发热

Lynne Strasfeld, M.D.

Infectious Disease Service

Memorial Sloan-Kettering Cancer Center

New York, NY 10021

Kent A. Sepkowitz, M.D.

Head, Clinical Infectious Disease Section

Infectious Disease Service

Memorial Sloan-Kettering Cancer Center

1275 York Avenue

New York, NY 10021

Phone:(212)639-2441

INTRODUCTION 概述

Fever is a common complaint among patients with HIV infection and may occur at any point during viral infection (144).

发热是HIV感染者的常见主诉，可发生在感染的任何阶段(144)。

Patients with primary HIV infection, the "acute retroviral syndrome," can present clinically with a febrile illness resembling mononucleosis. Symptoms may include headache, myalgia, pharyngitis, lymphadenopathy, maculopapular rash, aphthous ulcers, weight loss, retroorbital pain, nausea, diarrhea or meningeal signs (115).

患者感染HIV病毒后会出现发热及其他类似传染性单核细胞增多症的临床表现，称为急性逆转录病毒综合症。其症状包括头痛、肌痛、咽炎、淋巴结肿大、斑丘疹、口腔溃疡、体重减轻、眼球后疼痛、恶心、腹泻、或脑膜炎表现等(115)。多出现在感染后的2-6周，持续1-2周。诊断依靠血p24抗原或HIV-RNA阳性。

Symptomatic infection typically occurs two to six weeks after exposure to HIV-1 and usually resolves within one to two weeks. Establishment of the diagnosis typically requires demonstration of p24 antigenemia or evidence of HIV viral RNA in blood.

Following primary HIV infection, most patients enter a prolonged, asymptomatic phase characterized immunologically by a progressive decline in the CD4 count.　

急性期后，通常病程进入一个较长的无症状期，其间CD4细胞计数进行性下降。

 As the CD4 count continues to fall, opportunistic infections and malignancies that define clinical AIDS and characterize the later stages of immune dysfunction become increasingly common.　

随着免疫功能的下降，机会性感染和肿瘤的风险逐渐增加，标志着获得性免疫缺陷综合征（AIDS）的开始（发生）。

 In studies done prior to the availability of active antiretroviral therapy, the median time from seroconversion to AIDS was roughly seven to twelve years (4).

根据抗HIV病毒药物用于临床前的研究结果，从抗体出现到获得性免疫缺陷综合征（AIDS）约7-12年(4)。

DIFFERENTIAL DIAGNOSIS 　鉴别诊断

At each stage in the course of HIV infection, there are numerous potential causes of fever to consider. Studies have documented that with thorough investigation, the etiology of fever can be identified in over 80% of cases (13, 144).

HIV感染的各阶段都有多种（很多）可能导致发热的原因。通过系统仔细的诊断，至少80%(以上)的病例可以明确病因(13, 144)。

Numerous observational studies have confirmed the predictive value of the CD4 count as a rough guide to the temporal sequence of opportunistic infections and malignancies that occur throughout the lifetime of the AIDS patient (50, 157, 167).

大量的研究证实，CD4细胞计数水平与不同机会性感染和肿瘤的发生有较好的相关性(50, 157, 167)。

The Centers for Disease Control and Prevention (CDC) classification scheme for HIV infection stratifies patients according to CD4 count: patients with counts greater than 500/mm³, those with counts between 200 and 500/mm³, and those with counts less than 200/mm³ (35).

美国疾病预防控制中心将HIV患者分为3级：CD4大于 500/mm³, CD4在200－ 500/mm³，CD4小于200/mm³ (35)。

This breakdown provides a useful, though imperfect, framework to discuss the evaluation of fever in the HIV-infected patient in each of these categories.

这个分级系统为HIV患者发热的诊治提供了一个有用的但不完美的框架。

Preliminary studies have found little association between viral load and risk for opportunistic infections (48).

目前尚未发现病毒载量与各种机会性感染直接相关(48)。

Patients with CD4 cell counts greater than 500/mm³

CD4大于 500/mm³的患者

Patients with HIV and a CD4 cell count greater than 500/mm³ should generally be evaluated for fever as if they were relatively immunocompetent hosts (158).　 Infections that are more common in this group relative to their HIV-negative counterparts, however, include Mycobacterium tuberculosis (164) and bacterial sinopulmonary infections （to what extent, it is more common？references address the question，but since their unavailability to most chinese readers，I think it may be better to express it clearer in this text (75, 107).

当患者的CD4计数大于 500/mm³时，发热的处理与免疫力正常的人群相似(158)，只是结核(164)和细菌性呼吸道感染(75, 107)的发生率高于正常人群。

Patients with CD4 cell counts between 200 and 500/mm³

CD4介于200－ 500/mm³的患者

Patients with CD4 counts of 200 to 500/mm³ develop upper and lower bacterial respiratory tract infections more commonly than their HIV-negative counterparts, with a well-documented increased risk for bacterial pneumonia (75, 125, 168, 175). Opportunistic infections such as pneumocystic carinii pneumonia are seldom seen at CD4 counts greater than 250/mm³  (88). M. tuberculosis, however, remains of particular concern.　 Patients with tuberculosis and CD4 counts greater than 200/mm³  often present with typical reactivation disease affecting the lung apices （means apical segment？or including posterior segment of the upper lobes？）, whereas patients with lower CD4 counts often have atypicalradiographic presentations such as atypical infiltration and mediastinal lymphadenopathy (72, 92).

CD4计数在200－ 500/mm³时，患者发生上、下呼吸道感染的风险均高于无HIV感染者，如细菌性肺炎(75, 125, 168, 175)。卡氏肺囊虫感染（或卡氏肺孢子虫感染）在 CD4>250/mm³时很少见(88)。结核需要特别考虑：当CD4>200/mm³时,通常为典型的复发性结核表现、累及肺尖，而在CD4细胞计数较低的患者，影像学多为不典型部位的侵润或纵隔淋巴结肿大(72, 92)。

Patients with CD4 cell counts less than 200/mm³

CD4细胞计数小于200/mm³的患者

In the setting of advanced immunosuppression, which is the sin que non of advanced HIV-infection, fever is ever more common. With progressive decline in the CD4 count, both the frequency and variety of infectious complications increases. It is in this range that opportunistic infections such as pneumocystic carinii pneumonia, CMV, toxoplasmosis, disseminated MAC, disseminated histoplasmosis and coccidioidomycosis, and cryptococcal meningitis must be considered in the differential diagnosis of fever.

免疫力严重受损时，发热更加常见。随着CD4计数进行性下降，感染更易发生，同时感染的种类逐渐增多。在这个阶段，对发热的鉴别诊断应包括卡氏肺囊虫、巨细胞病毒、弓形体、播散性鸟分支杆菌复合体、播散性组织胞浆菌病、球孢子菌病、隐球菌性脑膜炎等机会性感染。

INFECTIOUS ETIOLOGIES 感染导致的发热（病原学）

Pulmonary肺部

The three most common infectious pulmonary etiologies of fever are pneumocystic carinii pneumonia, bacterial pneumonia, and tuberculosis (68, 143). During the early years of the HIV epidemic, pneumocystic carinii pneumonia was the most frequent pulmonary complication, accounting for nearly two-thirds of AIDS index diagnoses（Does it mean AIDS diagnosed by existence of PCP?）(169). However, increasing use of pneumocystic carinii pneumonia prophylaxis in the late 1980s led to a decline in the frequency of this disease. Coincident with this, changes in the demographic composition of the AIDS epidemic led to an increasing number of persons at risk for bacterial pneumonia. Specifically, the increasing proportion of patients with intravenous drug use as their HIV risk factor led to additional risk for bacterial pneumonia (168). Intravenous drug users have been found to be at higher risk for bacterial pneumonia and TB than other HIV-infected groups (68, 75, 168).

肺部感染中最常见的三种病原体是：卡氏肺囊虫、细菌、结核(68, 143)。 在HIV流行早期，卡氏肺囊虫感染是最常见的肺部并发症，2/3的AIDS因其诊断(169)。20世纪80年代预防性治疗使PCP的发病率明显下降，同时，伴随HIV流行特点的改变，更多的患者出现细菌性肺炎。因吸毒而感染HIV的患者比其它传播途径感染者发生结核和细菌性肺炎的风险大(68, 75, 168)，（。）吸毒人群在HIV感染者中比例的增加导致细菌性肺炎更加常见(168)。

The incidence of tuberculosis in patients with AIDS is 100 to 500 times the incidence in the general population (124) due to both increased risk of reactivation of latent tuberculosis infection (142) and an increased risk of progressive disease from primary infection (53). Whereas the lifetime risk for active tuberculosis among latently infected persons is approximately 10% in the general population, the risk of active tuberculosis among HIV-infected patients with positive tuberculin tests（>5mm?）is estimated to be 8% per year (142). Furthermore, active disease after exposure(5 years after expose?), which occurs in approximately 3 to 5% of normal hosts, may be seen in 30 to 40% of newly exposed HIV-positive persons (51).

AIDS患者中结核复发(142)或初次感染后出现进展性病变的风险均显著增加(53)，因此其活动性结核发病率是正常人群的100-500倍(124)。普通人群潜伏结核感染后，在一生中发生活动性结核（复发）的风险为10%;而PPD阳性的HIV感染者，活动性结核的发病率为每年8%(142)。普通人群感染结核后仅有3-5%出现活动性结核，在HIV感染者为30-40%(51)。

Tuberculosis in cases of advanced immunosuppression can present with dissemination, extrapulmonary disease and unusual radiographic manifestations (77). Patients with tuberculosis and CD4 counts greater than 200/mm³ often present with typical reactivation diseases affecting the apices. Tuberculosis in cases of advanced immunosuppression can present with dissemination, extrapulmonary disease, and unusual radiographic manifestations such as hilar adenopathy and pleural effusions (14, 65, 77, 92). Extrapulmonary tuberculosis is observed to be more common in patients with more severe HIV-induced immunosuppression (122, 159, 164).

免疫功能严重障碍时，结核更多地表现为播散性病变、肺外病变、出现不典型的影像学表现如肺门淋巴结肿大，胸腔积液；CD4>200/mm³的患者，典型的复发性结核多见，累及肺尖(14, 65, 77, 92)。免疫力受损越严重，肺外表现越多见(122, 159, 164)。

Both atypical mycobacteria and CMV should also be considered in the evaluation of AIDS patients with advanced disease who present with respiratory signs or symptoms. As opposed to MTB, serious infection with nontuberculous mycobacteria occurs only in patients with advanced immunodeficiency. Localized and clinically significant (means symptomatic?)pulmonary disease due to Mycobacterium avium intracellularae (MAC) occurs in HIV-infected patients, but is uncommon (76, 87, 136). One study found pulmonary MAC disease to be present in only 2.5% of patients with disseminated MAC infection (87). Respiratory tract colonization is much more common than true pulmonary disease (80).

晚期AIDS患者出现呼吸系统症状和体征时，应考虑不典型分枝杆菌和巨细胞病毒（CMV）感染。与结核不同，严重的非结核分枝杆菌感染仅见于疾病晚期。鸟分枝杆菌复合体（MAC）导致的局部的有症状（临床表现）的肺部病变在HIV感染者比较少见(76, 87, 136)。有研究发现播散性MAC感染仅有2.5%累及肺部(87)。MAC在呼吸道定植的比例远大于真正的肺部病变(80)。

Gastrointestinal

胃肠道

The gastrointestinal tract is a frequent site for opportunistic infections. Diarrhea is a common gastrointestinal manifestation, affecting 30 to 60% of North American patients with HIV (15, 69, 100, 152, 153). While frequent causes of HIV-associated diarrhea, the protozoans Cryptosporidium parvum and microsporidia species are rarely associated with significant fever (153). Salmonella species, Shigella species, and Campylobacter jejuni may present with high fever. AIDS patients either acquire or are symptomatic with these pathogens　（which ones? Include prozotoa?） more often than their HIV-negative counterparts (42). While Shigella is commonly diagnosed in the early stages of HIV infection, Campylobacter and Salmonella are associated with more severe immunodeficiency (112). The association between AIDS and infection with both typhi and non-typhi Salmonella species is well recognized (66), with a 20-fold increase in risk for infection seen among US patients with HIV (33, 81, 155). Septicemia with Salmonella is more likely to occur in individuals with more advanced immunosuppression.　 Relapse of bacteremia after appropriate antibiotic therapy is well described in AIDS patients (33). Thus, HIV-positive patients with Salmonella who have low CD4 counts and/or prior septicemia should receive life-long secondary prophylaxis (112).

机会性感染常累及胃肠道。腹泻常见，发生于30-40%的北美HIV患者(15, 69, 100, 152, 153)。虽然隐孢子虫和微孢子虫是HIV相关性腹泻的常见原因，发热者少（见）(153)。沙门氏菌、志贺氏菌和空肠弯曲菌的感染可以出现高热。与非HIV感染者相比，AIDS 患者更容易被上述病原(菌)感染或感染后出现症状(42)。志贺菌常见于HIV早期，而沙门氏菌和空肠弯曲菌多见于免疫缺陷较重的阶段(112)。对于AIDS患者，伤寒和非伤寒沙门菌感染的风险均显著增加(66)，为普通人群的20倍(33, 81, 155)。沙门氏菌血症多发生于严重免疫缺陷（的）阶段, 而且在适当的抗生素治疗后也会复发(33)。因此，CD4计数低的HIV感染者发生沙门菌感染或既往有菌血症病史应给予终生的二级预防(112)。

Clostridium difficile colitis, commonly presenting as diarrhea and abdominal pain with associated fever, is also more common among patients with AIDS (29).

难辨梭状芽孢杆菌导致的结肠炎在AIDS患者也不少见，表现为腹泻、腹痛、发热(29)。

The most common and serious viral infection affecting the gastrointestinal tract is cytomegalovirus. Approximately one third of all AIDS patients develop gastrointestinal cytomegalovirus infections (133). Although the colon is the site most often affected, involvement of any part from mouth to anus has been reported (63, 98). Manifestations range from esophageal ulcers to colitis to toxic megacolon with perforation.　 Most patients with colitis have fever, reflecting the invasive nature of cytomegalovirus, along with diarrhea which is sometimes bloody, crampy lower abdominal pain, tenesmus, weight loss, malaise, and anorexia. 病　Clinical cytomegalovirus disease usually occurs after the CD4 count has fallen below 100 (63).

病毒感染中以CMV感染最常见和严重。约1/3 的AIDS 患者发生消化道CMV感染(133)。结肠病变发生率最高，但整个消化道均可受累(63, 98)。临床表现可从食道溃疡到结肠炎到中毒性巨结肠症合并穿孔。结肠炎常伴发热，说明CMV感染的侵入性特点。可有血便、下腹绞痛、里急后重、消瘦、乏力、厌食。MCV相关的临床病变通常出现于 CD4<100/mm³时(63)。

Esophageal infection with Candida, HSV and CMV, as well as aphthous stomatitis, is not uncommon in the course of HIV infection. Dysphagia and odynophagia are the most frequent presenting symptoms of esophagitis. Fever accompanying esophageal symptoms is rare in Candidal or HSV esophagitis, but is more common in CMV. A review of presenting signs and symptoms of HIV-positive patients with esophageal infection revealed that 20% of patients with either CMV or mycobacterial esophagitis had fever (12). Likely this is because esophagitis in these instances is more often a representation of a systemic illness involving multiple organs in addition to the esophagus.

食道的念珠菌感染、单纯疱疹病毒（HSV）、CMV感染以及口腔溃疡在HIV患者中不少见。吞咽困难和吞咽痛是最常见的症状。发热在念珠菌和HSV中少见，但CMV感染中较多。约20%的食道CMV或分枝杆菌感染可有发热(12)，可能由于在这些病原感染中食道炎提示累及多器官的系统性感染。

In the evaluation of fever and abdominal pain in HIV-positive patients, pancreatitis always must be on the differential. As well as the usual etiologies such as alcohol use and gallstones, medications also must be considered, especially ddI, ddC, Trimethoprim-sulfamethoxazole, and intravenous or inhaled pentamidine (1, 120, 141,165). Certain opportunistic infections including CMV, Toxoplasma gondii, Cryptococcus neoformans, and MAI (=MAC? I think the two things are same, use MAC here may improve consistency ) are also reported to be potential etiologic agents of pancreatitis in AIDS patients (2, 42, 52, 58).

HIV感染者出现发热、腹痛要考虑胰腺炎，病因除常见的酒精和胆石外，还包括去羟基苷，双脱氧胞苷，甲氧卞啶－磺胺甲恶唑（TMP-SMZ），静脉或吸入喷他眯（用于治疗PCP）(1, 120, 141,165)。某些病原体如CMV、弓形体、新隐球菌、鸟胞内分枝杆菌也可能在AIDS患者中导致胰腺炎(2, 42, 52, 58)。

Biliary 胆道

Signs of biliary tract disease in HIV-infected patients are similar to those of HIV-negative patients – right upper quadrant pain, fever, and elevated serum alkaline phosphatase. Causes include gallstone disease as well as AIDS-related cholangitis. 病因可为胆石或AIDS相关性胆管炎。Although the pathogenesis of AIDS-related cholangitis remains unknown, it is suggested that several different opportunistic pathogens damage the biliary sphincter segment resulting in papillary stenosis (11). The pathogens most often identified include Cryptosporidium, cytomegalovirus, Microsporidia, and Mycobacterium avium intracellulare ; the clinical pattern is similar regardless of the organism involved (111). Patients typically have advanced AIDS and a CD4 count <100 (32).　Diagnosis is based on typical cholangiographic findings (papillary stenosis, sclerosing cholangitis, combined papillary stenosis and sclerosing cholangitis, and long extrahepatic bile duct strictures) in patients with advanced HIV disease (32). Abdominal ultrasound is a reasonable first step in diagnosis, as it is abnormal in approximately 75% of patients, with the gold standard defined as an abnormal cholangiogram (19, 24, 32).  If ultrasound reveals dilated ducts, an ERCP should be performed as it allows both diagnostic biopsy specimens to be obtained while at the same time allowing for a therapeutic sphincterotomy. Infection of the gallbladder itself with CMV and/or Cryptosporidium may occur, with a clinical presentation that mirrors typical cholecystitis (79).

HIV患者胆道感染的表现与HIV阴性人群相似：右上腹痛、发热、碱性磷酸酶升高。AIDS相关性胆管炎病因尚不明确，可能由于某些机会性感染病原体破坏胆道括约肌造成乳头狭窄所致(11)。 常见的病原是隐孢子虫、CMV、微孢子菌、鸟胞内分枝杆菌；不同病原体导致的临床症状是相似（同）的(111)。患者通常处于AIDS晚期、CD4计数<100/mm³(32)。 诊断依靠典型的胆管造影表现(乳头狭窄、硬化性胆管炎、乳头狭窄合并硬化性胆管炎，或长段的肝外胆管狭窄)和处于HIV晚期(32)。可先行腹部B超，在75%的患者中可有阳性发现，但胆管造影为金标准(19, 24, 32)。如果B超示胆管扩张，应作逆行胰胆管造影（ERCP），通过后者既可行活检又可行乳头肌切开的治疗。 CMV和隐孢子虫可感染胆囊，出现典型的胆囊炎表现(79)。

Neurologic 神经系统

Cerebral toxoplasmosis is the most common CNS opportunistic infection in AIDS (103). Caused by reactivation of infection by Toxoplasma gondii, cerebral toxoplasmosis typically manifests as a subacute focal syndrome characterized by single or, more frequently, multiple brain abscesses. One large retrospective study found the most common presenting symptoms to be headache (55%), confusion (52%), and fever (47%) (126). Fever is seldom high (>39 C?). Diagnosis is suggested by the finding of characteristic ring-enhancing lesions on neuroimaging.

脑弓形体感染是AIDS中最常见的中枢神经系统机会性感染(103)，由潜伏弓形体感染复发导致，表现为亚急性的颅内局灶受累，影像学为多发（常见），或单发脓肿。（根据）回顾性研究报道，常见的症状是头痛（55%）,意识不清（52%），和发热（47%）(126)。高热少见。边缘强化的影像学表现提示诊断。

Cryptococcal disease, the most common life-threatening fungal infection associated with AIDS, disseminates widely in the immunocompromised, especially to the CNS. Most patients who are infected with Cryptococcus neoformans develop meningitis, though infection of nearly every organ has been described. Approximately 6 to 10% of patients with AIDS will develop cryptococcal meningitis, usually in the setting of severe immunodeficiency with CD4 counts nearly always less than 100/mm³ (50, 127). Most often patients have features of subacute meningitis or meningoencephalitis characterized by fever, malaise, and headache generally for two to four weeks prior to presentation. Overt meningeal signs are unsual, and focal neurologic signs or seizures occur infrequently.　 One large retrospective analysis of 89 cases of culture-confirmed cryptococcal meningitis found that approximately two thirds reported fever, headache, and malaise, but only 15% had focal deficits and 27% had meningeal signs on examination (41). Presentation may be subtle, and it is thus important to include cryptococcal disease in the differential diagnosis of all AIDS patients with fever.

隐球菌可在免疫力低下的肌体中广泛播散，尤易感染中枢神经系统，是AIDS中最常出现的致命性真菌感染。感染者多出现脑膜炎，但隐球菌可累及任何器官。6-10%的AIDS患者会发生隐球菌脑膜炎，通常出现在CD4计数<100/mm³时(50, 127)。一般（通常）患者在就诊前2-4周出现亚急性脑膜炎或脑膜脑炎表现，如发热、乏力、头痛等。明显的脑膜激征、神经系统定位体征、癫痫发作不常见。一个回顾性研究报道在89名培养确诊的隐球菌脑膜炎患者中2/3主诉发热、头痛、乏力，仅15%查体有局灶体征，27%有脑膜刺激征(41)。由于临床症状可以很轻微，对所有发热的AIDS患者都应考虑隐球菌感染。

While HIV-infected patients with tuberculosis are at increased risk for meningeal involvement, comparison of the presentation of tuberculous meningitis in patients with and without HIV infection has revealed similar clinical manifestations, cerebrospinal fluid findings, and mortality (22, 55).

HIV患者感染结核后容易发生脑膜受累，临床表现、脑脊液检查、以及死亡率均与非HIV感染者相似。

CNS lymphoma, the second most common CNS mass lesion after toxoplasmosis may be associated with fever (116). Progressive multifocal leukocencephalopathy (PML), caused by reactivation of JC papovavirus, affects between 4-8% of HIV patients in the later stages of disease. Focal neurologic deficit is the clinical hallmark of PML, and fever is unusual (139).

中枢神经系统淋巴瘤是仅次于弓形体感染的中枢神经系统占位性病变，可有发热(116)。4-8%的晚期患者罹患由JC乳多空病毒导致的进展性多灶性白质脑病(PML)，局灶性神经系统障碍是PML的特点，合并发热者少(139)。

Multisystem Disease 多系统疾病

Endemic in the Midwestern and southeastern United States, Histoplasma capsulatum can cause acute pulmonary infection characterized by fever, hypoxia, and pulmonary infiltrates in immunocompetent hosts.　 In patients with HIV and defects in cell-mediated immunity, however, the picture is that of progressive disseminated disease (6, 25). Clinical presentation is often nonspecific; fever, weight loss, hepatosplenomegaly, lymphadenopathy, and anemia are common (83). Wheat and colleagues found that most patients presented with symptoms of fever and weight loss of at least one month's duration, which, if untreated, can progress to a fulminant picture resembling septicemia (173).

组织胞浆菌常见于美国中西部和东南部，在免疫功能正常人群可导致急性肺部感染，出现发热、低氧、肺部侵润。但在HIV感染者和细胞免疫缺陷的患者，造成进展的播散性病变(6, 25)。临床表现不特异，发热、体重下降、肝脾肿大、淋巴结肿大、贫血等较常见(83)。 Wheat等发现大多数患者以发热、体重下降至少一个月就诊，如无及时治疗，可迅速进展至类似败血症的爆发性病变（表现）(173)。

Coccidioidomycosis, a disease caused by the soil fungus Coccidioides immitis, is edemic in the southwestern United States, northern Mexico, and portions of Central and South America (119). Acquisition via inhalation of fungal arthrospores, and activities that involve repeated direct exposure to soil and dust have been shown to be associated with coccidioidomycosis (170). Among otherwise healthy persons, C. immitis may be asymptomatic or may manifest as a subacute and self-limited febrile illness (valley fever), pulmonary disease, or disseminated disease(in a samll part of patients?). While rare in immunocompetent hosts, disseminated disease is common in HIV-positive patients, particularly those with depressed CD4 counts, living in endemic regions (7, 85). Disseminated coccidioidomycosis, defined as the identification of C. immitis by histopathology, culture, or antigen detection at a site other than or in addition to the lungs or cervical or hilar lymph nodes, was added to the surveillance case definition for AIDS in 1987 (34). A retrospective review of clinical manifestations of patients with HIV and coccidioidomycosis at a single institution in Maricopa county Arizona found the most frequent symptoms to be fever and chills (68%), cough (64%), and weight loss (50%) (149). In this series, the lung was the most frequently involved organ (80%), followed by the meninges (15%). Chest radiographs revealed diffuse reticulonodular infiltrates in 65% of those with pulmonary involvement and focal pulmonary disease in 14%. Approximately two-thirds of respiratory secretions (either expectorated sputum or bronchoscopy with bronchoalveolar lavage) were positive either by culture or histopathology, with transbronchial biopsy even more sensitive.  HIV-positive patients with diffuse pulmonary involvement have been shown to have a high mortality (7,149).

球孢子菌病由一种土壤中的真菌所致，流行于美国西南部，墨西哥北部，中、南美州(119)。反复直接暴露于土壤和尘土，吸入真菌孢子是其危险因素(170)。在健康人群可无症状，或出现亚急性、自限性发热（山谷热），肺部病变，以及少数播散性病变。但HIV感染者，特别是生活在流行区的CD4计数较低的患者，播散性病变容易发生(7, 85)。1987年播散性球孢子菌病被添加到AIDS诊断条目中，定义为病理、培养、或抗原检测明确的肺、颈部淋巴结、肺门淋巴结外的器官受累(34)。根据美国亚里桑那州某医院的回顾性研究结果，最常见的症状为寒战发热（68%）、咳嗽（64%）、体重减轻（50%）(149)。肺部最常受累（80%），其次为脑膜（15%）。肺部受累者中，65%胸片示弥漫性网状结节样改变，14%为局部肺受累。2/3的病例气道分泌物（痰或支气管肺泡灌洗）培养或组织学阳性，经支气管活检阳性率更高。有弥漫性肺部病变者死亡率高(7,149)。

Penicillium marneffei, another systemic mycosis, should be considered in patients with history of travel to or residence in areas of endemicity that include Southeast Asia, the Guangxi Provence of China and in some areas of Hong Kong. Disseminated P. marneffei is an emerging pathogen, reported in 1994 to be the third most common opportunistic infection in HIV-infected patients in certain parts of Southeast Asia, following extrapulmonary tuberculosis and cryptococcosis (161). Although no definitive route of transmission has been determined, it is suggested that the organism is most often acquired via ingestion and inhalation. Clinical manifestations typically resemble those of other systemic fungal infections. The most common clinical features include fever, weight loss, anemia, and skin lesions; cough and pulmonary involvement has been reported as well (39, 56, 160).

有东南亚、中国广西、以及香港某些区域旅游和居住史的患者，要考虑马尼菲青霉菌。该菌近年来被逐渐重视，1994年报道为东南亚某些地区除肺外结核、隐球菌感染外的第三大机会性感染(161)。传播途径尚不明确，可能为吸入或进食。临床表现同其它系统性真菌感染，包括发热、体重减轻、贫血、皮疹、以及咳嗽、和肺部病变(39, 56, 160)。

Disseminated MAC is the most common opportunistic infection of bacterial origin among patients with AIDS in the United States (21). A prospective study at one urban institution revealed that 43% of patients who survived one year after their CD4 count fell below 200 developed MAC bacteremia (114). The most important risk factor for disseminated MAC is a low CD4 count, with infection rarely observed in patients with CD4 counts greater than 100 ( 37, 50, 74, 78,163). Whereas disease due to Mycobacterium tuberculosis commonly precedes the diagnosis of AIDS, Mycobacterium avium complex usually causes disease only in the late stages of HIV infection, when cellular immunity is severely impaired (108). MAC is ubiquitous, with the gastrointestinal tract the main portal for entry, and asymptomatic colonization often precedes disseminated MAC. When dissemination occurs, the most commonly affected sites are blood, bone marrow, liver, spleen, and lymph nodes. The most frequently described symptoms at presentation include fever, night sweats, diarrhea, and abdominal pain (21), and the laboratory abnormalities most often identified among patients with disseminated MAC are anemia and an elevated serum alkaline phosphatase level (74).

播散性鸟分枝杆菌复合体（MAC）是在美国最常见的细菌性机会性感染(21)。有研究报道CD4<200/mm³的患者一年内43%发生MAC菌血症(114)。CD4计数是影响播散性MAC感染的主要因素，CD4>100/mm³时这种机会性感染很少出现( 37, 50, 74, 78,163)。 结核分枝杆菌可以出现在AIDS发生之前，但MAC感染只见于HIV的晚期，细胞免疫严重受累的阶段(108)。MAC广泛分布，胃肠道是主要的入路，播散来源于无症状的定植，常侵及血液、骨髓、肝脾、和淋巴结。就诊症状通常是发热、盗汗、腹泻、腹痛(21)，化验示贫血、碱性磷酸酶升高(74)。

Most commonly, Toxoplasma gondii infection presents with central nervous system manifestations including fever, headache, change in mental status, seizure, and focal neurological deficits. Extracerebral manifestations are much less common, with fulminant sepsis described in case reports (27, 67). The small number of such cases described in the literature do not provide for a recognizable pattern of disease. Additionally, case reports have described attenuated, but probably disseminated, toxoplasmosis manifested by prolonged fever in patients receiving trimethoprim-sulfamethoxazole as pneumocystic carinii pneumonia prophylaxis (178). In patients with HIV-related fever and sepsis of unknown origin, disseminated T. gondii infection should be considered.　

中枢神经系统弓形体感染表现为发热、头痛、神志改变、癫痫发作、神经系统局部受累。颅外病变少见，有个案报道过爆发性败血症(27, 67)，但例数较少，尚不能总结出特征性表现。另外，在使用TMP-SMZ预防PCP的人群，有病例报道被部分抑制的，但仍有播散的弓形体感染可导致长期发热(178)。　HIV患者出现不明原因的发热和败血症，应考虑播散的弓形体感染。

Visceral leishmaniasis must be considered in patients with an appropriate travel history presenting with fever, hepatosplenomegaly, and/or pancytopenia (3). Leishmania species, typically transmitted through the bite of infected female sandflies, are endemic in the Mediterranean area, the Middle East, India, Central and South America, northern and eastern China, some of the former Soviet republics, and northern Africa. A large series of HIV-positive patients with visceral leishmaniasis in Spain revealed the presence of fever in 95% of patients, enlargement of the liver and/or spleen in 92.5%, and pancytopenia in 82.5% (110). Characteristic features of visceral leishmaniasis in HIV-infected patients include a lack of leishmania antibodies and a frequent chronic-relapsing course. While reliable in immunocompetent patients, the value of antibody testing is extremely limited in HIV-infected individuals. Thus, diagnosis in this population must rely upon direct detection of amastigotes in tissue samples or promastigotes in culture.  

有相关旅游史的患者，出现发热、肝脾肿大、和/或全血细胞减少，要考虑内脏利什曼原虫(3)。该病原体通常通过雌性白蛉叮咬传播，流行于地中海沿岸、中东、印度、中南美洲、中国北部和东部、原苏联某些地区、和非洲北部。西班牙的研究报道95%的患者有发热，92.5%有肝脾肿大，82.5%有全血细胞减少(110)。HIV患者中该感染的特点是抗体阴性和慢性复发病程。对于HIV感染者，抗体检查远不如在免疫正常人群中可靠。故诊断依赖在组织中找到无鞭毛体或培养出前鞭毛体。

Bacillary angiomatosis (typified by vascular-proliferative lesions that are classically cutaneous) and bacillary peliosis (characterized by vascular-proliferative disease affecting the liver and spleen) are different manifestations of the same infection caused by either Bartonella henselae or Bartonella quintana, with a broad spectrum of presentation in immunocompromised hosts. One case-control study revealed fever to be present in 93% of patients with HIV and histologically confirmed bacillary angiomatosis-bacillary peliosis; other common signs and symptoms included cutaneous or subcutaneous vascular lesions (55%), lymphadenopathy (21%), and abdominal symptoms (24%) (109).

巴尔通体导致的细菌性血管瘤病（皮肤血管增生性病变）和细菌性紫癜（肝脾血管增生性病变）在免疫力低下人群可有多种表现。有病例对照研究报道病理确诊的患者中93%有发热，55%有皮肤和皮下血管病变, 及淋巴结肿大(21%)和腹部症状(24%)(109)。

Cytomegalovirus (CMV) is the most common viral cause of serious opportunistic infection in HIV. A wide range of clinical syndromes are seen, most commonly retinitis, esophagitis, colitis, and gastirits as described above (63, 82). Positive blood or urine cultures of CMV provide supporting evidence for infection but do not establish end-organ involvement. Except in the case of retinitis, diagnosis of end organ disease should be based on histologic evidence of CMV (40, 54). There is, however, recent data suggesting that the detection of CMV antigenemia and/or CMV DNA by PCR in the blood of AIDS patients predicts the subsequent development of CMV disease (40,148). This may lead to the use of preemptive antiviral therapy to prevent the development of end-organ disease.

CMV是最常见的导致严重机会性感染的病毒。临床表现多样，以视网膜炎、食道炎、结肠炎、和胃炎最常见(63, 82)。血、尿培养阳性说明感染，但不能确定器官受累的情况。除视网膜炎外，其它器官受累的诊断需要病理检查在组织中发现CMV(40, 54)。近来有研究提示CMV抗原血症或PCR发现血DNA阳性的AIDS患者对预测随后的病变有帮助(40,148)。这提示先行性抗病毒治疗可能有助于控制随后的器官受累。

Fever of Unknown Origin 不明原因发热（FUO）

Since its first definition by Petersdorf and Beeson in 1961 as "fever higher than 38.3 C (101 F) on several occasions, persisting without diagnosis for at least 3 weeks in spite of at least 1 week's investigation in hospital" (121), fever of unknown origin remains a vexing clinical dilemma, particularly so in the HIV-positive population where the range of disease possibilities looms large. The criteria of Durack and Street (57) proposed in 1991 are used to define HIV-associated FUO: temperature of 38.3 C (101 F) or higher on several occasions; confirmed positive serology for HIV infection; fever of more than 4 weeks' duration for outpatients, or more than 3 days' duration in hospital; diagnosis uncertain after 3 days despite appropriate investigation, including at least 2 day's incubation of microbiologic cultures. The pursuit of a thorough investigation is warranted since diagnosis can be made in over 80% of patients with HIV and fever. HIV infection itself is rarely the cause of fever in patients with advanced immunosuppression (147). Several series have examined FUO in AIDS (10, 23, 64, 93, 102, 105, 106, 144) (Table 4). Although great variability with respect to the criteria used to define FUO, the demographics of the population studied and the diagnostic approach is evident among these studies, their conclusions bear similarity. The predominant etiologies of fever identified include mycobacterial diseases, leishmaniasis (in series from endemic regions), pneumocystic carinii pneumonia and lymphoma.

1961年Petersdorf和Beeson将不明原因发热定义（不明原因发热在1961年由Petersdorf和Beeson定义）为发热大于38.3度3周以上，同时经1周诊断仍原因不明(121)。由于有众多可能病因，在HIV中不明原因发热较难处理。1991年Durack和Street (57)将HIV相关性FUO定义为 HIV血清学阳性，体温>38.3 度,门诊病程>4周或住院病程>3天，经3天合理调查仍未确诊，其中包括至少2天微生物培养。在系统、仔细的调查后，80%的病例可明确病因。对于严重免疫力受损的患者HIV本身很少导致发热(147)。有关FUO的几个研究见表4(10, 23, 64, 93, 102, 105, 106, 144)。虽然多个研究对FUO的定义、研究人群、诊断步骤有所不同，但结论相似：分枝杆菌、利什曼原虫（流行区）、卡氏肺囊虫、和淋巴瘤是重要病因。

Highly Active Antiretroviral Therapy and Immune Restoration Disease

高效抗逆转录病毒治疗（HAART）和免疫重建综合征

The combination of antiretroviral agents containing protease inhibitors, referred to as highly active antiretroviral therapy (HAART), has significantly changed the pace of HIV-related disease and has reduced AIDS-related complications thereby decreasing morbidity and mortality (118). One recently described unexpected side effect of HAART, though, is "immune restoration disease."　 Thought to represent an exuberant inflammatory response around established infection in the setting of immune restoration, the clinical syndrome is characterized by lymphadenopathy, fever, leukocytosis, and malaise occurring soon after the initiation of HAART and predominantly in patients whose nadir CD4 count was less than 100 (62, 146). This immunologic phenomenon has been associated with infection with MAC and MTB manifesting as localized lymphadenitis (132), CMV manifesting as acute intraocular inflammation (174), hepatitis B and C virus infection manifesting as acute hepatitis flare (104, 166), and herpes simplex virus manifesting as extensive herpetic lesions that may be hemorrhagic (5).

包括蛋白酶抑制剂的抗逆转录病毒药物组合显著改善了HIV相关性疾病的进展、减少了AIDS相关性并发症，降低了疾病的发生和死亡(118)。免疫重建综合征是新近提出的一种与HAART相关的副作用。临床表现包括（为）淋巴结肿大、发热、白细胞高、乏力，多见于开始HAART治疗后短期和CD4曾小于100/mm³的患者(62, 146)，目前推测与免疫功能恢复后肌体对已经存在的感染原的反应有关。在该综合征中，MAC、结核感染与淋巴结炎(132)，MCV与急性眼球后炎症(174)，HBV、HCV与急性肝炎加重(104, 166)，HSV与广泛的肝脏病变伴出血相关(5)。

NON-INFECTIOUS ETIOLOGIES 非感染性病因导致的发热

a) Drug reactions are significantly more common in the HIV-infected population, occurring with an increasing incidence with advancing immunodeficiency (46, 151), commonly manifesting as maculopapular or morbilliform eruptions, and at times accompanied by fever, arthralgias, eosinophilia, and/or serum transaminase elevation (17). Possible explanations for the mechanism of increased drug reactivity seen in the HIV-positive population include an increased use of provocative drugs, an increased incidence of viral infections, and immune dysregulation (43, 150).

HIV患者中药物反应常见(46, 151)，出现斑丘疹或麻疹样皮疹，有时伴发热、关节痛、嗜酸细胞升高、转氨酶升高(17)。 药物反应增多可能的原因包括使用反应性强的药物、病毒感染较多以及免疫功能失调(43, 150)。

b) Several rheumatologic conditions have been associated with HIV-1 infection, notably Reiter's syndrome, psoriatic arthritis, Sjogren's syndrome, polymyositis, rheumatoid arthritis, Still's disease and vasculitis (8, 91). The reason for this association is not known.

几种免疫病与HIV感染有关，包括赖特〔Reiter〕综合征、银屑病性关节炎、多发性肌炎、类风湿关节炎、Still病，血管炎等(8, 91)。其原因不详。

c) The most common malignancies associated with fever in HIV infection are non-Hodgkin's lymphoma, primary CNS lymphoma, and rarely Kaposi sarcoma. While non-Hodgkin's lymphomas (usually aggressive high-grade B-cell lymphomas) can be found in early HIV infection and commonly cause fever, primary CNS lympomas are found almost exclusively in late-stage HIV and are less often associated with fever (116). It appears also that Hodgkin's disease with extranodal involvement occurs with increased frequency in the setting of HIV infection (45, 89). Fever is a common presenting and enduring symptom of HIV-related lymphoma.

与发热相关的肿瘤性疾病以非霍杰金淋巴瘤，原发中枢神经系统淋巴瘤最常见，偶见卡波济肉瘤。其中非霍杰金淋巴瘤（通常为进展性高分化B细胞淋巴瘤）出现在HIV感染早期，原发中枢神经系统淋巴瘤几乎仅见于晚期患者(116)。霍杰金淋巴瘤淋巴结外病变在HIV患者中较多出现(45, 89)。 发热常为HIV相关淋巴瘤的主诉和持续症状。

d) Thrombophlebitis is seen more commonly in the HIV-infected population (99), thought to be due to hypercoagulable states and predisposing factors such as immobility (18, 156).

另外，血栓性静脉炎在HIV人群中更多见(99)，可能与高凝状态和活动减少相关(18, 156)。

DIAGNOSTIC STUDIES 诊断

As with fever in any other setting, the diagnostic evaluation should be guided by the history, findings on physical examination, and underlying patient characteristics. The diagnostic evaluation of fever in the relatively immunocompetent group, i.e. patients with CD4 cell counts above 200/mm³, should be performed in a symptom-directed manner (Table 1), as guided by a comprehensive history and physical examination. Factors of particular relevance include travel and exposure history, associated conditions such as intravenous drug use, and medication history. Tests to consider early in the evaluation of fever include a complete blood count, bacterial blood cultures, chest radiography, urinalysis and urine culture, with more invasive studies pursued on a symptom-directed basis.

与其它情况中出现的发热类似，诊断过程基于病史，查体和患者的特点。对免疫力基本正常的患者，如CD4>200/mm³ ,应丛详细的病史查体开始，以伴随症状为指导（表1）。旅行和暴露史、静脉吸毒史、用药史均很重要。基本检查包括血常规、血细菌培养、胸片、尿常规和培养，根据症状决定有创性检查的选择。

In the severely immunosuppressed patients, i.e. those with CD4 cell count less than 200/mm³ with a myriad of infectious complications, can present in a similar and non-specific fashion with fever, malaise, anemia, and weight loss. Diagnostic acuity based on history and physical examination is diminished, and therefore the scope of diagnostic evaluation must be broadened (Table 1).

免疫力严重受损的患者，如CD4 <200/mm³，可以在各种感染后表现类似的症状，包括发热、乏力、贫血、体重下降。病史和查体的准确性减低，检查的范围需要扩大（表1）。

In pursuing the possibility of tuberculosis, demographic characteristics and previous tuberculosis exposure are of particular importance. A PPD should be placed in patients with CD4 cell counts at above 200/mm³ since anergy is unlikely (84). Normal chest radiographs are reported to occur in 5 to 10% of patients with HIV and TB (96, 101, 123, 135). Thus, chest radiography should play a complementary role with sputum AFB smear and culture, skin testing, and clinical examination in screening HIV-positive patients for TB. Sputum smears in patients with HIV and TB appear to be positive with the same frequency as in patients without HIV (154). A retrospective chart review of 52 of 54 HIV-infected patients with culture-proven TB evaluated at the Los Angeles County-University of Southern California Medical Center over a seven month period in the late eighties found that the most common error leading to delay in diagnosis and thus treatment was not due to atypical manifestations of TB, but rather due to failure to obtain at least three sputum samples for acid-fast smear and mycobacterial culture in patients with clinical and chest radiographic findings consistent with TB (96).

既往结核病史和当地的流行情况，对考虑结核感染很重要。CD4>200/mm³ 时，无反应力的现象少见，PPD结果有意义(84)。5-10%的HIV合并结核患者胸片正常(96, 101, 123, 135)。胸片可以作为痰涂片，痰培养，PPD皮试，及查体的补充。HIV患者痰涂片的阳性率与非感染者相似(154)。通过对52名培养阳性的结核-HIV合并感染者7个月情况的回顾，在八十年代晚期南加州洛杉矶大学医学中心发现导致延误结核诊治最常见的原因不是症状不典型而是没有对出现（有）典型临床和影像学表现的患者行至少三次痰涂片和培养(96)。

The typical radiographic presentation of Pneumoystis carinii pneumonia is a bilateral interstitial pattern which may be characterized as finely granular, reticular or ground-glass opacities (49). In immunodeficient HIV-infected patients, however, a normal chest radiograph does not exclude the diagnosis of pneumocystic carinii pneumonia. In a study conducted in a university hospital in Zurich, Switzerland over a 12 month period in 1989, 93 consecutive chest radiographs of HIV-infected patients (median CD4 count of 50) with their first documented pneumocystic carinii pneumonia episode were retrospectively reviewed by radiologists blinded to the diagnosis of the subjects. Findings on chest radiograph were judged as normal in 39%, interstitial in 36%, and acinar（parenchyma？）in 25%. Normal chest radiographs were predicted by low LDH and low peripheral blood granulocytes. Of note, no statistical correlation was found between the severity of lung infiltrates and the CD4 count or severity of clinical symptoms (117).。Consistent with standard practice in 1989, no primary pneumocystic carinii pneumonia prophylaxis had been given to the patients. Prophylaxis with aerosolized pentamidine, however, can impose additional diagnostic difficulties by altering the typical radiographic appearance of pneumocystic carinii pneumonia (36, 59, 86). Patients receiving aerosolized pentamidine may develop upper lobe infiltrates (16). When findings on chest radiograph suggest pneumocystic carinii pneumonia, empiric therapy should be initiated and definitive diagnosis pursued with examination of induced sputum and, if necessary, bronchoalveolar lavage (BAL). Treatment should also be offered to patients for whom there is a strong clinical suspicion of pneumocystic carinii pneumonia (including fever, cough, dyspnea, and oxygen desaturation with exercise) but in whom the chest radiograph is normal. Recent literature suggests that high resolution computed tomography (HRCT) is useful in the evaluation of such patients. The classic CT finding of pneumocystic carinii pneumonia is extensive ground-glass appearance. In one series of AIDS patients with active pulmonary disease, accurate diagnosis of pneumocystic carinii pneumonia was made by HRCT in 94% of cases (73). In several small series (70, 134), HRCT has been shown to have a 100% negative predictive value in HIV positive patients undergoing evaluation for possible pneumocystic carinii pneumonia. HRCT may allow the exclusion of pneumocystic carinii pneumonia in patients with normal or equivocal findings on chest radiography and may obviate the need for bronchoscopy or empiric therapy in patients with a low likelihood of pneumocystic carinii pneumonia. Given that the "gold standard" remains direct microscopic confirmation, BAL is still indicated for definitive diagnosis in patients with suggestive radiographic studies if induced sputum is unrevealing. Although sensitive, elevated serum LDH is not specific for the diagnosis of pneumocystic carinii pneumonia, as elevations are also found in patients with disseminated and pulmonary tuberculosis, bacterial pneumonias (131), and in disseminated histoplasmosis (47).

PCP典型的影像学表现是双侧间质改变、细小的结节、网格和毛玻璃样改变(49)。对于存在免疫缺陷的HIV感染者，正常胸片不除外PCP感染。一个在瑞士苏黎士完成的长达12个月的研究报道：放射科医生回顾性阅读93名连续诊断的首发PCP病例的胸片，其中39%被判断为正常,36%为间质改变,25%为肺实质改变；正常胸片与低LDH和低外周血粒细胞计数相关；值得注意的是，肺部侵润的严重程度与CD4计数和临床症状的严重程度无关。根据1989年的治疗标准，这组患者未给予预防性治疗(117)。吸入性喷他眯可能改变典型的影像学表现，从而增加诊断难度(36, 59, 86)。患者接受该治疗后可能出现上肺侵润表现(16)。如胸片提示PCP,即可开始经验性治疗，同时行诱导痰检查或支气管肺泡灌洗。对于临床上高度怀疑PCP（发热、咳、气短、活动后氧合下降），但胸片正常的患者，也应开始治疗。近来的研究提示高分辨CT（HRCT）有助于诊断。PCP在CT上典型的表现是广泛的毛玻璃样改变。研究报道在有活动性肺部病变的AIDS患者，HRCT诊断PCP的准确性是94%(73)。几个小规模的研究(70, 134)显示对怀疑PCP的患者，HRCT阴性基本可以排除该诊断。对于胸片正常或表现不明确的患者，PCP可能性不大，HRCT可以用来排除诊断，避免不必要的气管镜检查和治疗。金标准仍为显微镜下看到病原体，在使用诱导痰标本不能确诊时应考虑支气管肺泡灌洗。LDH升高对PCP敏感但不特异，也可见于肺结核，细菌性肺炎(131)，播散性组织胞浆菌(47)。

In evaluation of diarrhea in the febrile patient with advanced HIV, it is particularly important to elicit clues such as diet, travel history, medication profile, and sexual practices. Suggested diagnostic studies are outlined in Table 2. Initial work-up should include microscopic examination and culture for bacterial pathogens, standard acid-fast and ova and parasite preparations, Clostridium difficile toxin assay, and blood cultures in the setting of high fevers. Diagnosis of these bacterial enteropathogens is usually made by stool culture, with stool examination often revealing suggestive fecal leukocytes. Blood cultures, especially in the case of Salmonella, can reveal associated bacteremia.  

出现发热、腹泻的晚期HIV患者，了解饮食、旅游史、用药史、和性生活情况非常重要。需要的检查见表2。初始的检查可以包括粪便的细菌学涂片和培养，找抗酸杆菌，寄生虫和虫卵，难辨芽孢杆菌毒素检测；高热时行血培养。致病菌的诊断通常来自便培养，便常规可见白细胞。血培养可以诊断菌血症，以沙门氏菌常见。

Colonoscopy with biopsy should be considered in patients with persistent diarrhea and unrevealing stool studies. As mucosa can appear normal on endoscopy and infection frequently occurs in the right colon, full colonoscopy with multiple biopsies is often required (98). Diagnosis is established by the demonstration of characteristic histology and staining of biopsy samples.  

持续性腹泻，大便检查不能明确诊断的患者应考虑结肠镜和活检。由于结肠粘膜可以外观正常以及感染常见于右侧，结肠镜应检查全部结肠，并且多部位活检(98)。特征性病理表现和活检标本染色可明确诊断。

With regard to pancreatitis, diagnosis is suggested by elevated pancreatic enzymes and a compatible exam. Confirmation of opportunistic infection-related pancreatitis can be made either by CT-guided needle aspiration of the pancreas or via ERCP and culture of fluid obtained by pancreatic duct washing.

胰腺炎的诊断依靠查体和胰酶升高。确定导致胰腺炎的机会性感染病原体可行CT引导下的穿刺，或经ERCP获得胰管灌洗液培养。

In the evaluation of suspected abdominal tuberculosis, CT is the imaging study of choice, revealing radiographic evidence of disease and allowing for biopsy of involved lymph nodes in order to make a definitive microbiologic diagnosis with acid fast smear and culture (71, 162).

怀疑腹腔结核时，CT可提示诊断，同时能指导淋巴结活检以行抗酸染色和结核培养(71, 162)。

Patients with fever and headache or other neurologic symptoms should undergo contrast-enhanced head CT or MRI. If there are no contraindications, lumbar puncture should be performed for CSF evaluation (Table 3). Opening pressure should be recorded and cell count, protein, and glucose levels measured. Microbiologic studies should include Gram's stain, bacterial culture, India ink stain, cryptococcal antigen titer determination, fungal culture, AFB stain, and mycobacterial culture. Pursuit of a viral cause, such as HSV, CMV, VZV, should be reserved for specific cases in which suspicion for the diagnosis has been raised. Diagnosis of cryptococcal meningitis is made by demonstrating cryptococcal antigen titers in blood and CSF. Although less sensitive than either cryptococcal antigen or culture determination, India ink staining can provide an early diagnosis. CSF is typically characterized by a minimal lymphocytic inflammatory response with mild elevation of protein and a normal glucose.

发热伴头痛或其它神经系统表现的患者应行头颅CT或MRI。如无禁忌，要做腰穿和脑脊液检查，记录颅压，细胞数，蛋白和糖的水平（表3）。微生物检查应包括革兰氏染色，细菌培养，墨汁染色，隐球菌抗原滴度，真菌培养，抗酸染色，结核培养。HSV,CMV,水痘－疱疹病毒（VZV）的检查可在个别的病例中考虑。隐球菌脑膜炎的诊断依靠血和脑脊液中抗原检测阳性。墨汁染色虽然敏感性低于抗原检查，但可能提供早期诊断。典型的脑脊液检查结果为白细胞轻度升高以淋巴细胞为主，蛋白轻度增高，糖正常。

In the evaluation of patients with suspected CNS space-occupying lesions, contrast-enhanced CT is an appropriate first screening test, with MRI reserved for patients with negative scans in whom clinical suspicion remains high. Serum toxoplasmosis antibodies can be helpful to establish previous infection, but negative serology does not with certainty rule out infection (126). Standard practice is to treat CNS lesions in AIDS patients that are suspicious for toxoplasmosis with empiric therapy for 2 weeks and then reevaluate with CT (44).

怀疑颅内占位性病变时，首选增强CT，对于结果阴性但仍高度怀疑的患者，可行MRI。血清弓形体抗体阳性有助于诊断该感染，但阴性结果并不能完全排除弓形体感染(126)。通常的方案是对中枢神经系统病变疑为弓形体感染的患者给予2周经验性治疗，后再次行CT评价(44)。

Given the nonspecific nature of presentation, clinical suspicion is essential in the diagnosis of the systemic mycotic infections. A careful history with attention to region of residence and travel as well as occupation and hobbies is important. Laboratory evaluation often reveals cytopenias （which type of cells?） and elevated liver function tests, but is nonspecific. Pulmonary manifestations of Histoplasma capsulatum infection with prominent chest radiograph findings are significantly less common in the setting of disseminated disease in the AIDS population than in localized disease seen in the immunocompetent population (25). Coccidioidomycosis, however, frequently involves the lung and can mimic pneumocystic carinii pneumonia radiographically (149). Thus, given the lack of specificity of clinical presentation as well as laboratory and radiographic evaluation, fungal culture is recommended to confirm diagnosis. Yield for culture diagnosis of histoplasmosis is greatest from bone marrow biopsy, and for diagnosis of coccidioidomycosis in patients with pulmonary manifestations evaluation of respiratory secretions (obtained either as expectorated sputum or via bronchoscopy with bronchoalveolar lavage) is a reasonable first step with transbronchial biopsy reserved for those with negative washings. Fungal blood cultures have been shown to have limited diagnostic value in the evaluation of the febrile AIDS patient in the absence of other evidence of fungal infection, yielding unique diagnoses only in patients near death (38, 90).

全身性真菌感染无特异临床表现，想到此类感染是诊断的第一步。要详细询问有关居住地、旅游、职业和生活习惯的情况。实验室检查可发现血细胞减少，肝酶升高，但不特异。在AIDS患者的播散性组织胞浆菌感染中，胸片表现远不如在正常人群中局部感染那样突出(25)。球孢子菌病易导致肺部感染，影像学表现类似PCP(149)。由于缺乏特征性临床表现和实验室检查，确诊需行真菌培养。组织胞浆菌的骨髓培养阳性率较高，诊断肺部球孢子菌可先行痰或支气管肺泡灌洗液的检查，对结果阴性者可考虑经支气管活检。血的真菌培养对无其他提示的发热患者价值有限，通常仅在濒死者才有阳性结果(38, 90)。

Though nonspecific, one clue to diagnosis of histoplasmosis may be a markedly elevated serum LDH level (47). Infection of the reticuloendothelial system accounts for the majority of signs of disseminated histoplasmosis, with bone marrow involvement and resultant cytopenias common manifestations (97). Although the histoplasma urine antigen test is a very sensitive test, patients with a negative urine antigen and compatible syndrome may require bone marrow biopsy (172). Serology and skin testing are inconsistently positive（means one test is positive and another is negative？） in AIDS patients and are not specific for active disease (171). Reactive hemophagocytic syndrome, a disorder due to inappropriate monocyte activation and characterized by fever, unexplained cytopenias and bone marrow findings of hemophagocytic histiocytosis, has been described in patients with AIDS and disseminated histoplasmosis (94).

显著的LDH升高提示组织胞浆菌感染，但不特异(47)。播散性组织胞浆菌的多数症状是由其感染网状内皮系统造成，累及骨髓导致血细胞减少(97)。虽然尿抗原检查比较灵敏，临床上高度怀疑但尿抗原阴性的病例仍要做骨髓活检(172)。血清学和皮试检查（结果的一致性）在AIDS患者敏感性不高（差），且对活动性病变不特异(171)。反应性嗜血细胞综合症是由于单核细胞功能异常，导致发热、无明显原因的血细胞减少、骨髓中见嗜血组织细胞，可见于AIDS和播散性组织胞浆菌感染者(94)。

Diagnosis of C. immitis is established by culture from respiratory secretions or other pathology specimens or by recognition of the organism histopathologically. Serologic testing for complement-fixing antibodies to C. immitis is helpful, but negative serology does not exclude coccidioidomycosis in the HIV population (9, 7, 149). Intradermal skin testing is of little value in establishing the diagnosis of active  coccidioidomycosis in this population (7, 149).

球孢子菌病的诊断基于呼吸道分泌物培养或在其它组织标本中找到病原体。血清补体结合试验对诊断有帮助，但阴性不能排除该感染(9, 7, 149)。在HIV人群中皮内试验对诊断活动性球孢子菌病的价值有限(7, 149)。

With regard to Penicillium marneffei, diagnosis is established by culture from blood, bone marrow or other pathologic specimen, with a potential role for serodiagnosis (177).

马尼拉青霉菌的诊断依靠血、骨髓或其他标本的培养。血清诊断可能有用，正在研究中(177)。

Systemic MAC diagnosis is established by culture of the organism from any normally sterile site such as bone marrow, liver, lymph nodes and blood. Blood culture is the preferred method for diagnosis, with two blood cultures sufficient for the detection of the overwhelming majority of cases of MAC bacteremia (176).

全身性鸟分枝杆菌复合体的诊断依赖于血、骨髓、肝脏、淋巴结等正常状态下无菌组织的培养结果。通常，两次血培养可以发现大多数MAC菌血症(176)。

When considering disseminated Toxoplasmosis, markedly elevated lactate dehydrogenase level may suggest the diagnosis, which can be further investigated by means of polymerase chain reaction and serology for T. gondii DNA (27,178). Polymerase chain reaction testing of blood, which is available through commercial labs, may help establish the diagnosis.

LDH显著升高见于播散性弓形体感染，提示进一步PCR方法检测DNA或血清学检查(27,178)。其中血的PCR检测已有商业试剂盒。

In the initial approach to the evaluation of FUO, a careful history and examination, with particular attention to medication history as well as the local prevalence of certain diseases, is imperative. Patients on primary or secondary opportunistic infection prophylaxis may have attenuated and atypical presentations of disease (86, 145, 178). As in the HIV-negative population, the diagnostic evaluation of FUO in the HIV population is fraught with controversy. Routine laboratory tests tend to be nonspecific. A high serum LDH may suggest the diagnosis of pneumocystic carinii pneumonia, TB, extracerebral toxoplasmosis, histoplasmosis or lymphoma; anemia and an elevated serum alkaline phosphatase may suggest disseminated MAC or TB. Bone marrow examination （smear or culture？）has been shown to be a valuable method for detecting opportunistic mycobacterial and fungal infections (particularly MAC and histoplasmosis), as well as leishmaniasis in endemic regions, and non-Hodgkin's lymphoma. Several studies have examined the diagnostic utility of bone marrow biopsy and culture (20, 26, 60, 113, 137). While bone marrow biopsy and culture is indicated in the evaluation of pancytopenia, its role in the evaluation of fever alone is less clear cut. Bone marrow examination has been shown to be a valuable method for detecting opportunistic mycobacterial and fungal infections (particularly MAC and histoplasmosis), as well as leishmaniasis in endemic regions, and non-Hodgkin's lymphoma.（a copy of a sentence above） Although bone marrow biopsy may offer an earlier diagnosis of disseminated MAC through microscopic examination, blood culture is more sensitive (128). Bone marrow sampling has been shown to reveal the cause of fever in approximately 30% of HIV-infected patients with FUO (26); however, the same diagnosis can often be arrived at by less invasive means. Thus, a reasonable approach in the febrile, stable outpatient is to perform bone marrow sampling after three to four weeks have elapsed (to allow time for mycobacteria to grow in culture) following initial evaluation, with three blood cultures for bacteria and mycobacteria and appropriate imaging and tissue sampling based on presentation. The role of liver biopsy in the evaluation of FUO in this population is even less clear, with the reported yield ranging from 20 to 54% (30,138).

对于不明原因的发热（FUO），详细的病史、查体，特别是用药史和当地的流行病学情况非常重要。使用一级或二级预防的患者，症状可以较轻或不典型(86, 145, 178)。如非HIV感染者，对HIV感染者FUO的诊断流程尚有争议。常规检查的特异性低。高LDH提示PCP、结核、颅外弓形体感染、组织胞浆菌、淋巴瘤；贫血和碱性磷酸酶增高提示播散性MAC或结核。骨髓检查有助于诊断分枝杆菌和真菌感染，特别是MAC和组织胞浆菌，以及疫区的利什曼原虫、非霍杰金淋巴瘤。针对骨髓活检和培养的研究(20, 26, 60, 113, 137)显示，虽然这些检查对诊断全血细胞减少有帮助，其对孤立的发热的诊断价值尚不清楚。虽然骨髓涂片可以快速诊断播散性MAC，但血培养的敏感性更高(128)。约30%的HIV相关性FUO可以通过骨髓检查明确诊断(26)，但是这些诊断通常也可通过创伤性较小的检查获得。因此，对于情况稳定的发热患者，骨髓检查可以按排在初始检查（包括3次细菌和分枝杆菌血培养，适当的影像学检查以及根据患者主诉所行的活检）3-4周后（充分的分枝杆菌培养时间）进行。肝脏活检的意义尚不明确，在20-54%的病例中可以获得诊断(30,138)。

Of various radiographic techniques used to study FUO in HIV-infected patients, there is no one test that is uniformly revealing. Abdominal CT scanning has been shown to have a relatively low yield in this scenario, contributing to management in the minority. Sansom et al retrospectively evaluated the role of abdominal CT imaging in FUO, finding that in the majority of cases the diagnosis would have been made without resorting to CT if the results of culture from blood, bone marrow, or other tissues had been awaited (140). While useful in identifying extrathoracic infection, the insensitivity of technetium-99m-labeled antigranulocyte monoclonal antibody to pulmonary infection and lymphoma limits its role in FUO diagnosis (130). In contrast, gallium-67 citrate and indium-111-labeled polyclonal human immunoglobulin (¹¹¹In HIG) scanning more effectively image intrathoracic complications of AIDS but fail to identify gastrointestinal pathology given their lack of colonic activity（what does it mean?） (129). As a general rule of thumb, radiolabeled leukocytes are used in cases of fever of less that （than？）one week's duration and Ga-67 or ¹¹¹In HIG are used in fever of more than two week's duration. Given that most cases of FUO have a predominantly monocytic and/or lymphocytic infiltrate, gallium-67 or ¹¹¹In HIG imaging is preferable to the use of labeled leukocytes. Additionally, the use of radiolabeled leukocytes is less desirable in the HIV-positive population given the risk of needlestick injury with venipuncture and the theoretical risk of cross contamination of patients with HIV-infected blood products. （Need In－111 labeled HIG be administrated intravenously？）Ga-67 is quite sensitive for occult pulmonary, soft tissue, and bony infection but only moderately specific; ¹¹¹In HIG is just as sensitive as Ga-67 imaging, though significantly more accurate (28). The purpose of Ga-67 imaging is to localize a potential cause for fever which can then be further investigated with other modalities such as ultrasound, CT or MRI.

在多种可选的影像学检查中，没有哪一种对HIV相关性FUO是一定会有发现的。腹部CT的阳性率不高，仅在少数情况下对诊断有帮助。Sansom等的研究发现如果等待血、骨髓、和其他组织的培养结果，大多数FUO病例无需行腹部CT(140)。锝99标记的抗粒细胞单克隆抗体虽然对诊断肺外感染有帮助，其对肺部感染和淋巴瘤并不敏感，限制了该检查在FUO中的应用(130)。相反，枸橼酸镓67和铟111标记的多克隆人免疫球蛋白对诊断AIDS中肺内病变的价值较大，但由于其结肠活性差，不能用于诊断胃肠道病变(129)。通常，放射标记的白细胞用于发热小于1周的病例，镓67和铟111标记的人免疫球蛋白用于发热大于2周的病例。鉴于多数FUO病例都涉及单核细胞和淋巴细胞的侵润，镓67和铟111标记的人球蛋白优先考虑。另外，放射标记的白细胞需行静脉穿刺有增加穿刺伤和HIV血源性传播的风险。镓67对隐藏的肺部，软组织，骨感染敏感，但特异性有限；铟111标记的人球蛋白敏感性相当，同时特异性更高(28)。 使用镓67显象的目的是发现潜在病灶，指导其他检查手段，如超声，CT，MRI的使用。

The development of fever and evidence of systemic inflammation in a patient with HIV who has a virologic and immunologic response to antiretroviral therapy represents a diagnostic dilemma - possibilities include infection with an opportunistic pathogen, immune restoration disease, or drug reaction. Measurement of pathogen-specific immune responses may be a useful strategy in some circumstances (61, 95), though at this time there are no prospective trials demonstrating the clinical utility of such assays. Thus, in the case where immune restoration disease is the most likely cause of fever and inflammation, an advisable initial approach is the continuation of antiretroviral therapy, addition of antimicrobial therapy to suppress the replication of opportunistic pathogens, and anti-inflammatory therapy as necessary.

有些患者经抗病毒治疗后病毒学指标和免疫学指标好转但出现发热，可能的原因包括机会性感染、免疫重建、和药物反应。测定病原体特异性的免疫反应在某些情况下可能有效(61, 95)，但目前尚无前瞻性研究证明其作用。因此当考虑免疫重建为最可能的诊断时，合理的处理是继续抗病毒治疗，加用针对机会性感染病原体的抗生素，必要时使用抑制炎症反应的药物。

EMPIRIC THERAPY 经验性治疗

The role of empiric therapy for various opportunistic infections is not well established. After a thorough work-up, an empiric trial may be considered in cases where there is a high degree of clinical suspicion despite negative test results. Once appropriate cultures have been obtained, it is reasonable in some cases of suspected MAC to consider an empiric trial. Given the fact the many of the antimycobacterial agents have activity against both tuberculosis and MAC, one must be particularly cautious with the choice of antimicrobial agents. A practical approach is the combination of a macrolide (which has no activity against tuberculosis) with ethambutol (a relatively weak antituberculosis agent). Following initiation of this regimen, most patients with disseminated MAC will defervesce while few with tuberculosis would be expected to respond.

 经验性治疗对多种机会性感染的作用尚不明确。系统的检查后，对各项结果阴性但临床上高度怀疑的病例可以考虑经验性治疗。取得适当的培养后，怀疑MAC的患者可以给予试验性治疗。由于多种抗分枝杆菌的药物对MAC和结核均有效，应慎重选择。通常可以使用大环内酯类药物（对结核无效）和乙胺丁醇（弱抗结核药）的组合。这种组合可以使大多数MAC患者退烧，但对结核感染通常无效。

SUMMARY 总结

Fever continues to be a common symptom among HIV-infected patients at all stages of disease progression. While antiretroviral regimens and OI prophylaxis have had a significant impact on overall survival, they have also added a layer of complexity to the approach to fever in this population. The CD4+ T-cell count can be used as a rough, though imperfect, guide to the evaluation of fever. Patients with CD4+ T-cell counts greater than 500/mm³ and between 200 & 500/ mm³ are more prone to M. tuberculosis and bacterial sinopulmonary infections. The evaluation of fever in patients with CD4+ T-cell counts less than 200/mm³ is more challenging because the differential diagnosis is larger and the specificity of many presentations is lost.  The most common causes of fever are atypical mycobacteria, M. tuberculosis, pneumocystic carinii pneumonia, lymphoma and, in areas of endemicity, leishmaniasis. Despite the multitude of possible etiologies, studies have shown that the source of fever can be identified in the majority of patients. A thorough diagnostic evaluation should be pursued in all cases.

发热是各阶段HIV患者的常见症状。虽然抗病毒药物和机会性感染预防药物可以显著延长生存期，它们同时也使发热的诊断复杂化。CD4细胞计数可以为发热的诊断提供了一个有用的，但不完美的指导。 CD4大于500/mm3或介于200－500/ mm³的患者容易罹患结核和细菌性呼吸道感染。对于CD4小于200/mm³的患者，诊断困难，需鉴别情况多，临床表现不特异。最常见的病因包括非典型分枝杆菌、结核、PCP、淋巴瘤、和利什曼原虫（某些疫区）。虽然可能性较多，大多数病例可明确诊断。对所有病例均应行系统、细致的检查。

Tables and Figures

Table 1. Suggested Diagnostic Evaluation of the Febrile HIV-Infected Patient Based on CD4+ T-Cell Count   

对发热患者建议的检查（根据CD4计数） X表示选择，――表示不选

Table 2. Recommended Stool Sample Evaluation in the HIV-Infected Patient with Diarrhea  对发生腹泻的HIV推荐的粪便检查

· Bacterial culture 细菌培养

· Ova and parasite examination 找寄生虫和虫卵

· Modified Acid-fast stain for Isospora belli, Cryptosporidium parvum, Cyclospora cayetanensis 改良的抗酸染色 （贝氏等孢子球虫，隐孢子虫，环孢子虫）

· Clostridium difficile toxin assay  难辩梭状芽孢杆菌毒素检测

· Wright stain for fecal leukocytes 便中白细胞的Wright染色

· Consider colonoscopy in patients with persistent diarrhea and negative stool studies持续腹泻但便检查阴性的患者应考虑结肠镜

Table 3. Recommended CSF Evaluation in the HIV-Infected Patient

对HIV患者推荐的脑脊液检查

· Opening pressure 脑脊液压力

· Protein 蛋白

· Glucose 糖

· Cell count: WBC with differential, RBC 白细胞计数、分类，红细胞

· Bacterial studies: Gram stain and culture   细菌学：Gram染色、培养

· Mycobacterial studies: AFB smear and culture 分枝杆菌： 抗酸染色和培养

· Fungal studies: KOH preparation; India ink stain; cryptococcal antigen; fungal culture

   真菌：氢氧化钾溶液，墨汁染色；隐球菌抗原，真菌培养

· VDRL：非特异性抗原检测（VDRL）

Table 4. Summary of Series Examining Fever of Unknown Origin in HIV-Infected Patients  HIV患者FUO的临床研究

G: 男性同性恋

IV: 吸毒者

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