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1st tests to order

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Tuberculosis can occur throughout the course of HIV disease but the risk increases as the CD4 count decreases.[43]​​Pneumocystis jirovecii pneumonia and candidiasis are more likely when the CD4 count is below 200 cells/microliter. Cytomegalovirus, Mycobacterium avium complex, and toxoplasmosis are more likely with CD4 count below 50 cells/microliter.[1]

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variable

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In diagnosis of tuberculosis (TB) three sputum specimens should be obtained for acid-fast bacilli (AFB) smear and cultured.[76]

Examination of induced sputum is recommended as the initial screening test for Pneumocystis jirovecii pneumonia (PCP). Specimens should be evaluated with particular staining methods (e.g., Gomori-methenamine silver, Wright-Giemsa, Diff-Quick, or immunofluorescence). 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]​

Sputum culture is a definitive test for coccidioidomycosis infection. 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.

Result

AFB stain and mycobacterial culture are positive in TB and MAC; staining is positive in PCP; positive in coccidioidomycosis infection

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Two blood cultures are usually sufficient for the detection of disseminated Mycobacterium avium complex (MAC). One blood culture identifies 91% of patients with MAC bacteremia, while a second blood culture increases the yield to 98%.[165] However, up to 6 weeks of culture may be required, which limits the clinical utility.

Three-quarters of patients with HIV-associated cryptococcosis have positive blood cultures for Cryptococcus neoformans.[132] Blood cultures may be helpful if disseminated disease is suspected in the absence of meningitis.

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

Result

may be positive in MAC cryptococcus infection, and disseminated TB

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Measuring adenosine deaminase in pleural fluid is an easy and inexpensive test that may help establish the diagnosis of pleural tuberculosis when significantly elevated.[86] Adenosine deaminase sensitivity was 94% and specificity 95% in people living with HIV, regardless of CD4 counts, when the cutoff value was 30 U/L.[87]

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elevated in TB pleuritis

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The test is done using an enzyme-linked immunosorbent assay. 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.

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CMV-IgM titer is indicative of acute infection; CMV-IgG titer suggests past infection

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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]

Result

number of genomic CMV copies per volume of specimen or PCR

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Presence of anti-T gondii IgM antibodies does not necessarily indicate a recently acquired infection as they can remain elevated for more than 1 year. Recent T gondii infection is likely when serial specimens obtained at least 3 weeks apart and tested in parallel reveal at least a 4-fold increase in IgG titers.[166]​ A negative T gondii IgG makes toxoplasmic encephalitis significantly less likely but does not rule it out.[1]

Result

anti-T gondii IgM suggests recent infection and anti-T gondii IgG suggests past infection

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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]

Result

positive IgM and/or IgG

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Very specific and highly sensitive (>90%). High serum titers (≥1:160) indicates a higher risk for CNS disease in asymptomatic patients.[167] High initial cerebrospinal fluid (CSF) titers (≥1:1024) are a marker of poor prognosis and correspond to a high organism burden. CSF antigen titers typically fall with successful treatment.[150]

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from serum or CSF

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Anemia is common in people living with HIV with opportunistic infections. In disseminated Mycobacterium avium complex, the anemia is an important negative predictor for survival, is usually profound, and is often accompanied by leukopenia and thrombocytopenia.[168][169]

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anemia often accompanied by leukopenia and thrombocytopenia

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Alkaline phosphatase is typically elevated in people living with HIV with Mycobacterium avium complex or cytomegalovirus (CMV) hepatobiliary disease.[170] In CMV hepatitis, it is usually accompanied by elevation of aspartate aminotransferase and alanine aminotransferase.[171]

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elevated

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Often elevated in disseminated  Mycobacterium avium complex infection, and frequently elevated in Pneumocystis jirovecii pneumonia (PCP).

However, elevated LDH should be interpreted with caution, because it is also elevated in patients with various other lung diseases, such as pulmonary tuberculosis and other bacterial pneumonias, as well as a variety of noninfectious conditions.[103][170]

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elevated (but nonspecific)

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The arterial oxygen pressures (PaO₂) and P(alveolar-arterial [A-a])O₂ gradient correlate with prognosis. A P(A-a)O₂ of greater than 35 mmHg or a PaO₂ of less than 70 mmHg are associated with poorer outcome, and provide an indication for adjunctive corticosteroid therapy.[100]

Result

increased alveolar-arterial oxygen gradient, P(A-a)O₂; PaO₂ values vary widely depending on disease severity

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Should be performed in any person living with HIV (PLWH) with pulmonary symptoms.

Findings in PLWH with tuberculosis (TB) and a CD4 above 200 cells/microliter: upper lobe infiltrates and cavitation; a CD4 below 200 cells/microliter: mediastinal adenopathy is common and probably reflects an ineffective immune response.[2][144]

The prevalence of normal chest x-rays in patients with confirmed Pneumocystis jirovecii pneumonia (PCP) is about 10%.[147] Various atypical radiographic manifestations have been reported, including nodular densities and cavitary lesions. Pneumothorax can occur, and its management is often difficult.[172] If the chest x-ray appears normal but PCP is suspected, a high-resolution CT should be ordered.

Imaging studies are typically useful during the initial evaluation of coccidioidomycosis, but radiographic findings are nonspecific.

Chest x-ray may be used in subsequent monitoring for improvement.[173]

Result

variable; TB: upper lobe infiltrates and cavitation or mediastinal adenopathy; PCP: bilateral diffuse infiltrates beginning in the perihilar regions; cytomegalovirus: interstitial infiltrate

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Should be ordered in all patients with altered mental status.

In toxoplasmic encephalitis, lesions tend to involve the basal ganglia and hemispheric corticomedullary junction.[174]

In cryptococcal meningitis, CT findings may include single or multiple nodules (cryptococcomas), cerebral edema, or hydrocephalus.[150]

Result

toxoplasma encephalitis: multiple, bilateral, hypodense, ring-enhancing lesions; cryptococcal disease: normal or may show meningeal enhancement; tuberculosis meningitis: tuberculomas, postcontrast basal enhancement, hydrocephalus, and infarcts

Tests to consider

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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. 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.

Result

positive in TB infection

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Lateral flow tests that detect lipoarabinomannan (LAM) antigen in urine are potential point-of-care tests for TB. One Cochrane review found the lateral flow urine lipoarabinomannan (LF-LAM) assay to have a sensitivity of 42% in diagnosing TB in HIV-positive individuals with TB symptoms, and 35% in HIV-positive individuals not assessed for TB symptoms.[84] WHO recommends that LF-LAM can be used to assist in the diagnosis of active TB in HIV-positive individuals.[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 (DST).

Result

positive

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Bronchoscopy may be required in patients unable to produce sputum.

Extra caution should be exercised by the pulmonologist performing the BAL if tuberculosis is a consideration.[175][176][177]

Result

staining is positive in PCP; may be positive in disseminated cryptococcosis

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Potassium hydroxide 10% (KOH) slide preparation can confirm the diagnosis of candidiasis. Pseudohyphae and budding yeast are characteristic findings.

Cultures alone are not diagnostic because colonization is common and are usually not necessary unless the lesions fail to resolve on standard antifungal treatment.[178]

Result

presence of Candida species

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Due to the risk of brain herniation if mass effect is present, caution should be exercised when considering lumbar puncture.[166]

Toxoplasmosis infection: Giemsa staining can show tachyzoites.

Cryptococcal meningitis: India ink exam is positive in 70% to 90% of people living with HIV. CSF culture requires 48-72 hours. The opening pressure in the CSF is elevated in up to 75% of patients; CSF pressures greater than 250 mm of H₂O may require large-volume CSF drainage.[150][160]​​ CSF cryptococcal antigen is also important to include, as it is a very sensitive and specific test and can be rapidly performed.

Result

toxoplasma encephalitis: mild pleocytosis of mononuclear predominance and elevated protein; cryptococcal meningitis: WBC elevated with lymphocytosis, elevated protein, and low glucose

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Can be useful in the diagnosis of toxoplasmic encephalitis. PCR in CSF has a sensitivity that varies from 12% to 70% and a specificity of approximately 100% in patients with toxoplasmic encephalitis. A positive PCR in brain tissue does not necessarily indicate active infection because tissue cysts persist in the brain long after acute infection.[179]

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positive

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May be helpful in the diagnosis of disseminated Mycobacterium avium complex and tuberculosis, although acid-fast bacilli (AFB) blood cultures are the test of choice. Diagnostic sensitivity of bone marrow cultures may be no greater than that of blood cultures in these patients, but the histopathologic examination of bone marrow specimens results in the relatively rapid identification of infections in some patients who are culture negative.[180]​ In early disease, the sensitivity of bone marrow culture may actually be higher than that of AFB blood culture.

Result

granulomas; organism seen on acid-fast stain

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Lymph node fine-needle aspiration or biopsy allows a specific diagnosis in 100% of patients with Mycobacterium avium complex focal lymphadenitis.[181]

Result

granulomas; organism seen on acid-fast stain

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Should be considered when other less invasive tests have been nondiagnostic and the pulmonary process is progressive.

In patients with suspected tuberculosis (TB), transbronchial biopsy or biopsy of an extrapulmonary site (e.g., bone marrow, vertebral column) may be required. On pathologic examination 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 acid-fast bacilli (AFB) and cultured for mycobacteria.

Patients with clinical illness suggestive of tissue-invasive cytomegalovirus (CMV) disease should have tissue specimen (liver, intestinal mucosa, lung) obtained by biopsy for the detection of CMV.[182]

Positive histopathology gives a definitive diagnosis of coccidioidomycosis.

Result

TB: granulomas, visualization of AFB; CMV: demonstration of CMV-specific cytoplasmic and intranuclear inclusions in liver, intestinal mucosa, or lung specimens; coccidioidomycosis: identification of spherules on microscopy

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Can provide a definitive diagnosis of toxoplasmic encephalitis.

Excisional brain biopsy findings range from granulomatous reaction with gliosis and microglial nodules to necrotizing encephalitis. The presence of tachyzoites or cysts surrounded by inflammation is considered diagnostic.[149]

Result

toxoplasmic encephalitis: presence of tachyzoites or cysts surrounded by inflammation

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Consider in patients with abdominal pain or if disseminated Mycobacterium avium complex (MAC) is suspected.

The CT scan in abdominal tuberculosis (TB) usually shows ascites and omental thickening.[144][183] Hepatomegaly, splenomegaly, and small wall thickening may also be noted.[99]

Result

abdominal TB: visceral lesions and intra-abdominal lymphadenopathy with necrosis; disseminated MAC: enlarged intra-abdominal mesenteric and/or retroperitoneal lymph nodes

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When chest radiographic findings are normal, in someone with possible Pneumocystis jirovecii pneumonia (PCP), HRCT, which is more sensitive than chest x-ray, may reveal more faint ground-glass opacities or other subtle lesions. The sensitivity, specificity, positive predictive value, and negative predictive value of HRCT for the diagnosis of PCP are 100%, 83.3%, 90.5%, and 100%, respectively. HRCT is a reliable method for differentiating PCP from other infectious processes in HIV-positive patients and a good method to rule out PCP.[108][172]​​[184]

Findings include bilateral ground-glass opacities, patchy bilateral consolidation, and multiple nodules or mass-like areas of consolidation.[185]

Ground-glass opacities can be homogeneous (24% of episodes), spare the lung periphery (41%), or display a mosaic pattern (29%). Other findings can include: reticulation, tree-in-bud appearance, consolidation, or cystic lesions.[185]

Result

PCP: ground-glass opacities; cytomegalovirus: diffuse interstitial and parenchymal changes

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More sensitive than CT scan for toxoplasmic encephalitis and the preferred imaging technique, especially in patients without focal neurologic abnormalities. Patients with only one lesion or no lesions apparent on CT scan should undergo MRI to determine whether more than one lesion is present.[114]

MRI scan is more sensitive for detecting multiple enhancing nodules within the brain parenchyma, meninges, basal ganglia, and midbrain.[150]

Result

toxoplasmic encephalitis: multiple or solitary focal brain lesions; cryptococcal disease: multiple enhancing nodules

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Useful for distinction between central nervous system (CNS) lymphoma and infectious processes in people living with HIV with focal brain lesions.[116]

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increased uptake is an indicator of malignancy (CNS lymphoma)

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On biopsy, cytomegalovirus (CMV) intranuclear inclusions are identified in the densely inflamed granulation tissue of the ulcer base.[186]

In esophageal candidiasis, pathologic findings include: desquamated superficial hyperplastic hyperkeratotic squamous epithelium and inflammatory cells, with infiltration by fungal elements.[187]

Result

CMV colitis: lesions vary from punctate and superficial erosions to deep ulcerations, with granular and friable intervening mucosa

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Coccidioidal antigen testing can be performed on serum, urine, and cerebrospinal fluid.

Result

positive for coccidioidal antigen

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

Result

positive for coccidioidal DNA

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