Comprehensive Study Notes: TB, Candidiasis, CMV, EBV
Tuberculosis - Overview
Causative agent: Mycobacterium tuberculosis. Tuberculosis (TB) is transmitted primarily through airborne spread.
Global burden: TB is the leading cause of death among people with HIV.
2023 statistics: approximately 1.25 \times 10^6 deaths worldwide and 10.8 \times 10^6 diagnoses. In the United States, incidence has risen to above pre-pandemic levels.
Risk factors
Immunocompromised status
Immigration from high-risk countries
Immunosuppressive medication use
Healthcare worker
Unhoused
Illicit substance abuse
Prior history of TB
Disease progression
Primary infection: clinical illness directly after initial infection; most immunocompetent individuals mount an immune response to prevent progression to clinical illness by forming granulomas.
Secondary infection
Latent infection: equilibrium between host immune response and bacteria
Reactivation: latent infection activates to cause clinical illness
Primary infection (pulmonary TB)
Occurs soon after initial infection; majority asymptomatic
Symptoms (if present):
Atypical pneumonia features: fever, nonproductive cough
Chest imaging: unilateral lower-lobe patchy infiltrates or paratracheal/hilar lymphadenopathy
Tuberculous pleurisy with effusion: fever, cough, pleuritic chest pain, dyspnea; CXR shows unilateral pleural effusion
Latent TB
Asymptomatic
Approximately 5\text{--}15\% of patients progress to reactivation
Reactivation TB
Most common clinical form of TB
Symptoms develop over weeks to months: anorexia, weight loss, night sweats, low-grade fever, productive cough, hemoptysis, shortness of breath, pleuritic chest pain
Extrapulmonary TB
Accounts for about 20\% of newly recognized TB cases
More common in people with HIV or patients treated with TNF-alpha inhibitors
Common sites include meningitis, miliary TB, pericardial TB, cutaneous TB
Physical examination findings
Nonspecific: pallor, clubbing, wasting, dullness to percussion, crackles, decreased breath sounds
Diagnosis
Nucleic acid amplification testing (NAAT)
Xpert MTB/RIF: sputum sample; rapid TB diagnosis; detects rifampin resistance
Acid-fast bacilli smear microscopy
Ziehl-Neelsen stain: rapid TB diagnosis; cannot differentiate TB from nontuberculous mycobacteria
Mycobacterial culture
Gold standard; can assess drug susceptibility; may take up to 8 \text{ weeks} for results
Chest X-ray (CXR)
Helps differentiate primary infection from latent infection and reactivation
Primary infection: consolidation, hilar lymphadenopathy, Ghon focus (a small granulomatous lesion), Ghon complex (Ghon focus + regional lymph node involvement), Ranke complex (calcified Ghon complex)
Reactivation: upper lobe cavitary lesion, calcifications
Interferon-Gamma Release Assay (IGRA)
Serum blood test
Positive = TB infection likely; Negative = infection unlikely
Indeterminate results can occur with infection, inflammation, or immunosuppression
Tuberculin Skin Testing (TST)
0.1 \text{ mL} purified protein derivative (PPD) injected intradermally
Reading required at 48–72 hours
Consider BCG vaccination history when interpreting results
TST interpretation and cutoff points
Interpretation depends on induration size (mm) and risk factors
General cut points:
Induration ≥ 5 \text{ mm}: positive in
People living with HIV
Recent contacts of people with infectious TB
People with fibrotic changes on CXR suggestive of prior TB
Transplant recipients
Other immunosuppressed patients (e.g., prolonged corticosteroids ≥15 \text{ mg/day} prednisone or TNF-α antagonists)
Induration ≥ 10 \text{ mm}: positive in
People born in countries with high TB prevalence (e.g., Mexico, Philippines, Vietnam, India, China, Haiti, Guatemala)
People who misuse drugs or alcohol
People who live or work in high-risk congregate settings (nursing homes, homeless shelters, correctional facilities)
Mycobacteriology laboratory workers
People with certain medical conditions (e.g., silicosis, diabetes, severe kidney disease, some cancers, certain intestinal conditions)
Children
Candidiasis - Overview
Most common form is candidiasis due to Candida albicans
Found on the skin, oropharyngeal cavity, GI tract, GU tract, and vagina (oropharyngeal candidiasis = thrush)
Risk factors
Antibiotic or corticosteroid use (especially inhaled)
Immunosuppression (e.g., HIV/AIDS, chemotherapy, organ transplant)
Diabetes mellitus (poor glycemic control)
Denture wearers (poor hygiene)
Xerostomia (dry mouth)
Infancy and old age
Signs and symptoms
Dry mouth
Dysgeusia (distorted taste)
Pain with eating
Fissures at the corners of the mouth
White patches on the mouth, tongue, and/or esophagus that are adherent, painless, and may be discrete or confluent
Patches scraped away reveal red, inflamed, and/or bleeding areas
Diagnosis
Clinically (often)
KOH preparation: budding yeasts/hyphae/pseudohyphae
Esophagogastroduodenoscopy (EGD): direct visualization of white mucosal plaque-like lesions
Look for underlying causes (HIV testing; HbA1c)
Treatment
Oropharyngeal candidiasis treatments:
Nystatin oral solution 100,000 \text{ U/mL}, 4\text{--}6 \text{ mL} PO every 6 hours for 7–14 days
Clotrimazole troches 10 \text{ mg} PO, 5 times daily for 7–14 days
Miconazole mucoadhesive buccal tablet, applied over canine fossa mucosa, PO once daily for 7–14 days
Systemic therapy: Oral fluconazole 100\text{--}200 \text{ mg} PO daily for 7–14 days
Cytomegalovirus (CMV) - Overview
Human herpesvirus 5 (CMV)
The majority of individuals have been infected by adulthood; transmission occurs through prolonged exposure to bodily fluids; possible routes include sexual, transplacental, perinatal, and blood transfusion.
Lifelong infection; establishes latency in myeloid cells, and reactivation occurs with immunosuppression
Congenital CMV is considered a TORCH infection.
Signs and symptoms
Immunocompetent:
Most are asymptomatic or present with mononucleosis-like syndrome (fever, chills, fatigue, malaise); incubation 20–60 days; duration 2–6 weeks; heterophile antibody negative
Immunocompromised:
Often asymptomatic but can present with viral syndrome (malaise, fever, leukopenia, thrombocytopenia)
Pneumonia (usually after bone marrow transplant or AIDS): fever, nonproductive cough, dyspnea
CMV retinitis (can lead to vision loss if untreated)
Diagnosis
CBC with differential: lymphocytosis with >10\% atypical lymphocytes
Monospot testing: negative
Serology: CMV IgM antibodies (indicates acute infection); CMV IgG antibodies (fourfold rise indicates active infection; CMV IgG antibodies alone indicate past infection)
Direct viral detection: CMV DNA (viral load), used especially in immunocompromised patients to monitor infection and treatment response
Chest X-ray: diffuse pulmonary infiltrates (if pneumonia)
Fundoscopy: retinal hemorrhages and cotton-wool spots, characteristic of CMV retinitis
Treatment
Immunocompetent: supportive care
Immunocompromised: antivirals
Ganciclovir IV or valganciclovir PO (duration typically 14–21 days)
Alternatives: Foscarnet, cidofovir
Epstein-Barr Virus (EBV) - Overview
Human herpesvirus 4
Infectious mononucleosis (mono)
Most common in early childhood; second peak in late adolescence/early adulthood
By adulthood, >90\% of people have been infected with EBV
Transmission and incubation
Highly contagious
Transmitted through saliva (most common, hence "kissing disease"), blood, bone marrow
Incubation period: 4\text{--}6 \text{ weeks}
Signs and symptoms
Infants and young children: often asymptomatic or mild pharyngitis/tonsillitis
Adolescents/young adults: prodromal phase with fatigue, malaise, myalgia; illness phase with fever, pharyngitis, palatal petechiae, lymphadenopathy (especially posterior cervical), rash, hepatosplenomegaly
Elderly: prolonged fever, fatigue, malaise, myalgia (symptoms can be more severe or atypical in older individuals)
Diagnosis
CBC with differential: leukocytosis, often with atypical lymphocytes
CMP: elevated liver enzymes, particularly transaminases
Heterophile test (Monospot): high specificity (\approx 100\%), \sim 80\text{--}90\% accuracy in the third week of illness; false positives possible earlier, false negatives in young children
Serology: viral capsid antigen (VCA) antibodies
Anti-VCA IgM: indicates acute infection
Anti-VCA IgG: indicates past infection
Other findings: rash can occur with Ampicillin/Amoxicillin use in patients with acute EBV infection, not directly caused by EBV itself but an interaction.
Treatment
Supportive care (rest, hydration, pain relief)
Avoidance of contact sports during acute illness due to risk of splenic rupture (especially if splenomegaly is present)
Glucocorticoids (in select scenarios, e.g., impending airway
Tuberculosis - Overview - Presentation:
- Primary infection: Often asymptomatic. If symptomatic: atypical pneumonia features (fever, nonproductive cough), unilateral lower-lobe patchy infiltrates, or paratracheal/hilar lymphadenopathy. Tuberculous pleurisy: fever, cough, pleuritic chest pain, dyspnea; CXR shows unilateral pleural effusion.
- Latent infection: Asymptomatic.
- Reactivation (most common): Symptoms develop over weeks to months: anorexia, weight loss, night sweats, low-grade fever, productive cough, hemoptysis, shortness of breath, pleuritic chest pain.
- Extrapulmonary: Accounts for about 20\% of cases; more common in HIV/TNF-alpha inhibitor patients. Can affect meninges, miliary (disseminated), pericardium, skin.
- Diagnosis (Orders): Nucleic acid amplification testing (NAAT) like Xpert MTB/RIF, Acid-fast bacilli smear microscopy (Ziehl-Neelsen stain), Mycobacterial culture (gold standard), Chest X-ray (CXR), Interferon-Gamma Release Assay (IGRA), Tuberculin Skin Testing (TST).
- Expected Results:
- NAAT/AFB smear: Rapid diagnosis of Mycobacterium tuberculosis. AFB smear cannot differentiate TB from nontuberculous mycobacteria.
- Mycobacterial culture: Confirms diagnosis, allows drug susceptibility testing; may take up to 8 \text{ weeks}.
- CXR: Helps differentiate stages: Primary (consolidation, hilar lymphadenopathy, Ghon focus/complex, Ranke complex); Reactivation (upper lobe cavitary lesion, calcifications).
- IGRA/TST: Indicate TB infection (latent or active); positive = TB infection likely. Interpretation of TST depends on induration size (e.g., ≥5 \text{ mm} for high-risk, ≥10 \text{ mm} for moderate risk) and patient risk factors.
- Nuances:
- Transmitted airborne. Progression from primary to latent to reactivation is common.
- IGRA/TST detect infection, not necessarily active disease; culture/NAAT confirm active disease.
- Leading cause of death among people with HIV, often presenting with extrapulmonary forms.
Candidiasis - Overview
- Presentation:
- Oropharyngeal candidiasis (thrush): Dry mouth, dysgeusia (distorted taste), pain with eating, fissures at the corners of the mouth. Characteristic white, adherent, painless patches on mouth, tongue, and/or esophagus. Patches scrape away to reveal red, inflamed, and/or bleeding areas.
- Diagnosis (Orders): Clinical diagnosis (often), KOH preparation of scraped lesions, Esophagogastroduodenoscopy (EGD) for esophageal involvement. Investigation for underlying causes (HIV testing, HbA1c).
- Expected Results:
- KOH preparation: Budding yeasts/hyphae/pseudohyphae.
- EGD: Direct visualization of white mucosal plaque-like lesions in the esophagus.
- Nuances:
- Most commonly caused by Candida albicans, a normal commensal organism.
- Key risk factors: antibiotic/corticosteroid use, immunosuppression (HIV/AIDS, chemotherapy), diabetes mellitus (poor glycemic control), denture wearers.
- The adherent white patches that scrape away are pathognomonic.
Cytomegalovirus (CMV) - Overview
- Presentation:
- Immunocompetent: Most are asymptomatic or present with a mononucleosis-like syndrome (fever, chills, fatigue, malaise); incubation 20\text{--}60 \text{ days}, duration 2\text{--}6 \text{ weeks}. Heterophile antibody negative.
- Immunocompromised: Can present with viral syndrome (malaise, fever, leukopenia, thrombocytopenia), pneumonia (fever, nonproductive cough, dyspnea, often after bone marrow transplant or in AIDS), or CMV retinitis (can lead to vision loss).
- Diagnosis (Orders): CBC with differential, Monospot testing, Serology (CMV IgM, IgG), Direct viral detection (CMV DNA/viral load), Chest X-ray (if pneumonia), Fundoscopy (if retinitis).
- Expected Results:
- CBC: Lymphocytosis with >10\% atypical lymphocytes.
- Monospot testing: Negative (key differentiator from EBV).
- Serology: IgM indicates acute infection; a fourfold rise in IgG indicates active infection; IgG alone indicates past infection.
- CMV DNA (viral load): Used especially in immunocompromised to monitor infection and treatment response.
- CXR: Diffuse pulmonary infiltrates (if pneumonia).
- Fundoscopy: Retinal hemorrhages and cotton-wool spots, characteristic of CMV retinitis.
- Nuances:
- Human herpesvirus 5; establishes lifelong latency, reactivating with immunosuppression.
- Causes mononucleosis syndrome that is Monospot negative, distinguishing it from EBV.
- Congenital CMV is a TORCH infection.
- Retinitis is a critical opportunistic infection in immunocompromised patients.
Epstein-Barr Virus (EBV) - Overview
- Presentation:
- Primarily causes infectious mononucleosis (mono).
- Infants/young children: Often asymptomatic or mild pharyngitis/tonsillitis.
- Adolescents/young adults: Prodromal phase (fatigue, malaise, myalgia) followed by illness phase with fever, pharyngitis, palatal petechiae, prominent lymphadenopathy (especially posterior cervical), rash, hepatosplenomegaly.
- Elderly: May have prolonged fever, fatigue, malaise, myalgia; symptoms can be more severe or atypical.
- Diagnosis (Orders): CBC with differential, CMP, Heterophile test (Monospot), Serology (viral capsid antigen [VCA] antibodies).
- Expected Results:
- CBC: Leukocytosis, often with atypical lymphocytes.
- CMP: Elevated liver enzymes (transaminases).
- Heterophile test (Monospot): High specificity for mono (\approx 100\%), \sim 80\text{--}90\% accuracy in the third week of illness; can be false negative in young children.
- Serology (VCA antibodies): Anti-VCA IgM (indicates acute infection); Anti-VCA IgG (indicates past infection).
- Nuances:
- Human herpesvirus 4; commonly transmitted through saliva ("kissing disease").
- Causes mononucleosis syndrome that is Monospot positive (distinguishing from CMV).
- Risk of splenic rupture is critical in acute illness, requiring avoidance of contact sports if splenomegaly is present.
- Rash can occur if Ampicillin/Amoxicillin is used, and it's an interaction, not a direct EBV symptom.