infectious Disease

HIV/AIDS

Disease Course

HIV Testing

Treatment

HIV

Epidemiology

2018 – ~1.2 million persons in the United States living with HIV
- 37,968 new infections
~ 80% of new HIV transmissions were from persons who did not yet know they had HIV or were not receiving regular care

Pathology

HIV virus: lentivirus retrovirus (able to integrate its DNA to the host genome)
Viral Composition
- Composed of 2 copies of single-stranded RNA surrounded by structural proteins (p55, p24, p17)
- Reverse transcriptase polymeraseconverts viral RNA into DNA (a characteristic of retroviruses)
- Protease includes integrase (p32 and p10)
- p24 (core protein): levels can be used to monitor HIV disease
- p17 is the matrix protein
- Lipid envelope (gp41, gp120, and gp160)
  - gp120 is the outer envelope glycoprotein, which binds to cell surface CD4 molecules
  - gp41, a transmembrane protein, influences infectivity and cell fusion capacity
HIV-1: more prevalent, more virulent
HIV-2: differs in the molecular weight of the individual gene products, less virulentwith limited geographical distribution
Transmission
- Acquired via secretions and attaches to dendritic cells via DC-sign and Siglec-1receptors and transported to lymph nodes.
- There they will infect T-lymphocytes viaCD4 receptor and other co-receptors (CXCR4, CCR5) depending on the viral type.
- Once infected HIV replicates, proliferates and spreads to all parts of the body in amatter of days leading to eventual reduction in the level of CD4 T cells and immunedeficiency.

Also known as “acute retroviral syndrome” or “acute seroconversion”

Pathology
- Host immune response (Anti-HIV AB and Cytotoxic T-cells) resulting in a partial control of infection and transient reduction in peripheral CD4+ T lymphocyte counts which will rebound but not return to normal
Timing
- 2-6 weeks after exposure (up to 10): lethargy fatigue can last months
Symptoms
- Fever, headache, myalgia, and swollen lymph nodes;
- Pharyngitis (non-exudative)
- Gastrointestinal: nausea, anorexia, and diarrhea
- Skin lesions: pink-to-red macules or maculopapules on face, neck, and upper torso
  - Distinctive genital or mucocutaneous ulcers
- Absence of any respiratory symptoms
- Rare: aseptic meningitis, Guillain–Barré syndrome and 7th Cranial nerve palsy
Lab work
- Detectable by plasma HIV RNA levels (which are at their peak)
- WBC count normal or low with atypical lymphocytes; LFTs moderately elevated
- CSF: lymphocytes, normal glucose, and mildly elevated protein

Pathology
- HIV replication slowly continues as CD4 count declines
Symptoms
- Asymptomatic generally
Timing
- > 60% remain in latency for ~10 years
- 5% of patients will show no CD4 drop for > 10 years

Pathology
- Develops with ↑ viral load & ↓ CD4 count
Symptoms
- Constitutional symptoms
- Fever (persisting for >1 month), weight loss, diarrhea
- Persistent generalized lymphadenopathy (PGL)
  - Lymphadenopathy (>1 cm) @ ≥ 2 extra-inguinal sites for > 3 months in the absence of a cause
  - May be associated with splenomegaly
- Secondary Infections
- End Organ Dysfunction
- Secondary Neoplasm

Pathology
- Continued decline in CD4+ T-lymphocytes resulting in an immunodeficiency
- Defined by CD4+ < 200 cells/mm3 or AIDS-defining condition develops regardless of CD4 count
- Europe uses presence of AIDS defining illness only
Timing
- Can appear as early as 1-2 years after incubation (5-10% = rapid progressors)
- Incubation of >10 years is common

Candidiasis of bronchi, trachea or lungs
Cervical carcinoma (invasive)
Coccidioidomycosis, disseminated or extrapulmonary
Cryptococcosis, extrapulmonary
Cryptosporidiosis, chronic intestinal (1-month duration)
Cytomegalovirus (CMV) disease (other than liver, spleen or nodes)
- CMV retinitis (with loss of vision)
Encephalopathy, HIV-related
Herpes simplex, chronic ulcers (1-month duration), or bronchitis,pneumonitis or esophagitis
Histoplasmosis, disseminated or extrapulmonary
Isosporiasis, chronic intestinal (1-month duration)
Kaposi’s sarcoma
Lymphoma
- Burkitt, immunoblastic (or equivalent term), primary brain
Mycobacterium
- Avium- complex or M. kansasii,
- Tuberculosis , any site
- Other species or unidentified species, disseminated orextrapulmonary
Pneumocystis jirovecii pneumonia
Pneumonia, recurrent
Progressive multifocal leukoencephalopathy
Salmonella septicemia, recurrent
Toxoplasmosis of brain
Wasting syndrome, due to HIV

Patients with HIV are living long before their immune symstem is compromised enough to suffer from 2nd infections. This is thanks to the advances that have been made in treatment. Now-a-days, well managed HIV is kind of like Diabetes where chronic inflammation from the virus can result in end organ problems outside of a secondary immunocompromised infection

Skin
- General: pruritis (all stages of HIV), dry skin, thinning hair
- Eosinophilic folliculitis: urticarial lesions, face, arms and legs
Mucous membranes
- Oral hairy leukoplakia
- Periodontal disease
Hematological
- Lymphopenia
- Anemia of chronic disease
- Thrombocytopenia (Can occur with initial viral infection)
Neurological
- AIDS dementia complex (ADC)
- Range of symptoms from mild memory/concentration impairment to severe cognitive deficit, personality change and psychomotor slowing
- Neuropathy
  - Sensory: Legs Feet > hands
  - Autonomic: postural hypotension and diarrhea
Renal
- HIV-associated nephropathy: Rare, variant of focal segmental glomerulosclerosis (FSGS) also causing tubulopathy
- HIV-immune complex kidney disease: Glomerular disease
- Other: IgA nephropathy and Thrombotic Thrombocytopenic Purpura (TTP)
Cardiovascular: leading cause of death in HIV
- Early ischemic disease: ↓ HDL and chronic inflammation
- Cardiomegaly/CHF
- Myocarditis
Pulmonary
- Pulmonary Hypertension
- Lymphoid interstitial pneumonitis (LIP): seen in children; confused with PCP pneumonia
Gastrointestinal
- Weight loss
- HIV enteropathy: villous atrophy resulting in chronic malabsorption/diarrhea
- Hypochlorhydria: ↓ drug absorption and bacterial overgrowth

Workup

HIV Screening Recommendations
United States Preventative Services Task Force (USPSTF) and CDC

All patients aged 13–64 years (USPSTF – 15-65) in all health care settings once
More frequently depending on risk factors (3-6 months)
High-Risk
- Intravenous drug abuse (IVDA)
- Men who have sex with men (MSM)
- Other sexually transmitted infection
Screening does NOT mandate written consent for HIV testing or counseling

Emergency Room Screening – The American College of Emergency Physicians

“Routine HIV screening of adults, including pregnant women, is encouraged andmay be undertaken in the ED when feasible”

Active tuberculosis
Herpes zoster (healthy person age < 50 )
New severe psoriasis or other new unexplained severe skin disorder
History of hepatitis B or C
Cervical cancer
Thrush not related to recent antibiotic use
Unexplained cachexia or weight loss
Diffuse lymphadenopathy
Unexplained thrombocytopenia, leukopenia, or anemia
History of an opportunistic or unusual infection in an otherwise healthy individual
Prolonged unexplained illness despite evaluation
Any history of sexually transmitted infection

HIV Antigen/Antibody (Ag/Ab) Combination

Fourth generation testing: preferred testing method; limited in acute disease (2-3 weeks) composed of 2 tests
1. HIV-specific p24 Antigen: (+) test alone indicates window period in which the patient has not developed antibodies
2. ELISA HIV antibody (IgG & IgM): detection of HIV antibodies which develop after seroconversion takes place. specificity and sensitivity > 99%
Positive results should be confirmed with an antibody assay that can differentiate between HIV‑1 and HIV‑2 infections
Window period: infected with HIV but antibodies cannot be detected
5% of patients seroconvert in 7 days, 50% in 20 days, and > 95% in 90 days

HIV nucleic acid test (NAT): detects HIV RNA

Qualitative and quantitative test for RNA
Diagnostic 7 days before a p24 antigen test and 12 days before a sensitive HIVantibody test
Should be done if (+) P-24 and HIV antibody negative (or indeterminate)

Western blot test (1st generation)

HIV proteins are separated by electrophoresis and mixed with patients’ serum toconfirm binding of antibodies in patient serum
Being phased out of use

Rapid HIV-1 Antibody Test (most are 2nd generation)

IgG against synthetic peptides or recombinant proteins
Results in ~30 minutes; limited ability to detect acute infection (4-7 weeks)

Saliva test (OraQuick®)

Home test; has false (-) especially in early disease

Viral Load

Quantitively measures HIV RNA by reverse transcription polymerase chain reaction (RT-PCR) or nucleic acidsequence-based amplification (NASBA)
- Untreated HIV infection: 10,000–100,000 copies of HIV RNA per cubic millimeter
- “Undetectable” = < 5–50 copies of HIV RNA per cubic millimeter
Frequency: q4–6 weeks with start of ART until <50 copies/mL; then q3–4 months

CD4 lymphocytes (“CD4 Count”)

Gages the degree of immune deficiency
- CD4 < 200/μL = ↑ risk of opportunistic infections and tumors
- CD4 count may vary 10–30% between tests
Frequency: Every 3–6 months for the first 2 years after starting ART

HIV Genotype

Resistance testing for protease inhibitor (PI), nonnucleoside reverse transcriptase inhibitor (NNRTI), and nucleoside reverse transcriptase inhibitor (NRTI) mutations

Coreceptor Tropism Assay

Consider testing if use of C-C motif chemokine receptor 5 antagonist is being considered for treatment

Human leukocyte antigen subtype B*5701 

Consider testing if use of abacavir is being considered for treatment
(+) high risk for abacavir hypersensitivity reaction

Gonorrhea, chlamydia
- NAT testing at site of exposure
Trichomoniasis
- All patients that have vaginal intercourse
Syphilis
- Rapid plasma regain or treponemal-specific antibody tests
Hepatitis A, B, C
- HBsAg, HBsAb, HBcAb, HCV antibody; hepatitis A virus (HAV) with HAVimmunoglobulin G (IgG)
Mycobacterium tuberculosis
- Tuberculin skin test
Varicella virus
- Anti-varicella IgG if no known history

CBC
- Assess for anemia, neutropenia, thrombocytopenia
CMP
- Monitors on going liver damage nutritional status (albumin)
- Kidney function (abnormal in 30% of untreated patients)
Lipid profile
Hemoglobin A1c
Urinalysis
- Assess for evidence of proteinuria, hematuria

“Poor Man’s CD4 Count”
How to use an Absolute lymphocyte count (ALC) to approximate CD4

Absolute lymphocyte count (ALC) can be used as a surrogate for CD4 count
Absolute lymphocyte count (ALC) = White blood count x Lymphocyte percentage
- ALC of < 1,000 cells/mm3 is predictive of a CD4 count < 200 cells/mm3
  - Sensitivity 67% ; Specificity 96%
  - Positive predictive value of 91%; negative predictive value of 81%
- ALC of < 2,000 cells/mm3 is predictive of a CD4 count < 200 cells/mm3
  - Sensitivity of 97%; Specificity of 41%
  - Positive predictive value of 52%; Negative predictive value of 95%
Interpretation
- If ALC is < 1,000 then CD4 is probably < 200
- if ALC > 2000 then CD4 is probably > 200

Treatment

Principles of Highly Active Antiretroviral Therapy (HAART)

Indication for treatment = Presence of HIV
Combination therapy: typically, 3-drug regiment with once daily pills
Compliance: This will determine success & ↓ resistance
Goal: ↓ viremia by 50% after 6 months of treatment and ↓ viral RNA < 50 copies per cubic millimeter

Pharmacology Review: HAART

Mechanism: blocking reverse transcriptase by being preferentially incorporated into HIV DNA, halting synthesis

Examples NRTIs

Abacavir (ABC)
Didanosine (ddI)
Emtricitabine (FTC)
Lamivudine (3TC)
Stavudine (d4T)
Tenofovir disoproxil fumarate (TDF)
Tenofovir alafenamide (TAF)
Zalcitabine (DDC)
Zidovudine (AZT)

NRTIs Usage & Side effects

Tenofovir: renal dysfunction, Fanconi syndrome/RTA II, osteoporosis, exacerbation of chronic hepatitis B with discontinuation of TAF
TDF: ↑ renal toxicity & osteopenia; weakness
TAF ↓ renal toxic & osteopenia but weight gain, particularly in African women
Abacavir: potentially life-threatening allergic reactions, possible ↑ MI risk
Hypersensitivity symptoms: fever, rash, nausea, vomiting, diarrhea, abdominal pain, fatigue, or respiratory symptoms (sore throat, cough, or shortness of breath)
Emtricitabine (FTC): minimal toxicity, hyperpigmentation, exacerbation of chronic hepatitis B with discontinuation of FTC
Lamivudine (3TC): exacerbation of chronic hepatitis B with discontinuation of 3TC
Zidovudine (AZT): Anemia, hepatic steatosis, lactic acidosis, lipodystrophy
Stavudine (d4T): Neuropathy, pancreatitis, hepatic steatosis, lactic acidosis, lipodystrophy

BOARD Highlights

Lactic acidosis (life-threatening)
Hepatic steatosis
Pancreatitis (didanosine)
Bone marrow suppression (zidovudine – ↓WBC, ↓Hgb)
Nephrotoxicity (tenofovir)

Mechanism: causes enzymatic confirmational change to inhibit reverse transcription

Examples NRTIs

Delavirdine (DLV)
Doravirine (DOR)
Efavirenz (EFV)
Etravirine (ETR)
Nevirapine (NVP)
Rilpivirine (RPV)

NRTIs Usage & Side effects

Doravirine (DOR): HA, dizziness, abnormal dreams, diarrhea, abdominal pain
Efavirenz(EFV): may ↑ risk of depression, ↑QT, ↑LFTs, hyperlipidemia, rash, neuropsychiatric symptoms, false (+) THC & BNZ on drug testing
- Most widely used drug in high income countries
Nevirapine: may cause hepatic toxicity and rash in high CD4+ count patients
- Not initiated in Females with > 250 cells/μl or males with CD4+ > 400 cells/μl
Rilpivirine (RPV): ↑QT, ↑LFTs/hepatotoxic, insomnia, HA, depression, rash
- Best tolerated; ↓ effective in patients with high HIV RNA levels
- Viral load < 100,00 RNA/ml & CD+ > 200 cells/μl
Etravirine: used after other drugs have failed

BOARD Highlights

Neuropsychiatric effects (vivid dreams, psychosis — efavirenz)
Rash/Stevens-Johnson (especially nevirapine)
Hepatotoxicity

Mechanism: competitive enzyme inhibitor that ↓ cleavage of polypeptides preventing viral replication

Examples NRTIs

Amprenavir (APV)
Atazanavir (ATZ)
Darunavir (DRV)
Indinavir (IDV)
Lopinavir/ritonavir (LPV/r)
Nelfinavir (NFV)
Ritonavir (RTV)
Saquinavir (SQV)
Tipranavir (TPV)

PIs Usage & Side effects

↑ Cardiovascular disease (not darunavir & atazanavir)
Drug interaction via P450 system: anticoagulants, HMG-CoA reductase inhibitors, corticosteroids, antiarrhythmics, antiepileptics, antimalarials, and antidepressants.
Atazanavir (ATZ): ↑ indirect Bili, ↑ glucose, cholelithiasis/nephrolithiasis, AKI, fat maldistribution, ↑LFTs, rash
Darunavir (DRV): hepatotoxic, ↑ glucose , ↑LFTs, hyperlipidemia, rash (rare TENs, Stevens-Johnson), HA, diarrhea

BOARD Highlights

GI upset
Hyperglycemia
Hyperlipidemia
Lipodystrophy
Nephrolithiasis (indinavir)

Mechanism: prevents HIV genome from being integrated to host

Examples NRTIs

Bictegravir (BIC)
Dolutegravir (DTG)
Elvitegravir (EVG)
Raltegravir (RAL)

INSTIs Usage & Side effects

Generally, well tolerated
Nearly 90% of patients have attained/maintained undetectable viral load through 96 weeks
Elvitegravir: requires co‑administration with cobicistat to prevent rapid hepatic clearance.
- Cobicistat inhibits the renal secretion of creatinine, making it difficult to monitor kidney function
Dolutegravir (DTG): possible neural tube defects (if taken near time of conception), hepatotoxic, insomnia, depression, ↑ weight
Bictegravir (BIC) uncertain safety in pregnancy, headache, diarrhea, weight gain
Elvitegravir (EVG): Nausea, diarrhea, depression, ↑ weight
Raltegravir (RAL): Insomnia, HA, depression, nausea, diarrhea, fever, rhabdomyolysis, rash (rare TENs, Stevens-Johnson), ↑ weight

BOARD Highlights

Myopathy/rhabdomyolysis
Insomnia
Weight gain

Maraviroc: CCR5 inhibitor or entry inhibitor

Needs testing to make sure virus is not a variant that uses CXCR4
Rare hepatotoxicity and may cause hypotension in patients with renal impairment

Enfuvirtide (ENV): parenteral fusion inhibitor by inhibiting viral entry via gp120

Expensive; injected twice daily, associated with painful nodules @ injection site

Ibalizumab: Monoclonal anti-HIV antibody

Hypersensitivity reactions

RAL + TAF/FTC (Descovy®) = INSTI + NRTI x 2

Raltegravir (RAL)+ Tenofovir alafenamide (TAF) + Emtricitabine (FTC)

BIC/TAF/FTC (Biktarvy®) = INSTI + NRTI x 2

Bictegravir (BIC) + Tenofovir alafenamide (TAF) + Emtricitabine (FTC)

EVG/c/TAF/FTC (Genvoya®) = INSTI + NRTI x 2

Elvitegravir (EVG) + Tenofovir alafenamide (TAF) + Emtricitabine (FTC)

DTG (Tivicay®) + TAF/FTC (Descovy®) = INSTI + NRTI x 2

Dolutegravir (DTG) + Tenofovir alafenamide (TAF)+ Emtricitabine (FTC)

DTG/ABC/3TC (Triumeq®) INSTI + NRTI x 2

if HLA-B*5701 negative
Dolutegravir (DTG) + Tenofovir alafenamide (TAF) + Emtricitabine (FTC)

Prophylaxis

Pneumocystis jirovecii Pneumonia (PCP)

Indication: CD4 < 200 or after episode of PCP
Trimethoprim–sulfamethoxazole one double-strength tablet three times weekly, or one single-strength tablet q24h
- Alternative: Pentamidine aerosols 300 mg once monthly or Dapsone 50 mg q24h + pyrimethamine 50 mg q24h

Cerebral Toxoplasmosis

Indication: CD4 < 100
Trimethoprim–sulfamethoxazole one double-strength tablet three times weekly, or one single-strength tablet q24h

Mycobacterium (other than tuberculosis)

Indication: CD4 < 50
Azithromycin 1200 mg weekly

Cryptococcosis

Indication: CD4 < 50
Fluconazole 400 mg weekly, or 200 mg three times weekly

Cytomegalovirus Retinitis

Indication: CD4 < 50
Valganciclovir 450 mg PO q24h

Post Exposure Prophylaxis

Risk of HIV Based on Exposure	% Risk per Act
Blood Exposure
Percutaneous – Occupational	Occupational – 0.3% Needle sharing – 0.63%
Mucosal Membrane	0.09%
Nonintact skin	< 0.09%
Sexual
Anal Sex	Receptive – 1.38% Incentive – 0.11%
Vaginal Sex	Receptive – 0.08% Insertive – 0.04%

*Body fluid NOT associated with HIV transmission (unless bloody): Feces, Sputum and saliva, Sweat, Tears, Urine, Vomit

Prophylaxis for Exposure

HIV exposure must have occurred within 72 hours of PEP initiation with substantial risk of HIV transmission
Baseline HIV status of exposed person is negative
28-day course of HIV PEP prescribed
3-drug regimen prescribed based on CDC guidelines
Evaluation for other possible infectious exposures (eg, STI, hepatitis B or C)
Evaluate for possible pregnancy in exposed person

Medication Regiment

3-drug regimen (no renal dysfunction GFR ≥ 60 mL/min)

Tenofovir disoproxil fumarate (TDF) 300 mg
Emtricitabine (FTC) 200 mg once daily
Raltegravir (RAL) 400 mg BID or dolutegravir (DTG) 50 mg daily (avoid if pregnant)

3-drug regimen (no renal dysfunction GFR < 59 mL/min)

Zidovudine: dose adjusted for kidney function
Lamivudine: dose adjusted for kidney function
Raltegravir (RAL) 400 mg BID or dolutegravir (DTG) 50 mg daily (avoid if pregnant)

Side Effects

TDF-FTC: GI (nausea, vomiting, diarrhea), fatigue, skin discoloration/reaction
Renal dysfunction, worsening of chronic Hepatitis B with withdrawal
RAL: Severe skin and hypersensitivity reactions

Regimen

Tenofovir disoproxil fumarate + emtricitabine (Truvada) daily
Before starting treatment
- Should be documented as HIV negative before prophylaxis is started
- Baseline blood work should be checked
- HIV testing every 3 months
- Renal testing @ 3 months then every 6 months

Opportunistic Infections

Pneumonia & HIV

Epidemiology

Bacterial PNA = 25 x more common than the general population
Major cause of morbidity and mortality
U.S. Prevalence of organisms = Community acquired pneumonia
- Bacteria > PCP > Tuberculosis
Bacterial pneumonia = Most common admission diagnosis for an HIV patient
In Africa, tuberculosis is the most common pneumonia associated with HIV
Mortality with community-acquired pneumonia and HIV = 10-30%
Risk factors
- Cigarette and illicit drug smoking
- Injection drug abuse
- Older age
- Lower CD4 cell count (especially less than 200 cells/mL)
- Previous pneumonia
- Underlying comorbid
  - Cardiovascular disease, renal disease, respiratory diseases, hepatic cirrhosis, and alcoholism
- Lower socioeconomic status
- Potential genetic factors

Etiology of Pneumonia in HIV

Common
Frequent
Uncommon
Rare

Streptococcus pneumonia (pneumococcus)

20% of cases overall
40% of cases in which a microbiological diagnosis is made
70% of cases with bacteremic pneumonia
Higher incidence of bacteremia with pneumonia

H. influenza

10-15% of bacterial PNA
CXR: diffuse pulmonary infiltrate (atypical pattern rather than typical)

Staphylococcus aureus (MRSA and MSSA)

5% of cases
Higher association with IVDA, recent viral infection (influenza)
Complications: endocarditis, septic emboli

Gram-negative infections

Examples: Klebsiella pneumonia, Pseudomonas aeruginosa
Uncommon: <5% unless with advanced immunosuppression (CD4 < 40 cells/mm3)

Atypical infection

Legionella is more common with AIDS
Mycoplasma pneumoniae and Chlamydia Pneumonia (uncommon)

Rhodococcus equi

Advanced immunosuppression
Indolent disease course
Can mimic TB on chest X-ray (cavitation)

Nocardia

Aerobic actinomycete
Chronic clinical course but high mortality rate with dissemination

Nontuberculous Mycobacteria (NTM) Pneumonia in HIV

Pathology

Source: inhalation or ingestion from water and soil reservoir
No person-to-person transmission
Pathogens: Mycobacterium avium complex (MAC), which consists of M avium and M intracellulare
- Most common Nontuberculous mycobacteria
- Other: M kansasii and M xenopi, M simiae
Pathology: inhalation of a contaminated source causes disseminated disease with or without pulmonary involvement; no person-to-person transmission
- Rarely causes infection in non-AIDS patients
- More commonly causes disseminated disease in AIDS patients than isolated pneumonia

Constitutional: fever, night sweats, ↓ appetite, and weight loss
MAC and M genavense more commonly cause diarrhea, intra-abdominal adenopathy, and hepatosplenomegaly
Other presentations of MAC
- M kansasii: presents similarly to TB except for the occurrence of meningitis
- Abdominal: Retroperitoneal and intrabdominal lymphadenitis, Peritonitis, Small bowel ulcers
- MSK: Osteomyelitis, Bursitis, and tenosynovitis
- Skin: Peripheral lymphadenitis, cutaneous abscess
- Skin, soft tissue, bone, and joint involvement suggest infections from rapid-growing mycobacteria
  - M abscessus, M fortuitum, M chelonae

Lab Work

CBC: cytopenias
Alkaline phosphatase: elevated due to bone marrow and liver infiltration
CD4 count of < 50 cells/mm3 = risk for infection

Cultures

Blood cultures: can be (+) For MAC
Sputum Culture: requires 2 (+) expectorated or 1 (+) BAL culture to make diagnosis
- (+) finding may represent environmental contamination or airway colonization

Chest X-Ray

Multifocal bronchiectasis is the most common radiographic feature of MAC in HIV
Upper lobe involvement with or without cavitation (Like TB)
Other non-MAC mycobacteria findings
- Bilateral interstitial infiltrates, pleural effusions, mediastinal adenopathy, or normal Xray

Does NOT require empiric treatment; requires further workup to diagnose
No isolation required if the disease is suspected
Consultations
- If not done already, antiretroviral therapy should be started by infecious disease
- Pulmonary eval for Bronchoscopy and exclusion of other diagnoses if suspected
Anti-infective Treatment
- Macrolide and ethambutol +/- rifabutin and amikacin
- Duration: 12 months for those with disseminated disease from the last negative culture
- Also continued until CD4 count > 100 for > 6 months
Prophylaxis with azithromycin weekly for CD4 count of < 50 cells/mm3 is no longer recommended
- International Antiviral Society-USA (IAS-USA) guidelines of 2018

Nocardiaceae

Pathology

Family: Nocardiaceae
- Rhodococcus equi: gram-positive; weak acid-fast coccobacilli
  - Source: (zoonic) enteric in foals
- Nocardia: gram-positive; partially acid-fast; beading branching filaments
  - Source: soil
- Organisms: N asteroids, N brasiliensis
Inhalation from an exposed source leads to pulmonary infection in an immunocompromised host (HIV, organ transplant, etc.), followed by dissemination
- Inoculation through skin trauma also possible

Pulmonary
- Nonspecific fever, cough, SOB, chest pain
Extrapulmonary
- Brain and subcutaneous abscesses

Chest X-ray: consolidation with cavitation with or without mediastinal adenopathy
Blood cultures: (+) in 50% of R equi infections
Sputum culture: (+) in 50% of R equi infections

Nocardiosis: (2-3 Drug regimen)
- Iincluding TMP-SMX + amikacin, meropenem, 3rd-4th cephalosporin
Rhodococcosis: (2-drug regimen)
- Vancomycin, carbapenems, aminoglycosides, TMP-SMX, etc

Pneumocystis jirovecii Pneumonia (PJP)

Epidemiology

More than 43% of PCP cases occurred in persons NOT receiving medical care
- Most of whom were likely not known to be HIV-infected
- 41% were prescribed prophylaxis but were either nonadherent with PCP prophylaxis
Mortality with antiretroviral therapy is 9.7-11.6%

Pathogen: Pneumocystis jirovecii, a yeast-like fungus

Other Fungal Etiology
- Aspergillus species
- Cryptococcus neoformans
- Endemic Dimorphic fungi
  - Histoplasma capsulatum, Blastomyces dermatitidis, Coccidioides species, Paracoccidioides braziliensis, Penicillium marneffei

Risk Factors

HIV with CD4 count < 200 cells/mm3
Men > Women
CD4 count among persons who develop PJP while receiving antiretroviral therapy
- Taking antiretroviral therapy – Median was 29 cells/mL
- Not taking antiretroviral therapy – Median 13 cells/mL

History of Disease

Mistakenly described as a protozoan parasite
First recognized as a human pathogen in European orphanages after World War I
Described as the cause of interstitial plasma cell pneumonia among premature/malnourished
Found more and more with immunodeficiency and cancer patients
1981
- PCP was reported in 15 previously healthy men who had sex with other men (MSM) or who were injection drug users and heralded the advent of the global pandemic of human immunodeficiency virus [HIV]/AIDS
- Rare disease before the outbreak of AIDS in the 80s
- Substantial decline in PCP after the advent of prophylaxis in 1989
- Advent of antiretroviral therapy led to a steep decline in the disease

Triad

Exertional dyspnea
Nonproductive cough
Fever (days → weeks)

NOT hemoptysis
Prolonged prodromal: can be as long as 3-8 weeks of symptoms or sometimes faster over 7-10 days
Auscultation of the chest is usually normal, with possible expiratory crackles

Ambulatory Pulse Ox

A normal exercise test (without desaturation) virtually excludes the diagnosis of PCP
Oxygenation can also be used to grade the severity of disease
- PaO2 > 70 mm Hg on room air = mild disease
- PaO2 < 70 mm Hg on room air = moderate to severe disease

Lab Work

CD4 count < 200 cells/mm3
- Ordering this test in the ER is unable to assist in medical decision-making as the test is not resulted quickly enough to make clinical decision-making
- Ask the patient if they have had a test done recently and what the results were.
ABG
- Progressive hypoxia may be seen
- Alveolar-arterial oxygen gradient (A-aO2) is widened in more than 90% of patients with PCP
- Nonspecific finding, as this is needed in most lung diseases
- A-aO2 gradient can be used to grade disease
  - A-aO2 < 35 mm Hg = Mild disease
  - A-aO2 35-45 mm Hg = Moderate disease
  - A-aO2 > 45 mm Hg = Severe disease
Lactate dehydrogenase (LDH)
- Elevation is highly suggestive of PCP in an HIV patient with subacute respiratory symptoms
- However, this is a nonspecific

Imaging

Chest X-ray
- Early disease = may be normal
  - May alter from normal to markedly abnormal in 2-3 days
- Typical findings = Diffuse perihilar interstitial infiltrates progressing to diffuse bilateral alveolar consolidations resembling pulmonary edema or ARDS
- Atypical findings: cystic airspace and pneumatocele formation, unilateral consolidation, lobar infiltrates, nodules, mediastinal lymphadenopathy, pleural effusions, and upper zone infiltrates resembling tuberculosis
CT Chest
- Can be helpful if a patient is symptomatic with normal chest x-ray findings
- Finding: Patches of ground-glass shadowing

Sputum Culture

Patients rarely produce PCP (+) culture with spontaneously expectorated sputum
Increased diagnostic yield with bronchoscopy with methenamine silver stain will show the cystic form of disease, and Wright-Giemsa stain will show nuclei of Pneumocystis
PCR for Pneumocystis DNA from BAL or sputum induction is superior to culture

Empiric therapy for PCP can begin with symptoms, chest X-ray findings consistent with PCP pneumonia

Antimicrobial Treatment

Trimethoprim-sulfamethoxazole (TMP-SMX) – FIRST LINE!
- Dose: 20 mg/kg daily of TMP and 100 mg/kg daily of SMX given in 2-4 divided doses
- Duration: 21-days!!!
- Route
  - Moderate-severe disease then IV for first 7-10 days
  - Mild disease can be given PO Bactrim (much cheaper than IV $)
- Effective: 70- 80% of patients
- Side effects of prolonged Bactrim course:
  - Neutropenia, anemia (40%), rash (25%), Steven-Johnson’s, fever (30%) elevated LFTs (10%)
  - Acute kidney injury: interstitial nephritis
  - Renal Tubular acidosis (Type IV) – mild non-anion gap acidosis with HYPERKALEMIA
  - Hemolysis: if patient has glucose-6-phosphate dehydrogenase deficiency (G6PD)
- Alternative = Clindamycin + Primaquine (Alternative regiment)
  - Indication: sulfa allergy; can be given if failing TMP-SMX therapy
  - Dose: Clindamycin 450-600mg QID; primaquine 15-30 mg daily
  - The mechanism of action of the combination is not known
  - Route: PO for mild; IV for moderate to severe
  - Side effects: 2/3 = Rash; 1/3 diarrhea (?C-diff)
  - Methemoglobinemia (primaquine) occurs in 40% of patients (less likely at 15mg/kg dose)

Corticosteroids

Dose: Prednisone 40 mg twice daily for 5 days
- Then 40 mg daily for days 6-10, and then 11 further days of 20 mg daily and
  - If using methylprednisolone IV give 75% of the prednisone dose
Indications: moderate-severe PCP (i.e needs oxygen)
- HIV patients with proved/suspected PCP & PaO2 < 70 mm Hg
- HIV patients with proved /suspected PCP & A-ao2 > 35 mm Hg
Effect: ↓respiratory failure by 50%, and ↓ mortality by 1/3

Consultation Infectious Disease

Initiation of antiretroviral therapy in a naive patient is controversial

Disposition

Mild Disease: can be treated out patient with PO Bactrim
Moderate – Severe disease: IV antibiotics + Steroids + admission
Failure to respond after 5-7 days of treatment should be changed to alternative treatment
Initial worsening of disease may be seen in the first few days of treatment due to inflammatory response to dying Pneumocystis, or to Pneumocystis-induced changes in surfactant leading to worsening of lung injury

Indication: CD4 < 200 cells/mm3
Bactrim DS (160mg TMP and 800mg SMX) daily
- Side effects: rash (~20% of patients)
Alternative: dapsone 100mg daily

Cryptococcus

Pathology

Pathogen: Cryptococcus neoformans
Source: ubiquitous environmental yeast, can be found in pigeon droppings
- Cryptococcus gattii: found in tropical areas and can cause infections in healthy patients
Inhalation of spores or yeast and forms lymph node complex (like TB) be fore disseminating in an immunocompromised host
With HIV this infection can be reactivated as immune system fails or be a primary infection
Can cause colonization in patients with structural lung disease

Risk Factors

Neutropenia/ immunocompromised patients
AIDS with CD4 cell count < 50
Chronic Corticosteroid
Structural lung abnormalities
Hematologic malignancy
Lung transplant

Meningitis = most common presentation

Fevers, headache, and altered mental status, meningismus (infrequent) presenting over several weeks

Pneumonia: Localized pulmonary infection

Nonspecific and include cough, dyspnea, sputum production, chest pain, and pleurisy

Other: skin, bone, eye, prostate

CD4 cell count

< 200 cells/m = increased risk with HIV
If localized lung infection is found, the patient should have LP done to evaluate for meningitis

Serology: Cryptococcal antigen

Serum, CSF, BAL, pleural fluid
Sensitivity 93-100% and specificity 93-98%

Direct microscopic

Encapsulated yeasts by India ink preparation of CSF
Culture: CSF and blood cultures (+) 90% and 70% of patients with meningitis

Cytology and Histopathology: CSF or sputum

Shows round to ovoid spores with large capsules

Imaging – Chest X-ray or CT

The most common finding is single or multiple noncalcified nodules and bilateral diffuse interstitial infiltrates
Other: focal alveolar infiltrates, cavitary lesions, pleural effusions, and lymphadenopathy

Based on Severity

Severe pulmonary disease or meningitis
- Lipid formulations of amphotericin B + flucytosine for 2 weeks
  - Then high dose fluconazole (400 mg/d) for 8 weeks, then 200 mg for 1 year
Mild-to-moderate pulmonary disease
- Fluconazole (400 mg/d) for 6 to 12 months

HIV/AIDS

Chapter 16: HIV Infection.” Infectious Diseases: A Clinical Short Course, 4E, McGraw-Hill, 2020.
Sandilands, Euan A. “Sexually Transmitted Infections and Human Immunodeficiency Virus.” Essentials of Kumar and Clark’s Clinical Medicine, Elsevier, Amsterdam, 2021.
Infect Dis Clin N Am 33 (2019) 743–767
Emerg Med Pract. 2021 Jul;23(7):1-24. Epub 2021 Jul 1.
Medicine, 2021-03-01, Volume 49, Issue 3, Pages 140-144
Mayo Clinic Proceedings, 2013-12-01, Volume 88, Issue 12, Pages 1468-1474
Clinical Infectious Diseases 2021;73(11):e3572–60

Nontuberculous mycobacteria (NTM)

Infect Dis Clin N Am 33 (2019) 743–767
Clin Chest Med 34 (2013) 243–254
JAMA. 2018;320(4):379.

Bacterial & PCP HIV

Ann Emerg Med. 1998 Sep;32(3 Pt 1):323-8.
JAMA. 1993;269(5): 622-626
Clin Chest Med 34 (2013) 205–216
Clin Chest Med 34 (2013) 229–241