AIDS-defining Conditions

Human immunodeficiency virus (HIV) infection is a sexually transmitted or blood-borne infection that destroys CD4 T cells. Chronic HIV infection and depletion of CD4 cells eventually results in acquired immunodeficiency syndrome (AIDS), which can be diagnosed by the presence of certain opportunistic diseases called AIDS-defining conditions. These conditions include a wide spectrum of bacterial, viral, fungal, and parasitic infections as well as several malignancies and generalized conditions. These serious and life-threatening diseases are generally not seen in immunocompetent patients. Treatment of HIV is very important in managing these diseases, and the incidence of AIDS-defining conditions has declined with the use of antiretroviral therapy.

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Overview

The tables below summarize the defining conditions of acquired immunodeficiency syndrome (AIDS).

Table: Bacterial infections
AIDS-defining conditionCD4 count (cells/µL)Clinical presentationManagement (in addition to HIV treatment)
Mycobacterium avium complex< 50
  • Disseminated: fever, weight loss, night sweats, abdominal pain, diarrhea
  • Lymphadenitis
Treatment: macrolide and ethambutol
Mycobacterium tuberculosis< 200
  • Pulmonary: fever, cough, hemoptysis, weight loss, night sweats
  • Disseminated: lymphadenitis, meningitis, peritonitis, septic shock, respiratory failure
  • Treatment: isoniazid, rifampin, pyrazinamide, and ethambutol
  • All individuals should be screened.
Salmonella septicemia< 200
  • Fever, diarrhea
  • Infection can occur at any site.
IV fluoroquinolones or 3rd-generation cephalosporins
IV: intravenous
Table: Viral infections
AIDS-defining conditionCD4 count (cells/µL)Clinical presentationManagement (in addition to HIV treatment)
Cytomegalovirus (CMV)< 50
  • CMV colitis: fever, abdominal pain, watery, diarrhea
  • CMV encephalitis: progressive cognitive deficits, focal neurologic abnormalities
  • CMV retinitis: painless central vision loss
Ganciclovir, valganciclovir, foscarnet, or cidofovir
Herpes simplex virus< 100Non-healing lesions, tracheitis, pneumonitis, esophagitis, keratitis, meningoencephalitisAcyclovir, valacyclovir, or famciclovir
JC virus (progressive multifocal leukoencephalopathy)< 200Focal-neurologic deficits, cognitive impairmentSupportive
JC virus: named after the initials of an anonymous patient
Table: Fungal and parasitic infections
AIDS-defining conditionCD4 count (cells/µL)Clinical presentationManagement (in addition to HIV treatment)
Esophageal candidiasis< 100Odynophagia, oral thrush may be presentFluconazole
Pneumocystis jirovecii pneumonia< 200Fever, dyspnea, non-productive coughTreatment and prophylaxis: TMP-SMX
Cryptococcal meningitis< 100Fever, headache, neck stiffness, AMS, neurologic deficitsAmphotericin B and flucytosine, followed by fluconazole
CNS toxoplasmosis< 100Headache, fever, AMS, focal neurologic deficits, seizures
  • Treatment: pyrimethamine, sulfadiazine, and folinic acid
  • Prophylaxis: TMP-SMX
Coccidioidomycosis (disseminated, extrapulmonary)< 250Fever, night sweats, dyspnea, cough, lymphadenopathy, weight loss
  • Treatment: fluconazole, itraconazole, or amphotericin B
  • Prophylaxis: fluconazole
Histoplasmosis (disseminated, extrapulmonary)< 150Fever, night sweats, fatigue, weight loss, nausea and vomiting, dyspnea, cough, skin lesionsAmphotericin B or itraconazole
Cryptosporidiosis< 100Diarrhea, AIDS cholangiopathyNitazoxanide or paromomycin
Cystoisosporiasis< 50Watery, non-bloody diarrhea, anorexia, abdominal pain, vomitingTMP-SMX
AMS: altered mental status
TMP-SMX: trimethoprim-sulfamethoxazole
CNS: central nervous system
Table: Malignancies
AIDS-defining conditionCD4 count (cells/μl)Clinical presentationManagement (in addition to HIV treatment)
Lymphoma (Burkitt’s, DLBCL)Burkitt’s: < 50; DLBCL: VariableConstitutional symptoms, extranodal mass with rapid growthDepends on the stage and includes chemotherapy, immunotherapy, and radiation therapy
CNS lymphoma< 50Headache, AMS, focal neurological deficits, seizures, constitutional symptomsChemotherapy
Invasive cervical carcinomaVariableWatery, bloody vaginal discharge, pelvic pain
  • Treatment: depends on stage and includes chemotherapy, radiation, and surgery
  • Prevention: HPV vaccination
Kaposi’s sarcoma< 500Malignant vascular lesions of the skin, mucosa, GI, and respiratory tract
  • Optimize antiretroviral therapy
  • Intralesional or systemic chemotherapy
AMS: altered mental status
DLBCL: diffuse large B cell lymphoma
CNS: central nervous system
HPV: human papillomavirus
GI: gastrointestinal
Table: Other conditions
AIDS-defining conditionCD4 count (cells/μl)Clinical presentationManagement (in addition to HIV treatment)
Wasting syndromeVariableWeight loss of ≥ 10%, fatigue, fever, diarrheaNutritional care, treatment of secondary infections
HIV-associated dementia< 200Cognitive dysfunction, behavioral and mood changes, motor symptomsOptimize antiretroviral treatment.
HIV +≤ 200CD4 ≤ 200 is defined as AIDS per CDCART
ART: antiretroviral therapy

Wasting Syndrome

Definition

  • An unintentional weight loss of ≥ 10% in the presence of  ≥ 1 of the following:
    • Chronic diarrhea for ≥ 30 days
    • Chronic weakness
    • Documented fever for ≥ 30 days 
  • Not attributable to a concurrent condition other than HIV infection

Possible etiologies and pathophysiology

  • Inadequate caloric intake
  • GI malabsorption
    • Possibly due to AIDS enteropathy
    • Associated with: 
      • Motility disturbances
      • Mucosal atrophy
  • ↑ Metabolic rate → diversion of energy expenditures to immune function
  • Disruption in hormone function
    • ↓ Testosterone → ↓ muscle mass
    • ↓ Insulin-like growth factor production

Clinical presentation

  • Weight loss characterized by depletion of fat and lean tissue
  • Associated symptoms:
    • Fever (intermittent or constant)
    • Diarrhea (≥ 2 stools/day)
HIV wasting syndrome

A patient with wasting syndrome due to AIDS

Image: “HIV Wasting Syndrome” by Department of Medicine, Ahmadu Bello University Teaching Hospital (ABUTH), Zaria, Nigeria. License: CC BY 3.0

Management

  • Antiretroviral therapy
  • Treatment of secondary infections 
  • Optimize nutrition:
    • Dietary counseling
    • Multivitamin and mineral supplementation 
  • Medical therapy is reserved for those who fail the above measures.
    • Appetite stimulants
    • Growth hormone
    • Androgenic steroids

AIDS Cholangiopathy

Overview

  • Biliary obstruction due to strictures from opportunistic infections 
  • CD4 count < 200 cells/μL (usually < 100 cells/μL)
  • Mean survival after diagnosis is 7–12 months.
  • Common pathogens: 
    • Cryptosporidium parvum (20%–57% of cases)
    • Cytomegalovirus (10%–20% of cases)
    • Herpes simplex virus
    • Microsporidium
    • Giardia
    • Mycobacterium avium complex (MAC)
  • Pathophysiology: 
    • Opportunistic infections of the biliary system → chronic biliary inflammation → scarring, strictures, and stenosis
    • Biliary obstruction → cholestatic liver damage

Clinical presentation

  • Right upper and epigastric abdominal pain
  • Nausea and vomiting
  • Fever
  • Jaundice
  • Diarrhea (due to Cryptosporidium)

Diagnosis

  • Liver function tests
    • Alkaline phosphatase ↑
    • Aspartate transaminase (AST) and alanine aminotransferase (ALT) mild to moderately ↑
    • Bilirubin is usually normal or mildly ↑
  • Abdominal ultrasound
    • Dilated intra- and extrahepatic bile ducts
    • May appear normal
  • Magnetic resonance cholangiopancreatography (MRCP): Assess for biliary strictures and stenosis.
  • Endoscopic retrograde cholangiopancreatography (ERCP)
    • Biopsies and biliary aspiration
      • Determine etiology.
      • Exclude cholangiocarcinoma.
    • Allows for intervention on strictures or stenotic lesions

Management

  • ERCP
    • Sphincterotomy
    • Stenting
  • Ursodeoxycholic acid
    • For intrahepatic ductal disease
    • Limited data
  • Treat underlying infections (e.g., CMV, Cryptosporidium)
  • Antiretroviral therapy

Chronic complications

  • Acute cholangitis
  • Liver failure
  • Cholangiocarcinoma

Ocular Conditions

HIV retinopathy

  • A disease of small blood vessels (microvasculopathy) of the eye
  • 70% in advanced HIV
  • Possible pathophysiology:
    • Interruption of blood flow due to:
      • Immune complex deposition
      • ↑ Plasma viscosity
      • HIV invasion of vascular endothelium
    • Deposition of debris
  • Clinical presentation: Most are asymptomatic.
  • Fundoscopic findings:
    • “Cotton-wool” spots
    • Intraretinal hemorrhages
    • Microaneurysms
    • Telangiectasias
  • No treatment is required.

Herpes simplex keratitis

  • Corneal inflammation caused by herpes simplex virus (HSV) infection
  • Types:
    • Epithelial (dendritic) keratitis
    • Disciform (localized endotheliitis) keratitis
    • Stromal keratitis
  • Clinical presentation:
    • Tearing
    • Foreign body sensation
    • Vision loss
      • Reversible in disciform keratitis
      • Irreversible in stromal keratitis
    • Photophobia
  • Slit-lamp examination:
    • Dendritic corneal lesions are diagnostic.
  • Management:
    • Topical therapy:
      • Acyclovir, ganciclovir, or trifluridine
      • Corticosteroids for stromal keratitis
    • Systemic therapy: acyclovir or valacyclovir
Bilateral herpetic keratitis

Slit lamp examination showing dendritic lesions in herpetic keratitis:
Seen here as irregular geographic patterns of ulceration highlighted in green after the application of yellow-orange fluorescein dye. The dye is taken up by damaged cornea (where the surface has been disrupted) so the area appears green under cobalt blue light.

Image: “Bilateral herpetic keratitis” by Department of Ophthalmology, Myongji Hospital, Kwandong University College of Medicine, 697-24, Hwajung-Dong, Deokyang-Gu, Goyang-Si, Gyeonggi-Do, 112-270, Korea. License: CC BY 2.0

Retinitis

CMV retinitis:

  • CD4 count < 50 cells/μL
  • Pathophysiology:
    • Hematogenous spread of CMV to the eye
    • Causes retinal necrosis and edema → atrophic scar tissue
    • Tears in scar tissue → retinal detachment
  • Clinical presentation:
    • Painless central vision loss
    • Scotomata (blind spots)
    • Floaters
    • Photopsia (flashing lights)
  • Fundoscopic findings:
    • Perivascular yellow-white retinal lesions
    • Associated hemorrhage
  • Management:
    • Antiretroviral therapy
    • Ganciclovir, valganciclovir, or foscarnet

Toxoplasma chorioretinitis:

  • Ocular disease due to Toxoplasma gondii
  • CD4 count < 100 cells/μL
  • Pathophysiology:
    • Focal necrotizing retinitis
    • Granulomatous choroid inflammation
  • Clinical presentation:
    • Blurred vision
    • Floaters
    • Eye pain
  • Fundoscopic findings:
    • Raised, yellow-white cotton lesions
    • Nonvascular distribution
  • Management: 
    • Antiretroviral therapy
    • Pyrimethamine + sulfadiazine + folinic acid (leucovorin)

Varicella zoster retinitis:

  • Also known as progressive outer retinal necrosis
  • CD4 < 100 cells/μL
  • Pathophysiology:
    • Rapidly progressing retinal necrosis
    • Leads to retinal detachment
  • Clinical presentation:
    • Vision loss
    • Rapid progression to blindness
    • Some patients may have eye pain
  • Fundoscopic findings:
    • Patchy, peripheral retinal necrosis
    • No involvement of retinal vasculature
  • Management:
    • Antiretroviral therapy
    • Intravenous and intravitreal antiviral medications (ganciclovir, foscarnet, valganciclovir)

Central Nervous System Conditions

HIV-associated dementia

  • Previously known as: 
    • AIDS dementia complex
    • HIV encephalopathy
    • HIV encephalitis
  • CD4 count < 200 cells/μL
  • Clinical presentation: 
    • Cognitive dysfunction
      • Memory loss
      • Poor attention and concentration
      • Impaired executive functioning
    • Behavioral and mood changes
      • Apathy
      • Decreased motivation
      • Irritability
      • Sleeplessness
      • Restlessness and anxiety
      • Psychosis, paranoia, and hallucinations
    • Motor symptoms
      • Slowed movement and gait
      • Saccadic eye movements
      • Dysdiadochokinesia
      • Hyperreflexia
      • Frontal release signs (grasp, root, glabellar reflexes)
  • Diagnosis: 
    • Neuropsychological testing aids in the diagnosis.
      • ≥ 2 standard deviations below the mean in ≥ 2 cognitive domains on neuropsychological testing
      • Concomitant impairment in activities of daily living
      • Cannot be explained by other conditions
    • Magnetic resonance imaging (MRI) 
      • 1st-choice imaging modality
      • Diffuse, patchy white matter hyperintensity
      • Rule out other causes of encephalopathy.
    • Lumbar puncture with cerebral spinal fluid (CSF) analysis
      • Lymphocytic pleocytosis
      • CSF HIV viral load is generally > plasma viral load
      • Findings are nonspecific.
  • Management:
    • Antiretroviral therapy
    • Safety assessment
    • Psychiatric evaluation
HIV Encephalopathy

Magnetic resonance imaging in a patient with HIV-associated dementia
Axial T2 (a) and FLAIR (fluid-attenuated inversion recovery) (b) images showing bilateral symmetrical hyperintensity in the periventricular white matter

Image: “HIV Encephalopathy” by Division of Developmental Pediatrics, Department of Pediatrics and Child Health, University of Cape Town and Red Cross War Memorial Children’s Hospital, Cape Town, South Africa. License: CC BY 4.0

Central nervous system (CNS) toxoplasmosis

  • Most common CNS infection in patients with AIDS
  • CD4 count < 100 cells/μL
  • Etiology: 
    • Reactivation of prior infection with T. gondii
    • Transmitted through ingestion of oocysts after contact with infected cat feces
  • Clinical presentation: 
    • Headache
    • Fever
    • Altered mental status
      • Dull affect
      • Stupor
      • Coma
    • Focal neurologic deficits
    • Seizures
  • Diagnosis: 
    • Computed tomography (CT) or MRI
      • Single or multiple ring-enhancing lesions
      • MRI is more sensitive.
    • Lumbar puncture with CSF analysis
      • Lymphocytic pleocytosis 
      • ↑ Protein 
      • Polymerase chain reaction (PCR) to identify T. gondii
  • Management:
    • Antiretroviral therapy
    • Pyrimethamine + sulfadiazine + folinic acid (leucovorin)
    • TMP-SMX is an alternative.
    • Prophylaxis
      • TMP-SMX
      • Indicated in patients with a CD4 count < 100 cells/μL
Hemichorea hemiballismus

Toxoplasmosis and AIDS
MRI showing ring enhancing of the capsule-thalamic lesion in a patient with hemichorea-hemiballismus

Image: “Hemichorea-hemiballismus” by Department of Internal medicine, Hassan II University Hospital, Faculty of Medicine and Pharmacy, University Sidi Mohammed Ben Abdellah, Morocco. License: CC BY 2.0

Primary CNS lymphoma

  • Overview:
    • Extra-nodal non-Hodgkin’s lymphoma
    • Associated with Epstein-Barr virus (EBV) infection
    • CD4 count < 50 cells/μL
  • Clinical presentation: 
    • Headache
    • Confusion and lethargy 
    • Focal neurologic deficits (hemiparesis)
    • Seizures
    • Constitutional (“B symptoms”)
      • Fever
      • Night sweats
      • Weight loss
  • Diagnosis: 
    • CT and MRI: usually a single ring-enhancing lesion
    • Lumbar puncture and CSF analysis
      • PCR for EBV DNA
      • Cytology
    • Brain biopsy
  • Management:
    • Chemotherapy (methotrexate)
    • Antiretroviral therapy
Primary central nervous system lymphoma

Magnetic resonance imaging of a patient with primary CNS lymphoma
Image shows a single ring-enhancing mass in the left hemisphere.

Image: “MRI of the brain” by Dow Medical College, Dow University of Health Sciences, Baba-e-Urdu Road, Karachi 74200, Pakistan. License: CC BY 3.0

Progressive multifocal leukoencephalopathy (PML)

  • Overview:
    • Demyelinating disease of the CNS 
    • Caused by reactivation of John Cunningham polyomavirus (JCV)
      • Acquired during childhood
      • Remains latent in organs (kidneys, lymphoid organs, CNS)
    • CD4 count < 200 cells/μL
  • Clinical presentation: 
    • Rapidly progressive symptoms 
    • Hemiparesis (most common)
    • Aphasia and dysarthria
    • Hemianopia
    • Gait ataxia
    • Cognitive impairment
    • Impaired vigilance
    • Headache
    • Seizures (rare)
  • Diagnosis: 
    • CT or MRI
      • Disseminated, non-enhancing white matter lesions 
      • No mass effect
    • Lumbar puncture with CSF analysis: PCR for JCV DNA
    • Brain biopsy
  • Management:
    • Antiretroviral therapy
    • Supportive care
Axial fluid attenuated inversion recovery (FLAIR)

Magnetic reonance imaging in a patient with PML
Axial FLAIR (left) and axial T2-weighted images (right) show extensive diffuse lesions in the subcortical and periventricular white matter.

Image: “Axial fluid attenuated inversion recovery (FLAIR)” by Inonu University, Liver Transplantation Institute, Department of General Surgery, Malatya, Turkey. License: CC BY 3.0

Bacillary Angiomatosis

Overview

  • CD4 count < 100 cells/μL
  • Etiology:
    • Causative organisms:
      • Bartonella henselae (most common)
      • B. quintana
    • Transmission:
      • Fleas and lice
      • Cat scratches
  • Pathophysiology:
    • Bartonella infection → vascular proliferation → angiomatous skin lesions
    • Involvement of other organs:
      • Respiratory tract
      • Bone
      • Lymph nodes
      • GI tract
      • Brain

Clinical presentation

  • Cutaneous lesions 
    • Protuberant, red papules or nodules 
    • Friable (tend to bleed profusely with trauma)
  • Subcutaneous nodules that may ulcerate
  • Painful, osteolytic bone lesions
    • Frequently of the long bones
    • Associated with an overlying cellulitic plaque
  • Smooth, purple, mucosal papules or plaques
Bacillary angiomatosis

Nodular lesions due to bacillary angiomatosis in a patient with AIDS

Image: “Bacillary angiomatosis” by Instituto de Medicina Tropical Alexander von Humboldt, Universidad Peruana Cayetano Heredia, Lima, Peru. License: CC BY 4.0, edited by Lecturio.

Diagnosis

  • Biopsy of affected tissue
    • Vascular proliferation
    • Protuberant, plump endothelial cells
    • Scattered neutrophils and lymphocytes
    • Dark-staining bacteria seen with Warthin-Starry silver staining
  • Blood or tissue cultures
  • PCR
Bartonella quintana coinfection

Histopathology specimen from a patient with bacillary angiomatosis
A dark-staining cluster of B. quintana (indicated by an arrow) is revealed with Warthin-Starry staining of a tissue specimen.

Image: “Warthin-Starry staining” by Service de maladies infectieuses et de médecine tropicale, hôpital Nord, APHM, Marseille, France. License: CC BY 2.0

Management

  • Antibiotic therapy
    • Erythromycin
    • Doxycycline
  • Monitor antibody titers
  • Antiretroviral therapy

Kaposi’s Sarcoma

Overview

  • Aggressive, malignant vascular tumors
  • CD4 count < 500 cells/μL
  • Etiology:
    • Human herpesvirus type 8 (HHV-8)
    • Commonly transmitted via saliva and sexual contact

Clinical presentation

  • Cutaneous lesions 
    • Common sites:
      • Lower extremities
      • Face
      • Oral mucosa
      • Genitalia
    • Appearance:
      • Elliptical
      • Assorted colors (pink, red, purple, brown)
      • Papular or plaque-like 
      • Not painful or pruritic
      • Yellow-green peri-lesional “halo”
      • Associated lymphedema
  • Intraoral lesions 
    • Common sites:
      • Hard palate
      • Gingiva
    • Trauma can lead to bleeding, ulceration, or secondary infection.
  • GI tract lesions 
    • Hemorrhagic or submucosal nodules
    • Can occur anywhere along the GI tract
    • Symptoms: 
      • Asymptomatic (most common)
      • Weight loss and malabsorption
      • Abdominal pain
      • Nausea and vomiting 
      • Intestinal obstruction
      • GI bleeding
  • Pulmonary manifestations
    • Cherry-red, elevated lesions
    • Nodular, interstitial, or alveolar infiltrates
    • Pleural effusion
    • Symptoms:
      • Dyspnea
      • Fever
      • Cough and hemoptysis
      • Chest pain

Diagnosis

Biopsy confirms the diagnosis.

  • Samples may be obtained from:
    • Skin lesions
    • Endoscopy (GI symptoms)
    • Bronchoscopy (pulmonary involvement)
  • Findings:
    • Angiogenesis with aberrant proliferation of small vessels
      • Vessels lack a basement membrane.
      • Microhemorrhages
      • Hemosiderin deposition
    • Whorls of spindle-shaped cells
    • Leukocyte infiltration

Management

  • Antiretroviral therapy can lead to a marked response.
  • Local therapies to induce regression of tumors
    • Intralesional chemotherapy (vinblastine)
    • Radiation therapy
    • Topical alitretinoin
  • Systemic chemotherapy for advanced or rapidly progressing disease

Mycobacterium avium Complex Infection

Overview

  • CD4 count < 50 cells/μL
  • Causative organisms:
    • M. avium
    • M. intracellulare
  • Transmission: 
    • Inhalation
    • Ingestion of contaminated food or water
  • Bacteria disseminate through the lymphatic system.

Clinical presentation

  • Disseminated disease
    • High fever
    • Weight loss
    • Night sweats
    • Abdominal pain
    • Diarrhea
  • Focal lymphadenitis
    • Commonly results from immune reconstitution inflammatory syndrome
      • Occurs after initiation of antiretroviral therapy
      • Paradoxical worsening of preexisting infectious conditions
    • Fever
    • Lymphadenopathy
  • Other localized manifestations
    • Mastitis
    • Subcutaneous nodules
    • Osteomyelitis
    • Granulomatous hepatitis
    • Paravertebral abscess
    • Brain abscess
    • Lung infiltrates
    • Intestinal involvement

Diagnosis

  • Blood cultures
  • Tissue aspirate (lymph node)
  • Associated laboratory abnormalities:
    • Anemia
    • Thrombocytopenia 
    • ↑ Alkaline phosphatase
    • ↑ Lactate dehydrogenase

Management

  • Macrolide plus ethambutol 
  • Rifabutin may be added for:
    • Patients failing antiretroviral therapy
    • Patients with a high bacterial burden
  • Antiretroviral therapy

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