et al. Clinical Practice Guidelines for the Management of Patients with Histoplasmosis: 2007 Update by the Infectious Diseases Society of America. Clin Infect Dis 2007;45:807-825.

A vaccine against histoplasmosis may be needed is some circumstances (106), and is under investigation (107). First a more complete understanding of the epitopes that are involved in the development of protective immunity to H. capsulatum is needed. Then we must determine who should be vaccinated: the entire population, just those living in an endemic area, only those at increased risk for exposure because of occupation or avocation, or those with diseases that predispose to complications of histoplasmosis.

在某些情况下可能需要组织胞浆菌疫苗 (106)，这个课题一直在研究之中(107)。首先需要对表位更完全的认识以诱导出对荚膜组织胞浆菌有保护性的免疫。之后需要确定应该接种疫苗的人群：居住在流行地的居民，并且由于职业或副业有较高接触风险的人群，或因具有某些疾病使其易于出现并发症的人群。

Cavers and tour organizers should be aware of the high risk for histoplasmosis associated with exposure to bat guano in caves and familiar with the approaches to reduce that risk (112). Cavers should be advised to seek medical attention at the first sign of illness following potential exposure and should be aware of the potential benefit of antifungal treatment. Immunosuppressed individuals should be warned to avoid activities that place them at high risk for exposure to H. capsulatum.

应充分告知洞穴勘探者和旅游组织者，接触洞穴中的蝙蝠粪便会使患组织胞浆菌病风险增加，而且应告知他们减小风险的方法(112)。应该建议相关人员在暴露后出现症状时应及时就医，并且让他们知晓抗真菌治疗的益处。有免疫缺陷的人群应避免在有较大组织胞浆菌暴露风险的地区活动。

Immunosuppressed individuals with occupations or hobbies that expose them to dirt or to accumulations of composted bird or bat droppings may be at an increased risk for histoplasmosis. They should avoid activities associated with disturbance of an accumulation of bird or bat droppings.

免疫缺陷人群如因职业或爱好接触较多泥土或鸟类及蝙蝠排泄物则可能增加患组织胞浆菌的风险。他们应避免接触鸟类或蝙蝠的排泄物。

Another concern is the risk for reactivation of histoplasmosis in persons with evidence of prior infection who are to undergo immunosuppression. Situations raising this concern include persons with a history of prior histoplasmosis, those with calcifications on chest radiograph, or persons with positive serologic tests done as part of pre-immunosuppression screening. Our experience suggests that relapse is rare in such cases (113), and that prophylaxis or avoidance of immunosuppression (or transplantation) is unnecessary. However, if the clinical finding suggested that the episode of histoplasmosis was relatively recent (last 2 years) consideration should be given to prophylaxis with itraconazole.

另外，既往曾患组织胞浆菌者出现于免疫抑制状态时有复发的风险。有以下情况时应尤其警惕复发：既往曾患组织胞浆菌病，胸片可见钙化，免疫抑制治疗前评估发现血清学阳性。根据我们的经验以上情况复发少见(113)，没有必要给予预防性治疗或避免免疫抑制（或移植）治疗。不过如果有近期（2年以内）患组织胞浆菌病史，需要考虑使用伊曲康唑进行预防性治疗。

Prophylaxis in persons with AIDS with CD4 counts < 150 cells/mm³ is appropriate if the case rate exceeds 10/100 patient years. Itraconazole 200 mg daily reduced the case rate of histoplasmosis and cryptococcosis by 70% (114). Prophylaxis had no impact on survival, however, and may have promoted the development of resistance of C. albicans to itraconazole and fluconazole (115).

如果发病率超过10%每年，CD4细胞总数小于150cells/mm3的艾滋病患者需要预防治疗。应用伊曲康唑200mg 每日1次可以降低组织胞浆菌病和隐球菌菌病的发病率70％(114)。预防并不能改善生存率，并可能会增加白色念珠菌对伊曲康唑和氟康唑的耐药(115)。

Sites known or suspected to harbor H. capsulatum, particularly if cases have been diagnosed following exposure to those sites, should be posted as posing a danger of histoplasmosis. Such sites should be reported to public health authorities or the National Institute for Occupational Safety and Health (112), so that decontamination or quarantine procedures can be considered.

发现患病者或疑似病例的地点，应佈告表明當地有受组织胞浆菌咸染的风险。同时上报至有关卫生机构(112)，并应考虑净化或隔离这些地点。

Figure 1. Endemic Distribution of Histoplasmosis in the Americas. The Highest Incidence is in the Finely Stippled Area of North and Central America. Reprinted With Permission Of The Publisher (1).

图1.美国组织胞浆菌病的流行地区。发病率最高的地区为北美和中美的部分区域。

1. Rippon JW. Histoplasmosis Histoplasmosis capsulati.. In: Wonsiewicz M, editor. Medical mycology: the pathogenic fungi and the pathogenic actinomycetes. Philadelphia: W.B. Saunders Company, 1988: 381-423. [PubMed]

3. Emmons CW, Klite PD, Baer GM, Hill WB Jr. Isolation of Histoplasma capsulatum from bats in the United States. Am J Epidemiol 1966; 84:103-109. [PubMed]

4. Hasenclever HF, Shacklette MH, Young RV, Gelderman GA. The natural occurrence of Histoplasma capsulatum in a cave. Am J Epidemiol 1967; 86:238-245. [PubMed]

5. Johnson J, Kabler JD, Gourley MF, D'Alessio DJ, Dodge RW, Golubjatnikov R et al. Cave-associated histoplasmosis: Costa Rica. MMWR 1988; 37:312-313. [PubMed]

6. Sacks JJ, Ajello L, Crockett LK. An outbreak and review of cave-associated histoplasmosis capsulati. J Med Vet Mycol 1986; 24:313-327. [PubMed]

7. Wheat LJ, Wass J, Norton J, Kohler RB, French ML. Cavitary histoplasmosis occurring during two large urban outbreaks: Analysis of clinical, epidemiologic, roentgenograghic, and laboratory features. Medicine Baltimore. 1984; 63:201-209. [PubMed]

8. Ward JI, Weeks M, Allen D, Hutcheson RH Jr., Anderson R, Fraser DW et al. Acute histoplasmosis: Clinical, epidemiologic and serologic findings of an outbreak associated with exposure to a fallen tree. Am J Med 1979; 66:587-595. [PubMed]

9. Wheat LJ, Stein L, Corya BC, Wass JL, Norton JA, Grider K et al. Pericarditis as a manifestation of histoplasmosis during two large urban outbreaks. Medicine Baltimore. 1983; 62:110-119. [PubMed]

10. Rosenthal J, Brandt KD, Wheat LJ, Slama TG. Rheumatologic manifestations of histoplasmosis in the recent Indianapolis epidemic. Arthr Rheum 1983; 26:1065-1070. [PubMed]

11. Kataria YP, Campbell PB, Burlingham BT. Acute pulmonary histoplasmosis presenting as adult respiratory distress syndrome: Effect of therapy on clinical and laboratory features. South Med J 1981; 74:534-537. [PubMed]

12. Loyd JE, Tillman BF, Atkinson JB, des Prez RM. Mediastinal fibrosis complicating histoplasmosis. Medicine Baltimore. 1988; 67:295-310. [PubMed]

13. Larrabee WF, Ajello L, Kaufman L. An epidemic of histoplasmosis on the isthmus of Panama. Am J Trop Med Hyg 1978; 27:281-285. [PubMed]

14. Loosli CG, Grayston JT, Lester W Jr., Tanzi F, Combs LW, Alexander ER. Some epidemiological and clinical aspects of pulmonary histoplasmosis in a farm family. Trans Assoc Am Physic 1952; LXV:159-167. [PubMed]

15. Rubin H, Furcolow ML, Yates JL, Brasher CA. The course and prognosis of histoplasmosis. Am J Med 1959; 27:278-288. [PubMed]

16. Brodsky AL, Gregg MB, Kaufman L, Mallison GF. Outbreak of histoplasmosis associated with the 1970 Earth Day activities. Am J Med 1973; 54:333-342. [PubMed]

17. Sollod N. Acute fulminating disseminated histoplasmosis. J S Carol Med Assoc 1971; 67:231-234. [PubMed]

18. Wheat LJ, Slama TG, Eitzen HE, Kohler RB, French MLV, Biesecker JL. A large urban outbreak of histoplasmosis: Clinical features. Yearbook of Medicine 1982;203-205. [PubMed]

19. Wheat LJ, Slama TG, Eitzen HE, Kohler RB, French MLV, Bieseckler JL. A large urban outbreak of histoplasmosis: Clinical features. Ann Intern Med 1981; 94:331-337. [PubMed]

20. Coss KC, Wheat LJ, Conces DJ Jr., Brashear RE, Hull MT. Esophageal fistula complicating mediastinal histoplasmosis: Response to amphotericin B. Am J Med 1987; 83:343-346. [PubMed]

21. Kunkel WM Jr., Clagett OT, McDonald JR. Mediastinal granulomas. J Thorac Surg 1954; 27:565-574. [PubMed]

22. Garrett HE Jr., Roper CL. Surgical intervention in histoplasmosis. Ann Thorac Surg 1986; 42:711-722. [PubMed]

23. Landay MJ, Rollins NK. Mediastinal histoplasmosis granuloma: Evaluation with CT. Rad 1989; 172:657-659. [PubMed]

24. Lerner MH, Deluca SA. Mediastinal granuloma secondary to histoplasmosis. AFPRH 1991; 43:1649-1651. [PubMed]

25. Schowengerdt CG, Suyemoto R, Beachley F. Granulomatous and fibrous mediastinitis. J Thorac Cardiovasc Surg 1969; 57:365-379. [PubMed]

26. Rabinowitz JG, Prater W, Silver J, Phillips JC, Wieder S. Mediastinal histoplasmosis. Mt Sinai J Med 1980; 47:356-363. [PubMed]

27. Bilgi C, Slesar S. Constrictive pericarditis and pericardial calcification with positive histoplasmin skin test. Can Med Assoc J 1976; 114:877-882. [PubMed]

28. Klieger HL, Fisher ER. Fibrocalcific constrictive pericarditis due to Histoplasma capsulatum. N Engl J Med 1962; 267:593-596. [PubMed]

29. Wooley CF, Hosier DM. Constrictive pericarditis due to Histoplasma capsulatum. N Engl J Med 1961; 264:1230-1232. [PubMed]

30. Picardi JL, Kauffman CA, Schwarz J, Holmes JC, Phair JP, Fowler NO. Pericarditis caused by Histoplasma capsulatum. Am J Cardiol 1976; 37:82-88. [PubMed]

31. Sellers TF Jr., Price WN Jr., Newberry WM Jr. An epidemic of erythema multiforme and erythema nodosum caused by histoplasmosis. Ann Intern Med 1965; 62:1244-1262. [PubMed]

32. Thornberry DK, Wheat LJ, Brandt KD, Rosenthal J. Histoplasmosis presenting with joint pain and hilar adenopathy: Pseudosarcoidosis. Arthr Rheum 1982; 25:1396-1402. [PubMed]

33. Medeiros AA, Marty SD, Tosh FE, Chin TD. Erythema nodosum and erythema multiforme as clinical manifestations of histoplasmosis in a community outbreak. N Engl J Med 1966; 274:415-420. [PubMed]

34. Goodwin RA, Jr., Owens FT, Snell JD, Hubbard WW, Buchanan RD, Terry RT et al. Chronic pulmonary histoplasmosis. Medicine Baltimore. 1976; 55:413-452. [PubMed]

35. Sathapatayavongs B, Batteiger BE, Wheat LJ, Slama TG, Wass JL. Clinical and laboratory features of disseminated histoplasmosis during two large urban outbreaks. Medicine Baltimore. 1983; 62:263-270. [PubMed]

36. Goodwin RA Jr., Shapiro JL, Thurman GH, Thurman SS, des Prez RM. Disseminated histoplasmosis: Clinical and pathologic correlations. Medicine Baltimore. 1980; 59:1-33. [PubMed]

37. Wheat LJ, Connolly-Stringfield PA, Baker RL, Curfman MF, Eads ME, Israel KS et al. Disseminated histoplasmosis in the acquired immune deficiency syndrome: clinical findings, diagnosis and treatment, and review of the literature. Medicine Baltimore. 1990; 69:361-374. [PubMed]

38. Wheat LJ, Batteiger BE, Sathapatayavongs B. Histoplasma capsulatum infections of the central nervous system: a clinical review. Medicine 1990; 69:244-260. [PubMed]

39. Bazan CI, New PZ. Intramedullary spinal histoplasmosis efficacy of gadolinium enhancement. N 1991; 33:190. [PubMed]

40. Anaissie E, Fainstein V, Samo T, Bodey GP, Sarosi GA. Central nervous system histoplasmosis: An unappreciated complication of the acquired immunodeficiency syndrome. Am J Med 1988; 84:215-217. [PubMed]

41. Gaynes RP, Gardner P, Causey W. Prosthetic value endocarditis caused by Histoplasma capsulatum. Arch Intern Med 1981; 141:1533-1537. [PubMed]

42. Kanawaty DS, Stalker MJ, Munt PW. Nonsurgical treatment of Histoplasma endocarditis involving a bioprosthetic valve. Chest 1991; 99:253-256. [PubMed]

43. Rogers EW, Weyman AE, Noble RJ, Bruins SC. Left artial myxoma infected with Histoplasma capsulatum. Am J Med 1978; 64:683-690. [PubMed]

44. Arrigoni MG, Bernatz PE, Donoghue FE. Broncholithiasis. J Thorac Cardiovasc Surg 1971; 62:231-237. [PubMed]

45. Davis A, Pierson D, Loyd JE. Mediastinal fibrosis. Sem Resp Infect 2001; 162.:119-130. [PubMed]

46. Goodwin RA, Nickell JA, des Prez RM. Mediastinal fibrosis complicating healed primary histoplasmosis and tuberculosis. Medicine Baltimore. 1972; 51:227-246. [PubMed]

47. Goodwin RA Jr., Snell JD Jr. The enlarging histoplasmoma: Concept of a tumor-like phenomenon encompassing the tuberculoma and coccidioidoma. Am Rev Respir Dis 1969; 100:1-12. [PubMed]

48. Ciulla T, Piper H, Xiao M, Wheat LJ. Presumed ocular histoplasmosis syndrome: update on epidemiology, pathogenesis, and photodynamic, antiangiogenic, and surgical therapies. Current Opinion in Ophthalmology 2001; 12:442-449. [PubMed]

49. Spaeth GL. Presumed Histoplasma uveitis: continuing doubts as to its actual cause. In: Ajello LP, Chick EM, Furcolow MMS, editors. Histoplasmosis. Springfield, IL: Charles C. Thomas, 1971: 221-230. [PubMed]

50. Suttorp-Schulten MS, Bollemeijer JG, Bos PJ, Rothova A. Presumed ocular histoplasmosis in the Netherlands - An area without histoplasmosis. Br J Ophthalmol 1997; 811.:7-11. [PubMed]

51. Specht CS, Mitchell KT, Bauman AE, Gupta M. Ocular histoplasmosis with retinitis in a patient with acquired immune deficiency syndrome. Oph 1991; 98:1356-1359. [PubMed]

52. Wheat LJ. Laboratory diagnosis of histoplasmosis: A review. Sem Resp Infect 2001; 16(2):131-140. [PubMed]

53. Wheat LJ, French ML, Kohler RB, Zimmerman SE, Smith WR, Norton JA et al. The diagnostic laboratory tests for histoplasmosis: Analysis of experience in a large urban outbreak. Ann Intern Med 1982; 97:680-685. [PubMed]

54. Williams B, Fojtasek M, Connolly-Stringfield P, Wheat J. Diagnosis of histoplasmosis by antigen detection during an outbreak in Indianapolis, Ind. Arch Pathol Lab Med 1994; 118:1205-1208. [PubMed]

55. Wheat LJ. The role of the serologic diagnostic laboratory and the diagnosis of fungal disease. In: Sarosi GA, Davies SF, editors. Fungal Diseases of the Lung. NewYork: RavenPress, 1993: 29-38. [PubMed]

56. Wheat LJ, French ML, Kamel S, Tewari RP. Evaluation of cross-reactions in Histoplasma capsulatum serologic tests. J Clin Microbiol 1986; 23:493-499. [PubMed]

57. Wheat LJ, Kohler RB, Tewari RP. Diagnosis of disseminated histoplasmosis by detection of Histoplasma capsulatum antigen in serum and urine specimens. N Engl J Med 1986; 314:83-88. [PubMed]

58. Wheat LJ, Connolly-Stringfield P, Blair R, Connolly K, Garringer T, Katz BP. Histoplasmosis relapse in patients with AIDS: detection using Histoplasma capsulatum variety capsulatum antigen levels. Ann Intern Med 1991; 115:936-941. [PubMed]

59. Edwards LB, Acquaviva FA, Livesay VT, Cross FW, Palmer CE. An atlas of sensitivity to tuberculin, PPD-B and histoplasmin in the United States. Am Rev Respir Dis 1969; 99:1-18. [PubMed]

60. Vail G, Goldberg JS, Durkin MM, Goldman M, Wheat J. In vitro determination of cell mediated immunity in histoplasmosis. abstract , 141. 1998. [PubMed]

61. Goodwin RA Jr., des Prez RM. Histoplasmosis. Am Rev Respir Dis 1978; 117:929-956. [PubMed]

62. Deepe GS Jr., Bullock WE. Histoplasmosis: A granulomatous inflammatory response. In: Gallin JI, Goldstein IM, Snyderman R, editors. Inflammation: Basic Principals and Clinical Correlates. New York: Raven, 1988: 733-749. [PubMed]

63. Andes D, Stamsted T, Conklin R. Pharmacodynamics of amphotericin B in a neutropenic-mouse disseminated-candidiasis model. Antimicrob Agents Chemother 2001; 453.:922-926. [PubMed]

64. Newman SL. Cell-Mediated Immunity to Histoplasma capsulatum. Sem Resp Infect 2001; 162.:102-108. [PubMed]

65. Wu-Hsieh B, Howard DH. Histoplasmosis. In: Murphy JW, editor. Fungal Infections and Immune Responses. New York: Plenum Publishing, 1993: 213-250. [PubMed]

66. Allendoerfer R, Biovin GP, Deepe GS Jr. Modulation of immune responses in murine pulmonary histoplasmosis. J Infect Dis 1997; 1754.:905-914. [PubMed]

67. Wheat LJ, Slama TG, Norton JA, Kohler RB, Eitzen HE, French MLV et al. Risk factors for disseminated or fatal histoplasmosis. Ann Intern Med 1982; 96:159-163. [PubMed]

68. Zhou P, Sieve MC, Bennett J, Kwon-Chung KJ, Tewari RP, Gazzinelli RT et al. IL-12 prevents mortality in mice infected with Histoplasma capsulatum through induction of IFN-gamma. J Immunol 1995; 155:785-795. [PubMed]

69. Salzman SH, Smith RL, Aranda CP. Histoplasmosis in patients at risk for the acquired immunodeficiency syndrome in a nonendemic setting. Chest 1988; 93:916-921. [PubMed]

70. Davies SF, Khan M, Sarosi GA. Disseminated histoplasmosis in immunologically suppressed patients. Am J Med 1978; 64:94-100. [PubMed]

71. Keath EJ, Kobayashi GS, Medoff G. Typing of Histoplasma capsulatum by restriction fragment length polymorphisms in a nuclear gene. J Clin Microbiol 1992; 30:2104-2107. [PubMed]

72. Powell KE, Hammerman KJ, Dahl BA, Tosh FE. Acute reinfection pulmonary histoplasmosis. Am Rev Respir Dis 1973; 107:374-378. [PubMed]

73. Schwarz J, Baum GL. Reinfection in histoplasmosis. Arch Pathol 1963; 75:475-479. [PubMed]

74. Goodwin RA, Loyd JE, des Prez RM. Histoplasmosis in normal hosts. Medicine Baltimore. 1981; 60:231-266. [PubMed]

75. Connolly P, Wheat J, Schnizlein-Bick C, Durkin M, Kohler S, Smedema M et al. Comparison of a new triazole antifungal agent, Schering 56592, with itraconazole and amphotericin B for treatment of histoplasmosis in immunocompetent mice. Antimicrob Agents Chemother 1999; 432.:322-328. [PubMed]

76. Goldberg J, Connolly P, Schnizlein-Bick C, Durkin M, Kohler S, Smedema M et al. Comparison of nikkomycin Z with amphotericin B and itraconazole for treatment of histoplasmosis in a murine model. Antimicrob Agents Chemother 2000; 446.:1624-1629. [PubMed]

77. Kohler S, Wheat LJ, Connolly P, Schnizlein-Bick C, Durkin M, Smedema M et al. Comparison of the Echinocandin Caspofungin with Amphotericin B for Treatment of Histoplasmosis following Pulmonary Challenge in a Murine Model. Antimicrob Agents Chemother 2000; 447.:1850-1854. [PubMed]

78. LeMonte A, Washum K, Smedema M, Schnizlein-Bick C, Kohler R, Wheat LJ. Amphotericin B combined with itraconazole or fluconazole for treatment of histoplasmosis. J Infect Dis 2000;182.:545-550. [PubMed]

79. Sorensen KN, Sobel RA, Clemons KV, Pappagianis D, Stevens DA, Williams PL. Comparison of fluconazole and itraconazole in a rabbit model of coccidioidal meningitis. Antimicrob Agents Chemother 2000; 446.:1512-1517. [PubMed]

80. Li RK, Ciblak MA, Nordoff N, Pasarell L, Warnock DW, McGinnis MR. In vitro activities of voriconazole, itraconazole, and amphotericin B against Blastomyces dermatitidis, Coccidioides immitis and Histoplasma capsulatum. Antimicrob Agents Chemother 2000; 44(6).:1734-1736. [PubMed]

81. Lo Y, Tintelnot K, Lippert U, Hoppe T. Disseminated Penicillium marneffei infection in an African AIDS patient. Trans R Soc Trop Med Hyg 2000; 94(2).:187. [PubMed]

82. Wynne JW, Olsen GN. Acute histoplasmosis presenting as the adult respiratory distress syndrome. Chest 1974; 66:158-161. [PubMed]

83. Prior JA, Saslaw S, Cole CR. Experiences with histoplasmosis. Ann Intern Med 1954; 40:221-244. [PubMed]

84. Dismukes WE, Bradsher RW Jr., Cloud GC, Kauffman CA, Chapman SW, George RB et al. Itraconazole therapy for blastomycosis and histoplasmosis. Am J Med 1992; 93:489-497. [PubMed]

85. Wheat J, Hafner R, Korzun AH, Limjoco MT, Spencer P, Larsen RA et al. Itraconazole treatment of disseminated histoplasmosis in patients with the acquired immunodeficiency syndrome. Am J Med 1995; 98:336-342. [PubMed]

86. Wheat J, Marichal P, Vanden Bossche H, Le Monte A, Connolly P. Hypothesis on the mechanism of resistance to fluconazole in Histoplasma capsulatum. Antimicrob Agents Chemother 1997; 41:410-414. [PubMed]

87. Savides TJ, Gress FG, Wheat LJ, Ikenberry S, Hawes RH. Dysphagia due to mediastinal granulomas: Diagnosis with endoscopic ultrasonography. Gastroenterology 1995; 109:366-373. [PubMed]

88. Greenwood MF, Holland P. Tracheal obstruction secondary to Histoplasma mediastinal granuloma. Chest 1972; 62:642-645. [PubMed]

89. Gilliland MD, Scott LD, Walker WE. Esophageal obstruction caused by mediastinal histoplasmosis: Beneficial results of operation. Sur 1984; 95:59-62. [PubMed]

90. Furcolow ML. Course and prognosis of untreated histoplasmosis. JAMA 1961; 177:292-296. [PubMed]

91. Sutliff WD, Andrews CE, Jones E, Terry RT. Histoplasmosis cooperative study: Veterans Administration-Armed Forces Cooperative Study on histoplasmosis. Am Rev Respir Dis 1964; 89:641-650. [PubMed]

92. Putnam LR, Sutliff WD, Larkin JC, Baum GL, Busey JF, Johns LE et al. Histoplasmosis cooperative study: Chronic pulmonary histoplasmosis treated with amphotericin B alone and with amphotericin B and triple sulfonamide. Am Rev Respir Dis 1968; 97:96-102. [PubMed]

93. Urschel HC Jr., Razzuk MA, Netto GJ, Disiere J, Chung SY. Sclerosing mediastinitis: Improved management with histoplasmosis titer and ketoconazole. Ann Thorac Surg 1990; 50:215-221. [PubMed]

94. Mathisen DJ, Grillo HC. Clinical manifestations of mediastinal fibrosis and histoplasmosis. Ann Thoracic Surgery 1992; 54:1053-1058. [PubMed]

95. McNeil MM, Nash SL, Hajjeh RA, Phelan MA, Conn LA, Plikaytis BD et al. Trends in mortality due to invasive mycotic diseases in the United States, 1980-1997. Am J Hum Genet 2001; 693.:641-NIL7. [PubMed]

96. Furcolow ML. Comparison of treated and untreated severe histoplasmosis. JAMA 1963; 183:121-127. [PubMed]

97. Johnson P, Wheat LJ, Cloud G, Thomas C, Dismukes W, Goldman M et al. A Multicenter Randomized Trial Comparing Amphotericin B AmB. and Liposomal Amphotericin B AmBisome, LAmB. as Induction Therapy of Disseminated Histoplasmosis DH. in AIDS Patients. Ann Intern Med 2002; in press. [PubMed]

98. Groll AH, Giri N, Petraitis V, Petraitiene R, Candelario M, Bacher JS et al. Comparative efficacy and distribution of lipid formulations of amphotericin B in experimental Candida albicans infection of the central nervous system. J Infect Dis 2000; 1821.:274-282. [PubMed]

99. Paya CV, Hermans PE, van Scoy RE, Ritts RE Jr., Homburger HA. Repeatedly relapsing disseminated histoplasmosis: Clinical observations during long-term follow-up. J Infect Dis 1987; 156:308-312. [PubMed]

100. Sarosi GA, Voth DW, Dahl BA, Doto IL, Tosh FE. Disseminated histoplasmosis: Results of long-term follow-up. Ann Intern Med 1971; 75:511-516. [PubMed]

101. McKinsey DS, Gupta MR, Riddler SA, Driks MR, Smith DL, Kurtin PJ. Long-term amphotericin B therapy for disseminated histoplasmosis in patients with the acquired immune deficiency syndrome. Ann Intern Med 1989; 111:655-659. [PubMed]

102. Wheat J, Hafner R, Wulfson M, Spencer P, Squires K, Powderly W et al. Prevention of relapse of histoplasmosis with itraconazole in patients with the acquired immunodeficiency syndrome. Ann Intern Med 1993; 118:610-616. [PubMed]

103. Schwarz J. Histoplasmosis of the eye. Histoplasmosis. New York, NY: Praeger, 1981: 317-350. [PubMed]

104. Fine SL, Wood WJ, Isernhagen RD, Singerman LJ, Bressler NM, Folk JC et al. Laser treatment for subfoveal neovascular membranes in ocular histoplasmosis syndrome: Results of a pilot randomized clinical trial. Arch Ophthalmol 1993; 111:19-20. [PubMed]

105. Macular Photocoagulation Study Grp. Laser photocoagulation for neovascular lesions nasal to the fovea: Results from clinical trials for lesions secondary to ocular histoplasmosis or idiopathic causes. Arch Ophthalmol 1995; 113:56-61. [PubMed]

106. Deepe GS Jr. Prospects for the Development of Fungal Vaccines. Clin Microbiol Rev 1997; 10(4).:585-596. [PubMed]

107. Deepe GS Jr., Gibbons R. Recombinant Murine Granulocyte-Macrophage Colony-Stimulating Factor Modulates the Course of Pulmonary Histoplasmosis in Immunocompetent and Immunodeficient Mice. Antimicrob Agents Chemother 2000; 44(12).:3328-3336. [PubMed]

108. Wheat LJ, Cloud G, Johnson PC, Connolly PA, Goldman M, Le Monte A et al. Clearance of Fungal Burden during Treatment of Disseminated Histoplasmosis with Liposomal Amphotericin B versus Itraconazole. Antimicrob Agents Chemother 2001; 458.:2354-2357. [PubMed]

109. Wheat J, Sarosi G, McKinsey D, Hamill R, Bradsher R, Johnson P et al. Practice guidelines for the management of patients with histoplasmosis. Clin Infect Dis 2000; 304.:688-695. [PubMed]

110. Clemons KV, Lutz JE, Stevens DA. Efficacy of interferon-gamma and amphotericin B for the treatment of systemic murine histoplasmosis. Microbe Infect 2001; 31.:3-10. [PubMed]

111. Zhou P, Sieve MC, Tewari RP, Seder RA. Interleukin-12 modulates the protective immune response in SCID mice infected with Histoplasma capsulatum. Infect Immun 1997; 653.:936-942. [PubMed]

112. Lenhart S. Recommendations for Protecting Workers from Histoplasma capsulatum Exposure During Bat Guano Removal from a Church's Attic. Appl Occup Environ Hyg 1994; 94.:230-236. [PubMed]

113. Vail G, Young R, Filo RS, Cornetta K, Wheat J, Goldman M. Incidence of histoplasmosis following allogeneic bone marrow transplant aBMT. or solid organ transplant SOT. in a hyperendemic area. Program and Abstracts of the 36th Infectious Diseases Society of America Meeting in Denver, CO, November 11-14, 1998. 141. 1998. [PubMed]

114. McKinsey DS, Wheat LJ, Cloud GA, Pierce M, Black JR, Bamberger DM et al. Itraconazole prophylaxis for fungal infections in patients with advanced human immunodeficiency virus infection: Randomized, placebo-controlled, double-blind study. Clin Infect Dis 1999; 285:1049-1056. [PubMed]

115. Goldman M, Cloud GA, Smedema M, LeMonte A, Connolly P, McKinsey DS et al. Does long-term itraconazole prophylaxis result in in vitro azole resistance in mucosal Candida albicans isolates from persons with advanced human immunodeficiency virus infection? Antimicrob Agents Chemother 2000; 446:1585-1587. [PubMed]