Opportunistic Infections in HIV

Introduction and Epidemiology

• Opportunistic infections (OIs) are infections that occur more frequently and are more severe in individuals with weakened immune systems, such as children living with HIV, compared to those with healthy immune systems.
• In the absence of combination antiretroviral therapy (cART), OIs are the primary cause of morbidity and mortality in HIV-infected children.
• The risk of developing specific OIs correlates with the degree of immunosuppression, typically measured by CD4+ T-lymphocyte counts or percentages.
• Infants (<1 year) are at higher risk of developing AIDS-defining OIs and have higher mortality rates even at higher CD4 counts compared to older children and adults, necessitating age-specific monitoring and prophylaxis.
• With the widespread use of cART, the incidence of OIs has declined significantly (e.g., cytomegalovirus retinitis, Mycobacterium avium complex), but they remain a threat in undiagnosed children or those with poor adherence,,.

Pneumocystis jirovecii Pneumonia (PCP/PJP)

• Epidemiology:

  • Pneumocystis jirovecii is a ubiquitous fungus that causes pneumonia almost exclusively in immunocompromised hosts,.
  • It is the most common serious opportunistic infection in HIV-infected children, particularly in the first year of life,.
  • The peak incidence occurs between 3 and 6 months of age, often in infants whose HIV status is yet unknown,,.
  • Without prophylaxis, high mortality rates (median survival of 1 month in untreated infants <1 year) are observed.

• Clinical Manifestations:

  • Infantile/HIV Pattern: Onset is often insidious or subtle with tachypnea, progressing to feeding difficulties, fever (may be low grade or absent), and marked hypoxemia,,.
  • Symptoms: Cough (often nonproductive), dyspnea, and significant respiratory distress with intercostal/subcostal retractions and nasal flaring,.
  • Physical Exam: Auscultation is often disproportionately normal relative to the degree of respiratory distress and hypoxia, though rales may be absent or minimal,.
  • Hypoxia: Hypoxemia is invariable and often severe, with an elevated alveolar-arterial oxygen gradient,.

• Diagnosis:

  • Radiology: Chest X-ray typically shows diffuse, bilateral, symmetric interstitial or alveolar infiltrates extending from the perihilar region to the periphery ("ground-glass" appearance),,. Normal chest X-rays can occur early in the disease.
  • Laboratory: Serum lactate dehydrogenase (LDH) levels are often elevated but are non-specific,.
  • Organism Detection: Definitive diagnosis requires demonstration of the organism.
    • Bronchoalveolar Lavage (BAL): Sensitivity of 75–95%; preferred diagnostic method,.
    • Induced Sputum: Less sensitive (20–40%) than in adults; a negative result does not rule out PCP,.
    • Staining: Methenamine silver, Giemsa, or immunofluorescent monoclonal antibody stains are used.
    • PCR: Highly sensitive but may not distinguish colonization from active disease,.

• Treatment:

  • First-line: Intravenous Trimethoprim-Sulfamethoxazole (TMP-SMX).
    • Dose: 15–20 mg/kg/day (TMP component) divided every 6 hours,,.
    • Duration: 21 days,.
  • Adjunctive Therapy: Corticosteroids (Prednisone or Methylprednisolone) are recommended for moderate to severe disease (PaO2 <70 mm Hg or A-a gradient >35 mm Hg) to prevent deterioration due to inflammatory response,,.
    • Regimen: 2 mg/kg/day for 7–10 days, followed by tapering.
  • Alternatives: IV Pentamidine (4 mg/kg/day) for patients intolerant to TMP-SMX or failing therapy after 5–7 days,. Other options include Atovaquone, Clindamycin + Primaquine, or TMP + Dapsone (for mild-moderate disease),,.

• Prophylaxis:

  • Mandatory: All HIV-exposed infants starting at 4–6 weeks of age until HIV infection is excluded,.
  • HIV-Infected Infants (<1 year): Universal prophylaxis regardless of CD4 count,.
  • Children 1–5 years: Prophylaxis if CD4 <500 cells/µL or <15%,.
  • Children ≥6 years: Prophylaxis if CD4 <200 cells/µL or <15%,.
  • Regimen: TMP-SMX (150 mg/m²/day TMP) given daily or 3 days/week,,.

Tuberculosis (TB)

• Interaction with HIV:

  • HIV and Mycobacterium tuberculosis act synergistically; HIV accelerates TB progression, and TB increases HIV viral replication,.
  • TB is a leading cause of death in HIV-infected children.
  • The risk of active TB is 5-10 times higher in HIV-infected children compared to uninfected children.

• Clinical Manifestations:

  • Pulmonary TB:
    • Similar to HIV-uninfected children but more likely to be severe or progressive.
    • Common symptoms: Prolonged fever, unremitting cough (>2 weeks), weight loss/failure to thrive, night sweats,.
    • Radiographic patterns include lobar consolidation, cavitation (more common in HIV), and intrathoracic lymphadenopathy,.
    • Can mimic Lymphoid Interstitial Pneumonitis (LIP) or bacterial pneumonia.
  • Extrapulmonary TB: Significantly more frequent in HIV-infected children,. Sites include lymph nodes (scrofula), CNS (meningitis, tuberculoma), pleura, and disseminated (miliary) disease,.

• Diagnosis:

  • Challenges: Tuberculin Skin Test (TST) may be negative (anergy) due to immune suppression; Interferon-gamma release assays (IGRA) also have reduced sensitivity,.
  • Criteria: Diagnosis is often based on the "Golden Triad": Clinical features + Abnormal CXR + Positive TST/IGRA/History of contact.
  • Microbiology: Gastric aspirate (GA) or induced sputum for Acid-Fast Bacilli (AFB) smear and culture/NAAT (GeneXpert) is the gold standard but paucibacillary nature makes confirmation difficult,.
  • Algorithm: In HIV-infected children, any persistent cough or fever should trigger evaluation for TB.

• Treatment:

  • Regimen: Standard 4-drug therapy (Isoniazid, Rifampicin, Pyrazinamide, Ethambutol) for 2 months, followed by 4 months of Isoniazid + Rifampicin,.
  • Daily Dosing: Essential for HIV-infected children; intermittent regimens are not recommended.
  • Drug Interactions: Rifampicin induces CYP450, lowering levels of Nevirapine (NVP) and Protease Inhibitors (PIs).
    • If on NVP: Increase NVP dose by ~30% or switch to Efavirenz,.
    • If on PI (Lopinavir/ritonavir): Avoid Rifampicin if possible (use Rifabutin) or super-boost Ritonavir,.
  • ART Initiation: Start ART within 2–8 weeks of starting TB treatment to reduce mortality, monitoring for IRIS.

• Prophylaxis (TPT):

  • Isoniazid Preventive Therapy (IPT) is recommended for all HIV-infected children >12 months without active TB,.
  • Duration: 6 months of Isoniazid (6H) or 3 months of Isoniazid + Rifapentine (3HP).

Mycobacterium avium Complex (MAC)

• Epidemiology:

  • Occurs in children with severe immunosuppression (CD4 <50–75 cells/µL),.
  • Incidence has dropped significantly with cART.
  • Acquired via inhalation or ingestion; colonization of GI/respiratory tract precedes dissemination.

• Clinical Manifestations:

  • Disseminated Disease: Fever, night sweats, weight loss, failure to thrive, severe anemia, neutropenia, and chronic diarrhea,.
  • Organ Involvement: Generalized lymphadenopathy, hepatosplenomegaly, and abdominal pain (mesenteric adenitis),.

• Diagnosis:

  • Isolation of MAC from sterile sites (blood, bone marrow, lymph node),.
  • Stool/respiratory cultures alone represent colonization, not necessarily disease,.

• Treatment:

  • Combination therapy to prevent resistance.
  • Regimen: Clarithromycin or Azithromycin + Ethambutol,.
  • Add-on: Rifabutin, Ciprofloxacin, or Amikacin may be added for severe disease.
  • Lifelong therapy (secondary prophylaxis) unless immune reconstitution occurs.

• Prophylaxis:

  • Indicated for severe immunosuppression (e.g., CD4 <75 cells/µL for ages 2–6; <50 for >6 years).
  • Drug: Azithromycin (weekly) or Clarithromycin (daily),.

Fungal Infections

1. Candidiasis

• Oropharyngeal (Thrush):
  • Most common fungal infection.
  • Features: White, curd-like plaques on erythematous mucosa; may cause pain and poor feeding.
  • Significance: Persistent thrush in an infant >6 months or failure to respond to topical therapy suggests HIV progression,.
  • Treatment: Topical Nystatin or Clotrimazole; Oral Fluconazole for refractory cases,.
• Esophageal Candidiasis:
  • AIDS-defining condition.
  • Features: Dysphagia, odynophagia, retrosternal pain, weight loss,.
  • Treatment: Systemic Fluconazole or Itraconazole for 14–21 days,.

2. Cryptococcosis

• Epidemiology: Rare in young children; occurs in adolescents with severe immune depletion.
• Clinical: Meningitis is the most common presentation (fever, headache, elevated intracranial pressure),. Can also cause pneumonia or disseminated disease.
• Diagnosis: CSF India ink stain, Cryptococcal Antigen (CrAg) in CSF/serum (highly sensitive), Culture.
• Treatment: Induction with Amphotericin B + Flucytosine followed by Fluconazole consolidation and maintenance.

3. Endemic Mycoses

• Histoplasmosis/Coccidioidomycosis:
  • Occur in endemic areas.
  • Disseminated disease in HIV causes fever, hepatosplenomegaly, pancytopenia, and skin lesions,.
  • Treatment: Amphotericin B for severe disease; Itraconazole for mild/maintenance.

Viral Infections

1. Cytomegalovirus (CMV)

• Epidemiology: Disseminated disease occurs with severe immunosuppression (CD4 <50 cells/µL).
• Manifestations:
  • Retinitis: Most common severe manifestation (though less common in children than adults), causing "pizza pie" retinopathy (hemorrhage and necrosis) and blindness,.
  • GI Disease: Esophagitis, colitis (bloody diarrhea, pain),.
  • CNS: Encephalitis, polyradiculopathy.
• Treatment: IV Ganciclovir or Foscarnet. Valganciclovir for maintenance,.

2. Herpes Simplex Virus (HSV)

• Manifestations:
  • Chronic, ulcerative mucocutaneous lesions persisting >1 month (AIDS-defining).
  • Recurrent severe gingivostomatitis.
  • Disseminated infection (visceral organs).
• Treatment: Acyclovir (IV for severe/disseminated; oral for mild/maintenance). Foscarnet for Acyclovir-resistant strains,.

3. Varicella Zoster Virus (VZV)

• Primary Infection (Chickenpox): Can be severe, prolonged, and complicated by bacterial superinfection, pneumonia, or hepatitis in HIV-infected children.
• Herpes Zoster (Shingles): Reactivation is common; can be multidermatomal, recurrent, or disseminated,.
• Prevention: Varicella vaccine is recommended for HIV-infected children if CD4 ≥15% (not severely immunocompromised).

4. Lymphoid Interstitial Pneumonitis (LIP)

• Etiology: Associated with Epstein-Barr Virus (EBV) and HIV infection of lung lymphoid tissue,.
• Clinical: Chronic, slowly progressive lung disease. Insidious onset of cough, tachypnea, and mild hypoxemia,.
• Diagnosis: Bilateral reticulonodular infiltrates on CXR; often associated with generalized lymphadenopathy and parotitis,.
• Prognosis: Good prognosis; indicates a slower progression of HIV compared to PJP.
• Treatment: Steroids if significant hypoxemia exists,.

5. Progressive Multifocal Leukoencephalopathy (PML)

• Etiology: Reactivation of JC Virus in oligodendrocytes.
• Clinical: Progressive focal neurologic deficits (hemiparesis, ataxia, visual field loss), cognitive decline, seizures,.
• Diagnosis: MRI (white matter lesions without mass effect), JC Virus DNA in CSF.
• Prognosis: Poor survival; treatment relies on immune reconstitution via ART.

Gastrointestinal/Parasitic Infections

• Cryptosporidiosis:
  • Protozoan Cryptosporidium causes self-limited diarrhea in healthy hosts but severe, chronic, watery diarrhea (cholera-like) in HIV-infected children with low CD4,.
  • Can cause biliary tract disease (sclerosing cholangitis).
  • Treatment: Nitazoxanide (partial efficacy); Immune reconstitution with ART is key.
• Isosporiasis: Causes chronic diarrhea; treatable with TMP-SMX.
• Toxoplasmosis (CNS):
  • Reactivation of Toxoplasma gondii.
  • Clinical: Encephalitis with focal signs, seizures, headache,.
  • Imaging: Ring-enhancing lesions on CT/MRI.
  • Treatment: Pyrimethamine + Sulfadiazine + Leucovorin.
  • Prophylaxis: TMP-SMX (covers both PJP and Toxoplasmosis).

Recurrent Serious Bacterial Infections

• Considered an AIDS-defining condition in children.
• Types: Bacteremia, pneumonia, meningitis, osteomyelitis, deep abscesses.
• Pathogens: Encapsulated bacteria (S. pneumoniae, H. influenzae, Salmonella) due to B-cell dysfunction. Pseudomonas and Staphylococcus in advanced disease,.
• Management: Prompt antibiotic therapy and IVIG for children with hypogammaglobulinemia,.

Immune Reconstitution Inflammatory Syndrome (IRIS)

• Definition: Paradoxical worsening of pre-existing infectious symptoms or unmasking of subclinical infections following the initiation of ART, driven by the recovery of the immune system.
• Common Pathogens: TB (most common), MAC, CMV, Cryptococcus, PJP,.
• Clinical: Fever, enlarging lymph nodes, worsening pulmonary infiltrates shortly after starting ART (usually first few weeks/months).
• Management:
  • Continue ART in most cases.
  • Treat the underlying OI.
  • Anti-inflammatory agents (NSAIDs) or Corticosteroids for severe inflammation (e.g., airway compression, CNS involvement),.

Prevention and Prophylaxis

• Chemoprophylaxis:
  • PJP: TMP-SMX for all infants <1 year and older children with low CD4.
  • MAC: Azithromycin/Clarithromycin for severe CD4 depletion.
  • TB: Isoniazid for contacts or latent TB.
  • Toxoplasmosis: TMP-SMX for IgG positive patients with severe immunosuppression.
• Immunization:
  • Follow standard schedule with exceptions for live vaccines.
  • Contraindicated: BCG, OPV, and Yellow Fever in symptomatic/immunocompromised children,.
  • Allowed: MMR and Varicella only if CD4 >15% (no severe suppression),.
  • Recommended: Pneumococcal (PCV + PPSV23), Meningococcal, Influenza (inactivated),.