Approach

Once a person has been diagnosed with HIV infection, it is important to measure their CD4 count, in addition to viral load. The CD4 count is a highly sensitive and specific marker that determines the susceptibility to particular opportunistic infections.[71]

Tuberculosis (TB) can occur at any CD4 count, but the risk increases with lower CD4 counts.[43][72]​​​​ ​​The risk of Pneumocystis jirovecii pneumonia (PCP) and oropharyngeal or esophageal candidiasis is significantly higher when the CD4 count is below 200 cells/microliter. When the CD4 count is below 100 cells/microliter, patients are at a higher risk for toxoplasmosis. The risk of cytomegalovirus (CMV) end-organ disease and Mycobacterium avium complex (MAC) is highest when the CD4 count is below 50 cells/microliter.[1]

Patients who are not receiving suppressive antiretroviral treatment are more likely to develop opportunistic infections.[52]

Tuberculosis

The diagnosis of TB in people living with HIV (PLWH) can be can be challenging, as it may present with signs and symptoms (such as fevers, weight loss, and malaise) that may be attributed to HIV itself, and the clinical manifestations of pulmonary TB may be different depending on the level of immunosuppression.[2] Patients with a CD4 count less than 350 cells/microliter are more likely to present with less common manifestations of TB, such as lower lobe pulmonary disease, miliary disease, and extrapulmonary disease.[73] Whether or not a patient has pulmonary signs or symptoms, evaluations for TB should begin with a chest x-ray, or even a computed tomography (CT) scan if feasible, since CT scans may detect infiltrates not seen on a chest x-ray.[74] Depending on the involved site, TB may present with shortness of breath, cough, lymphadenopathy, headache, meningism, abdominal pain, dysuria, or abscess formation.

A high index of suspicion must be maintained when evaluating PLWH with symptoms suggestive of TB, as chest x-rays may appear normal.[75] Diagnostic workups should include smear, culture, and nucleic acid testing if available, and should be targeted based on the anatomic site of involvement (e.g., respiratory specimen or other tissue or fluid sample).[1]

Acid-fast bacilli (AFB) stain and culture

  • Three sputum specimens should be obtained for AFB smear, and culture.[76]

  • Specimens obtained through bronchoscopy with bronchoalveolar lavage and transbronchial biopsy may be useful in the evaluation of a patient with an abnormal chest x-ray when sputum smears are negative.

  • In extrapulmonary TB, AFB smear and cultures should also be performed on specimens from other sites.[76]​​

Molecular tests (nucleic acid amplification; polymerase chain reaction [PCR])

  • Several rapid nucleic acid amplification tests (NAATs) are available for the diagnosis of TB, and some are also able to detect resistance to some TB drugs.[77][78][79][80][81][82]​​​​​​​​​​ Since NAATs are more sensitive than smears, and can help distinguish between M tuberculosis and nontuberculous mycobacteria, they should be performed on at least one specimen from patients with suspected pulmonary TB.[83]​ Although NAATs were originally designed and approved for respiratory specimens, they may also be requested on specimens from other sites where involvement of TB is suspected (e.g., cerebrospinal fluid, lymph node aspirate, lymph node biopsy, pleural fluid, peritoneal fluid, pericardial fluid, synovial fluid, or urine).[77] In the US, use of NAATs for extrapulmonary specimens is not approved by the Food and Drug Administration and use would be off-label.

Lipoarabinomannan assay

  • Lateral flow tests that detect lipoarabinomannan (LAM) antigen in urine have emerged as potential adjunctive point-of-care tests in certain countries. One Cochrane review found the lateral flow urine lipoarabinomannan (LF-LAM) assay to have a sensitivity of 42% and specificity of 91% in diagnosing TB in HIV-positive individuals with TB symptoms.[84]

  • WHO recommends that LF-LAM can be used to assist in the diagnosis of active TB in HIV-positive individuals, when used in combination with other tests.[77] This approach is supported by another Cochrane review, which found reductions in mortality and an increase in treatment initiation with use of LF-LAM in inpatient and outpatient settings.[85]​ Culture would still be required for drug susceptibility testing. 

In vitro assays

  • High levels of adenosine deaminase (ADA) in pleural fluid have been shown to be highly sensitive and specific for TB pleuritis, regardless of CD4 count. Although other conditions, such as cancer, may also cause elevated pleural fluid ADA, the levels generally do not exceed the cutoff values suggested for TB.[86] In one study, adenosine deaminase sensitivity was 94% and specificity 95% in PLWH, regardless of CD4 counts, when the cutoff value was 30 U/L.[87]

Imaging

  • Chest x-ray should be performed on all patients with suspected TB. An upper lobe infiltrate, with or without cavities, is highly suggestive of pulmonary TB, although many people with HIV and TB coinfection present with atypical chest x-rays.[88] Patients with a CD4 count less than 200 cells/microliter can have TB culture-positive sputum and a normal chest x-ray.

  • Computed tomography (CT) scanning is useful for detecting pulmonary TB in patients with normal chest x-rays and for detecting extrapulmonary lesions. CT of the head is recommended if TB meningitis is suspected; findings include tuberculomas, postcontrast basal enhancement, hydrocephalus, and infarcts.[89] CT of the abdomen should be considered in patients with abdominal pain.

Biopsy

  • May be transbronchial or of an extrapulmonary site (e.g., bone marrow, vertebral column, liver, lymph node).

  • On pathologic exam, tuberculous granulomas are detected in 60% to 100% of cases, depending on the patient's immune status and the site of sampling.[90]

  • The specimen obtained should also be examined for AFB and cultured for mycobacteria.

Blood cultures

  • Mycobacterial blood cultures may be positive in disseminated TB.[91]

Disseminated MAC disease

Disseminated MAC disease only occurs in people with advanced immunosuppression; in PLWH, it mainly occurs in those with a CD4 count less than 50 cells/microliter. Clinical presentation may include nonspecific symptoms and signs, such as high fever, night sweats, fatigue, weight loss, anemia, and anorexia. Abdominal pain may result from involvement of retroperitoneal lymph nodes and chronic diarrhea from gut mucosal involvement. Other manifestations include hepatosplenomegaly, lymphadenopathy, and leukopenia. More unusual presentations include palatal and gingival ulceration, septic arthritis, osteomyelitis, endophthalmitis, pericarditis, and gastrointestinal (GI) bleeding.[92][93][94]

Laboratory investigations

  • Complete blood count (CBC) may show anemia (often severe, hematocrit <25%) and leukopenia.

  • Abnormal liver function tests, including elevated alkaline phosphatase and lactate dehydrogenase (LDH), and low albumin.

  • Cultures: AFB blood cultures detect over 90% of cases and are the test of choice for the diagnosis of disseminated MAC; they should be drawn from all patients with risk factors and clinical features.[95][96]​ MAC will not grow in standard blood culture media. The isolation of MAC from other sterile sites, such as bone marrow, lymph nodes, joints, and gastrointestinal specimens may also be useful.[97]

Imaging

  • An abdominal CT can be helpful in the diagnostic evaluation of a patient with disseminated MAC as it is likely to demonstrate mesenteric and abdominal lymph node enlargement, as well as hepatosplenomegaly and small bowel wall thickening.[98]​ However, normal abdominal CT scans have been reported in 25% of patients with AIDS with disseminated MAC.[99]

P jirovecii pneumonia

Patients with Pneumocystis pneumonia (PCP) typically present with worsening dyspnea with exertion, fever, and nonproductive cough. Compared with individuals who are medically immunosuppressed without HIV infection, those with HIV generally have symptoms that progress over a longer duration (28 days, on average, compared with 5 days, respectively).[100][101]​​​

​The initial evaluation of a patient suspected of having PCP should begin with a chest x-ray. If the chest x-ray appears normal but PCP is suspected, a high-resolution CT (HRCT) should be ordered.[1]

The diagnosis of PCP is established by visualization of the cystic or trophic forms in respiratory specimens obtained from induced sputum or bronchoscopy with bronchoalveolar lavage (BAL), which has a significantly higher diagnostic yield.[102]Pneumocystis cannot be cultured.

Laboratory investigations

  • Serum lactate dehydrogenase (LDH) concentration is frequently increased and may be suggestive of PCP in patients with risk factors and compatible clinical features.[103]

  • Decreased blood oxygenation is the most common laboratory finding among patients with PCP. Widened alveolar-arterial oxygen (PAO₂-PaO₂) gradients have been reported in >90% of cases, and the magnitude can reflect disease severity and be useful for monitoring in severe cases.[104] Oxygen desaturation during exertion can be an especially sensitive finding.[105]

Sputum induction (by inhalation of aerosolized hypertonic saline solution)

  • The diagnostic yield of expectorated sputum is too low to be of any clinical utility. Exam of induced sputum is recommended as the initial screening test. Since the negative predictive value of this test is relatively low, a negative test should prompt a referral for fiberoptic bronchoscopy with BAL, which significantly increases the diagnostic yield to >90%.[102] Specimens should be evaluated with particular staining methods (e.g., Gomori-methenamine silver, Wright-Giemsa, Diff-Quick, or immunofluorescence). PCR is increasingly used to aid in the diagnosis of PCP, yet a positive test may reflect colonization rather than active disease.[1]

Imaging

  • Chest x-ray should be performed on all the patients with suspected PCP. A diffuse interstitial infiltrate is typical. Cavitation or cystic lesions, abscess, lobar consolidation, nodular lesions, effusions, and pneumothorax are less common presentations.[106] Upper lobe infiltrates may be seen in patients with PCP who are using aerosolized pentamidine.[107]

  • CT of the chest: HRCT has a sensitivity of 100%, and should be considered when the chest x-ray is normal, since a normal HRCT essentially rules out PCP. HRCT findings in patients with early PCP include reticular, nodular, and ground glass opacities. In more advanced cases, CT can demonstrate consolidations, upper lobe thin-walled cysts, or pneumothoraces.[108]​​

Biopsy

  • Transbronchial biopsies can be performed if initial BAL is negative but clinical suspicion of PCP is high or other diagnoses are considered likely. Sensitivity of transbronchial biopsies is 95% to 100%.[1]

  • Open biopsy is no longer recommended, given the advantages of BAL and molecular techniques. In rare cases, video-assisted thoracic surgery biopsies are considered when bronchoscopy is inconclusive.

Toxoplasmosis

In patients with AIDS, toxoplasmic encephalitis generally presents with fever and symptoms of encephalitis, including headache, seizures, motor weakness, and/or a range of mental status changes.[109] Less common extracerebral manifestations include pneumonitis and chorioretinitis.[110][111]​​​ Gastrointestinal and musculoskeletal involvement may also occur.

A presumptive diagnosis can be made with a 90% probability in a patient with CD4 count below 100 cells/microliter and:

  • Seropositivity for Toxoplasma gondii immunoglobulin G (IgG) antibodies

  • Lack of effective previous prophylaxis for toxoplasma

  • Brain imaging with typical radiographic appearance (such as multiple ring-enhancing lesions).

In such cases, it is common practice to treat empirically for toxoplasmosis. However, if the patient does not respond to empiric therapy after 2 weeks (based on clinical or radiographic improvement), a brain biopsy should be performed.[112]

Serology

  • Seropositivity for anti-toxoplasma IgG antibodies makes the diagnosis more likely; however, absence of these antibodies does not exclude it.

Lumbar puncture

  • Cerebrospinal fluid (CSF) findings are nonspecific and often show mild mononuclear pleocytosis and elevated protein. Giemsa staining can show tachyzoites. Detection of T gondii in the CSF by PCR establishes the diagnosis, yet a negative result does not rule it out.[113]

Imaging

  • CT and magnetic resonance imaging (MRI) should be considered; MRI is more sensitive than CT.[114] CT and MRI of the brain usually show ring-enhancing lesions, often associated with edema. Multiple lesions are more common than single lesions.[115]

  • Thallium single photon emission CT (SPECT) and positron emission tomography (PET) can be useful in distinguishing toxoplasmosis (or other intracranial infections) from central nervous system lymphoma.[116][117]​​​ To differentiate cerebral lymphoma from toxoplasma encephalitis, a F-fluorodeoxyglucose (FDG) PET scan may be helpful; F-FDG uptake is typically significantly higher in cerebral lymphoma. Thallium scans in the era of ART are of limited utility.[118][119]

Brain biopsy (open or stereotactic)

  • Establishes a definitive diagnosis of cerebral toxoplasmosis, although patients are typically treated based on a presumptive diagnosis without a brain biopsy, which is associated with a significantly high risk of complications. PCR testing for toxoplasma also establishes a definitive diagnosis and has made brain biopsies less necessary.[120]

CMV

Retinitis is the most common clinical presentation of CMV disease in patients with AIDS and can cause severe visual impairment. Fundoscopic exam is helpful. Visual floaters are common, and areas of infarction, hemorrhage, perivascular fluffy white retinal infiltrates, and retinal opacification are often seen.[121] The diagnosis is made clinically by an ophthalmologist. Other less commom manifestations may include colitis (second most common), ventriculitis, cholangitis, encephalitis, and gastritis.[122] Pain and weakness may indicate the presence of CMV polyradiculopathy.[123]​​​

Laboratory investigations

  • CBC may show anemia, leukopenia, or thrombocytopenia.

  • Serology: CMV-specific IgM antibodies are suggestive of recent seroconversion. A fourfold increase or greater in CMV-specific IgG titers, in paired specimens obtained at least 2-4 weeks apart, is consistent with infection. The utility of CMV serology is limited because invasive disease is more commonly due to reactivation than to primary infection, and a negative IgM does not rule out CMV disease in a person with advanced HIV. Serology is not considered to be useful for diagnosing CMV retinitis.

  • Quantitative CMV PCR can be best used to rule in, rather than to rule out, CMV disease in individuals living with HIV at high risk. When the cutoff is at the test's limit of detection of CMV viremia (400 copies/mL), sensitivity of the test is 47% and the negative predictive value is 70%.[124] CMV viremia may be present without CMV end-organ disease. Conversely, CMV viremia is absent in more than half of patients with CMV retinitis.[125]​ 

Cryptococcus infection

Usually presents as a subacute meningitis or meningoencephalitis with fever, malaise, and headache. Patients can also present with neck stiffness, photophobia, vomiting, and altered mental status. Disseminated disease can also occur, with or without concurrent meningitis. In such cases, pulmonary involvement or skin lesions may be present.

Lumbar puncture

  • Lumbar puncture is required for the diagnosis. Opening pressure of the spinal fluid should be measured as it is elevated (with pressures >200 mm of H₂O) in up to 75% of patients.

  • CSF findings are often fairly unremarkable, with minimally elevated mononuclear cells and protein and decreased or normal glucose; the CSF profile can be normal in approximately a quarter of cases.[126][127]

    India ink exam of the CSF remains a rapid test that is positive in more than 60% of patients with AIDS with cryptococcal meningitis.[128] A negative India ink stain exam does not rule out infection, however. CSF cryptococcal antigen (CrAg) tests are highly sensitive and specific and should always be included in the diagnostic evaluation.[129] CSF fungal cultures should also be performed.

  • Serum CrAg should also be performed, as the sensitivity compares to that of CSF CrAG, and since lumbar punctures may sometimes be delayed or not feasible.[130]

  • Cryptococcal PCR assays are included in some multiplex PCR tests, although the performance and clinical value of these tests requires further study.[131]

Blood cultures

  • Three-quarters of patients with HIV-associated cryptococcosis have positive blood cultures for Cryptococcus neoformans, which can grow on most bacterial and fungal media.[132]

Mucocutaneous candidiasis

Oral Candida infections can cause thrush, a common OI in patients with AIDS characterized by creamy white, curd-like patches on the tongue and oral mucous membranes that can be removable by scraping. Thrush can be asymptomatic or can cause a cottony sensation in the mouth and potentially altered taste and difficulty swallowing.[133] Patients may also develop Candida esophagitis, which can present with painful swallowing, an obstruction sensation, and sometimes substernal chest pain.[134] Mucosal candidiasis involving the vaginal and rectal regions can also occur, causing edema, pruritis, and thick, curd-like discharge.[135]

Candidiasis is clinically diagnosed, usually based on characteristic symptoms and appearance of lesions.

Laboratory investigations

  • Diagnostic confirmation of thrush can be made with a scraping for microscopic exam, using a 10% potassium hydroxide (KOH) smear or gram stain, which may show characteristic findings, including hyphae, pseudohyphae, and budding yeast.[136]

  • Cultures are usually not necessary unless the lesions fail to resolve on antifungal treatment.

Imaging

  • Upper GI endoscopy is helpful in the diagnosis of esophageal candidiasis.[137][138]

  • Barium swallow is of limited utility as the radiographic appearance alone cannot determine the cause of the lesions.

Coccidioidomycosis

The symptoms of pulmonary coccidioidomycosis are often similar to typical respiratory illnesses and patients often present with signs and symptoms suggestive of a viral respiratory infection or community-acquired pneumonia; therefore, a high index of suspicion is important in patients with endemic exposures.[139] While the typical incubation period is 1-3 weeks, individuals who develop immune suppression from advanced HIV infection can develop symptomatic disease several years after exposure.[140] Establishing the diagnosis of coccidioidomycosis depends on either detecting anticoccidioidal antibodies from blood, CSF, or other body fluid, or recovering Coccidioides species or spherules from a clinical specimen. Immunocompromised patients, such as those with advanced HIV infection, may not be able to produce an antibody response, in which case antigen and/or PCR testing may be necessary, in addition to cultures.[141]

Culture

  • Isolation of Coccidioides organisms from a patient’s sputum or other clinical specimen definitively establishes the diagnosis of coccidioidomycosis and should not be considered to represent colonization. Organisms grow well within 5-7 days of incubation on most mycologic and bacteriologic media. When growth is noted, appropriate biocontainment measures are imperative, as cultures are highly infectious and laboratory personnel are at risk of infection.[142]

Serology

  • Serologic tests are most frequently used to diagnose primary pulmonary coccidioidomycosis and are highly specific for infection.[143] If serologic testing is negative in suspected infection, repeat serologic testing is recommended since it can take several weeks to develop an adequate antibody response.

  • Enzyme immunoassay (EIA) is widely available and detects specific IgM and IgG antibodies against Coccidioides. Positive EIA results should be confirmed with immunodiffusion and complement fixation.[1]

Antigen testing

  • Coccidioidal antigen testing can be performed on serum, urine, and CSF.

PCR

  • Real-time PCR can be used for detection of Coccidioides.

Histopathology

  • Biopsy is a definitive test. Positive histopathology gives a definitive diagnosis of coccidioidomycosis, because there is no colonized state. Spherules are identified using microscopy.

Imaging

  • Imaging studies, such as chest x-ray or CT scan, are typically useful during the initial evaluation but radiographic findings are nonspecific.

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