History and exam
Key diagnostic factors
common
no antiretroviral treatment (ART) or failure of ART
Individuals who are not receiving suppressive ART are more likely to develop opportunistic infections.[57]
fever
In people living with HIV with fever of undetermined cause, diagnostic studies for extrapulmonary tuberculosis should be considered.[154]
In the US, disseminated Mycobacterium avium complex is the leading cause of HIV-associated fever of unknown origin and usually presents with fever, night sweats, weight loss, anemia, and elevated serum levels of alkaline phosphatase.[155][156]
In individuals with Pneumocystis jirovecii pneumonia, fever is usually accompanied by dry cough and dyspnea.[157]
Cytomegalovirus accounts for approximately 5% to 11% of cases of prolonged, undifferentiated fever in people living with HIV.[155][158]
Toxoplasmic encephalitis can present with fever that is usually accompanied by headache and altered mental status.[159]
Disseminated histoplasmosis in individuals with HIV often presents with systemic symptoms such as fever, weight loss, fatigue, respiratory symptoms, and hepatosplenomegaly.[1]
headache and altered mental status
In cryptococcal chronic or subacute meningoencephalitis, these symptoms may be present for several weeks and can be accompanied by fever and malaise.[160]
Tuberculous meningitis may present with fever, lassitude, weight loss, behavior changes, headache, and vomiting. A delay in diagnosis may lead to neurologic deficits, loss of consciousness, or convulsions.[161]
In toxoplasmosis, focal encephalitis with headache and confusion is common.[159][160]
Cytomegalovirus encephalitis may also present with confusion and focal neurologic abnormalities.[162]
Individuals with central nervous system histoplasmosis often present with fever and headache; cases involving the brain may additionally result in altered mental status.[1]
dyspnea or cough
Mainly suggestive of tuberculosis or Pneumocystis jirovecii pneumonia (PCP) infection, particularly if exertional.
Less commonly, toxoplasmosis may cause pneumonitis, which can be difficult to distinguish from PCP.[117]
Cough and dyspnea occur in approximately 50% of people with histoplasmosis.[1][43][153]
abdominal pain, diarrhea, weight loss
Weight loss and diarrhea are common symptoms of disseminated Mycobacterium avium complex and may precede the onset of fever.[156]
In cytomegalovirus disease, diarrhea is the most common gastrointestinal (GI) tissue-invasive symptom.[129] Cholangitis and gastritis are less common manifestations.
Diarrhea in an individual with AIDS may also be due to parasitic infections caused by organisms such as cryptosporidia, microsporidia, and cystoisosporiasis.
In one study of people living with HIV in Panama, 50% of people with histoplasmosis experienced diarrhea, with or without fever.[163] Another study from French Guiana reported GI symptoms in 70% of people with histoplasmosis.[164]
dysphagia
Oropharyngeal candidiasis (OPC) may present with burning pain, altered taste sensation, and difficulty swallowing liquids and solids.
Esophageal candidiasis usually causes dysphagia and odynophagia, yet 40% of individuals may be asymptomatic. Esophageal disease can present without concomitant OPC.
lymphadenopathy
Focal lymphadenopathy and/or lymphadenitis due to Mycobacterium avium complex can be seen shortly after the initiation of antiretroviral treatment as a result of restoration of immune function (immune reconstitution inflammatory syndrome).
Cervical, intra-abdominal, and mediastinal lymph nodes are most commonly involved.[165]
Lymphadenopathy in people with AIDS may also be due to tuberculosis, Bartonella henselae, and various endemic mycoses, such as coccidioidomycosis and histoplasmosis.
visual floaters, eye pain, and blindness
Cytomegalovirus (CMV) chorioretinitis is the most common manifestation of CMV disease in people living with HIV and generally causes visual floaters and visual impairment.[166]
Toxoplasmic chorioretinitis typically presents with eye pain and impaired visual acuity.[167]
Visual loss can also occur as a result of cryptococcal meningitis.[168]
Endophthalmitis is rarely caused by disseminated Mycobacterium avium complex.[100]
ocular hemorrhage
Ocular hemorrhages are associated with CMV retinitis and with advanced toxoplasmic chorioretinitis.[169]
mucosal changes
White plaques on the buccal mucosa, gums, or tongue are typical of oral pseudomembranous candidiasis (thrush). Acute atrophic candidiasis (erythematous mucosa) or chronic hyperplastic candidiasis (leukoplakia) are less common.[146]
Vaginal erythema with adherent white discharge, marked itching, watery to curd-like discharge, dyspareunia, and swelling of labia and vulva with discrete pustulopapular peripheral lesions are seen in vaginal candidiasis.
Disseminated Mycobacterium avium complex rarely results in palatal and gingival ulceration.[98]
Other diagnostic factors
common
hepatosplenomegaly
Suggestive of disseminated Mycobacterium avium complex and disseminated histoplasmosis.
exercise-induced oxygen desaturation
Oxygen desaturation occurring with exercise is highly suggestive of Pneumocystis jirovecii pneumonia.[170]
uncommon
blurred vision and photophobia
papilledema
In cryptococcal meningitis, papilledema may be present on fundoscopic exam.[160]
meningismus, focal neurologic findings
In cryptococcal meningitis, signs are often absent but may include depressed level of consciousness, cranial nerve palsies, and other focal neurologic findings.
Manifestations of toxoplasmic encephalitis include seizures, cranial nerve abnormalities, visual field defects, sensory disturbances, cerebellar dysfunction, meningismus, movement disorders, and neuropsychiatric disturbance.[159]
pain and weakness
May indicate the presence of toxoplasmic encephalitis, or cytomegalovirus polyradiculopathy.[130]
bone or joint pain
Unusual presentation of disseminated Mycobacterium avium complex.[99]
skin lesions
Erythema nodosum (painful raised erythematous nodules over pretibial region) is an uncommon manifestation of tuberculosis.[173][174]
Papular umbilicated skin lesions may rarely be seen in disseminated Cryptococcus infection.[175]
Erythema nodosum and erythema multiforme are relatively manifestations of coccidioidomycosis.[176]
Risk factors
strong
post-HIV seroconversion with any CD4 count
Tuberculosis (TB) can occur after HIV seroconversion and throughout the course of HIV disease, including after antiretroviral treatment initiation. TB incidence doubles in the first year after HIV seroconversion.[45][46] The annual risk of reactivation of latent TB is 3% to 16% per year for people with untreated HIV infection, which is approximately the lifetime risk of reactivation in those without HIV infection.[1]
TB risk further increases as CD4 count decreases.[47]
CD4 count below 250 cells/microliter
Individuals with a CD4 count less than 250 cells/microliter living in or visiting areas in which Coccidioides species are endemic are at increased risk for coccidioidomycosis.[42]
CD4 count below 200 cells/microliter
Individuals with a CD4 count less than 200 cells/microliter are at increased risk for Pneumocystis jirovecii pneumonia (PCP) infection or candidiasis. The development of thrush or fever significantly and independently increases the risk of PCP in these individuals.[48]
CD4 count below 150 cells/microliter
Individuals with a CD4 count below 150 cells/microliter who live in or have traveled to areas endemic for Histoplasma capsulatum are at increased risk for developing progressive disseminated histoplasmosis. The risk is particularly high in regions with significant exposure to soil contaminated with bird or bat droppings. Inhalation of fungal spores leads to infection, with dissemination occurring due to impaired cell-mediated immunity.[1]
CD4 count below 100 cells/microliter
Toxoplasmic encephalitis usually occurs in people living with HIV with CD4 counts below 100 cells/microliter (particularly when CD4 counts are below 50 cells/microliter), and it is almost always caused by reactivation of a chronic infection.[49] Seroprevalence ranges geographically, from approximately 10% among people living with HIV in the US to 50% to 80% among people living with HIV who live in certain countries in Europe, Latin America, and Africa.[50][51][52] One systematic review and meta-analysis which reviewed data published between 1993 and 2023, reported a pooled seroprevalence of toxoplasmosis among the general population in Spain of 32.3%; most of the included studies were in pregnant women and the pooled seroprevalence of toxoplasmosis in pregnant women was 24.4%.[53]
CD4 count below 50 cells/microliter
More than three-quarters of cryptococcal infections associated with AIDS develop when the CD4 count falls below 50 cells/microliter.[54] The incidence is higher among individuals with AIDS in Africa and Southeast Asia than in the US; incidence is lower in Europe than in the US.[55]
Individuals with AIDS who have a CD4 count below 50 cells/microliter are at highest risk of developing organ-invasive cytomegalovirus disease.
The risk of developing disseminated Mycobacterium avium complex infection inversely correlates with absolute CD4 count values.[56]
no antiretroviral treatment (ART) or failure of ART
All opportunistic infections are more likely in individuals not receiving ART; in the period after initiating ART, resulting from an inflammatory immune response that was previously absent; or in individuals in whom ART fails because of viral resistance.[57]
men who have sex with men (MSM)
Cytomegalovirus is common among nearly all populations around the world, and it is generally acquired during childhood, although sexual activity is an important mode of transmission, and higher rates of infection have been noted among MSM living with HIV compared with MSM without HIV (98% vs. 80%).[58]
black or Hispanic race
People living with HIV who are black or Hispanic who use intravenous drugs are at increased risk of tuberculosis.[59]
intravenous drug use
socioeconomic factors (poverty, overcrowding, homelessness, poor nutrition)
dust inhalation in areas endemic for Coccidioides and Histoplasma
Coccidioidomycosis is acquired when airborne fungal arthroconidia are inhaled; therefore, occupational (e.g., construction, digging) or recreational activities that increase the likelihood of dust inhalation in endemic areas also increase the likelihood of infection.
Activities that disturb soil contaminated with bird or bat droppings, such as excavation, construction, or caving, can lead to inhalation of Histoplasma capsulatum spores, increasing the risk of histoplasmosis in endemic regions.[1][64]
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