Lymphoma: Overview & Classification

Key Differences: HL vs. NHL

• Robbins, Cotran & Kumar Pathologic Basis of Disease, Table 13.7

1. Hodgkin Lymphoma (HL)

• Accounts for ~0.7% of all new cancers in the US (~9,000 cases/year)
• Bimodal age distribution: one peak in young adults, a second in adults >55 years
• First human cancer successfully cured with radiation + chemotherapy

Defining Pathology: Reed-Sternberg (RS) Cells

• Large cells (~45 µm), multinucleated or multi-lobed, with prominent inclusion-like "owl-eye" nucleoli (~5-7 µm)
• RS cells derive from germinal center or post-germinal center B cells (clonal IGH rearrangements confirmed)
• Despite B-cell origin, they fail to express B-cell genes including immunoglobulin - due to epigenetic reprogramming
• Key signaling: NF-κB activation (via EBV LMP-1, IκB mutations, or TNF pathway) rescues "crippled" GC B cells from apoptosis
• RS cells secrete cytokines (IL-5, IL-10, M-CSF, eotaxin) that recruit reactive T cells, eosinophils, histiocytes, and plasma cells - which comprise >90% of tumor bulk
• RS cells express PD-L1/PD-L2 (chromosome 9p gains), enabling immune evasion

WHO Classification of HL (5 subtypes)

• Different immunophenotype: L&H ("popcorn") cells, CD20+, CD45+, CD15-, CD30-
• Origin: germinal center B cell
• Indolent course; middle-aged men; peripheral adenopathy; excellent survival
• Note: The 2022 International Consensus Classification (ICC) has renamed this "nodular lymphocyte-predominant B-cell lymphoma", dropping the "Hodgkin" designation entirely
• EBV not a feature (unlike cHL)
• Grainger & Allison's Diagnostic Radiology; Robbins, Cotran & Kumar Pathologic Basis of Disease

2. Non-Hodgkin Lymphoma (NHL)

• 85-90% are B-cell in origin in the US and Europe
• Incidence increases steadily with age (unlike HL's bimodal pattern)
• Classified by the 2016 WHO classification (integrating genetic data, morphology, immunophenotype, and molecular features)

Classification Framework (2016 WHO Revision)

1. Cell of origin: B-cell vs. T/NK-cell
2. Maturation stage: Precursor (immature) vs. peripheral (mature/post-thymic)

Mature B-Cell Neoplasms (most common)

Mature T & NK Neoplasms (10-15% of NHL)

Special Categories

• Post-transplant lymphoproliferative disorders (PTLD): EBV-driven; 4 broad types
• Lymphomas in HIV: Burkitt, DLBCL, primary effusion lymphoma, plasmablastic
• Goldman-Cecil Medicine, Table 171-4; Grainger & Allison's Diagnostic Radiology

Genetic Hallmarks

Epidemiology & Risk Factors

• NHL risk is elevated ~20-fold after prior Hodgkin lymphoma treatment
• Associations: EBV (Burkitt, NLPHL, NK/T-cell), HTLV-1 (adult T-cell), H. pylori (gastric MALT), HHV-8 (primary effusion), HIV/immunosuppression
• Environmental: phenoxy herbicides (2,4-D), ionizing radiation, organic solvents, anti-TNF agents (hepatosplenic T-cell lymphoma), breast implants (ALCL)
• Heavy smoking: increased follicular lymphoma risk
• Low vitamin D: associated with recurrent lymphoma and worse outcomes
• Goldman-Cecil Medicine, Non-Hodgkin Lymphoma chapter

A Note on the 2022 Updates

Klebsiella pneumoniae: Complete Overview

1. Microbiology & Characteristics

• Large polysaccharide capsule (K antigen) - the primary virulence factor; responsible for the characteristic mucoid, "mucoviscous" colony appearance on agar
• Capsule creates a negative (clear) halo around rods on Gram stain
• Non-motile (unlike E. coli, Proteus)
• Indole-negative (K. oxytoca is the exception - indole positive)
• Lactose-positive, oxidase-negative
• Normal colonizer of the colon (5-35%), oropharynx (1-5%), and transiently of skin in healthy humans; colonization rates rise significantly with hospitalization or LTCF residence
• Medical Microbiology 9e; Quick Compendium of Clinical Pathology

2. Two Clinical Pathotypes

Classic K. pneumoniae (cKp)

• Primarily causes healthcare-associated and LTCF infections
• Gains notoriety for acquiring antimicrobial resistance determinants
• Clonal groups ST258, ST11, ST15, ST101, ST307 are undergoing international dissemination
• Nearly 4x more transmissible than E. coli; carbapenemase-producing strains spread even more readily

Hypervirulent K. pneumoniae (hvKp)

• First recognized in Taiwan in 1986; now described globally but most common in Asian Pacific Rim populations and individuals with diabetes mellitus
• Causes serious infections in younger, healthy individuals from the community
• Distinguished by a hypermucoviscous phenotype ("positive string test" - colony forms a string >5mm when stretched with a loop)
• Metastatic spread: infection can disseminate from a primary site to multiple distant organs simultaneously
• Identification: presence of all 5 biomarkers - iucA, iroB, peg-344, rmpA, and rmpA2 is the most accurate method
• Increasingly acquiring carbapenemase and ESBL genes (MDR/XDR hvKp) - a growing global threat
• Harrison's Principles of Internal Medicine 22E (2025)

3. Clinical Infections

Pneumonia (most classic presentation)

• Most frequent cause of Gram-negative bacterial pneumonia
• Classic presentation in debilitated patients: chronic alcoholics, diabetics, COPD, malnourished individuals
• Produces abundant viscid capsular polysaccharide - patient has difficulty expectorating
• Characteristic "currant jelly sputum" (blood-tinged, thick, gelatinous) from hemorrhagic necrosis
• Tends to involve upper lobes (unlike other Gram-negative pneumonias)
• Pathology: lobar pattern with extensive hemorrhagic necrotizing consolidation, cavity/abscess formation, pleural effusion, empyema
• hvKp pneumonia: increasingly common in Asia rivaling S. pneumoniae; can occur in healthy young patients; bilateral nodular densities if from metastatic spread

Urinary Tract Infections (UTI)

• Only 1-2% of UTIs in healthy adults, but 5-17% of complicated UTIs (catheter-associated, structural/functional abnormalities)
• hvKp UTI more often presents as renal or prostatic abscess (bacteremic spread) rather than ascending infection

Pyogenic Liver Abscess

• Hallmark presentation of hvKp
• Monomicrobial, community-acquired, in patients without prior hepatobiliary disease
• Most common in Asian Pacific Rim (replacing E. coli as leading cause); seen in previously healthy individuals
• Can metastasize to spleen, eye (endophthalmitis), brain, psoas muscle

Abdominal Infections

• Intraabdominal infections, biliary infections, spontaneous bacterial peritonitis, splenic abscess

Other Sites

• Bacteremia/sepsis (secondary to any primary site)
• Meningitis - neonatal, post-neurosurgical; hvKp: spontaneous meningitis without trauma
• Endophthalmitis - devastating vision loss, characteristic of hvKp
• Surgical site infections, soft tissue infections (usually in devitalized tissue - decubitus/diabetic ulcers, burns)
• Intravascular device infections
• Osteomyelitis, nosocomial sinusitis

Other Klebsiella Species

• Harrison's 22E; Jawetz Medical Microbiology; Medical Microbiology 9e

4. Antimicrobial Resistance

Intrinsic Resistance

• Ampicillin and ticarcillin - all Klebsiella are intrinsically resistant (produce chromosomal β-lactamase)

Acquired Resistance (cKp)

• Confer resistance to all penicillins and cephalosporins (including 3rd/4th generation)
• 25% of U.S. K. pneumoniae isolates are ESBL-producing (USNHSN 2015-2017 data); rates >50% in Asia, South America, Africa
• Most common: CTX-M ESBLs (plasmid-mediated, transferable)
• Key sequence type: ST16 (ESBL-producing; carbapenem-susceptible)
• Treatment: carbapenems are the drugs of choice for serious ESBL infections

• Confer resistance to all β-lactams including carbapenems
• Typically also resistant to multiple other drug classes via co-acquired plasmid resistance genes
• ~8.6% of U.S. K. pneumoniae are carbapenem-resistant (USNHSN 2015-2017)
• Key sequence type: ST258 - the most widely disseminated carbapenem-resistant clone globally

• Harrison's 22E; Current Surgical Therapy 14e

5. Treatment

Susceptible / ESBL-negative strains

• Carbapenems (meropenem, imipenem, ertapenem) - most reliable
• Piperacillin-tazobactam, cefepime (if not ESBL-producing)
• Fluoroquinolones, TMP-SMX (if susceptible)
• Amikacin

ESBL-producing strains

• Carbapenems remain drug of choice for serious infections
• Oral options are limited: fosfomycin (~80% susceptible), pivmecillinam, omadacycline (if tetracycline-susceptible)
• Note: nitrofurantoin has poor activity against Klebsiella (unlike against E. coli)

Carbapenem-Resistant K. pneumoniae (CR-Kp)

• Harrison's 22E; Harriet Lane Handbook 23e; Current Surgical Therapy 14e

Recent Evidence (2024-2025)

• "Hypervirulent and carbapenem-resistant K. pneumoniae: A global public health threat" (Lei TY et al., Microbiol Res, 2024 - PMID 39141971): documents the convergence of hvKp virulence with carbapenem resistance on transferable plasmids, creating MDR/XDR strains with catastrophic clinical outcomes.
• "ESKAPE pathogens: antimicrobial resistance, epidemiology, clinical impact and therapeutics" (Miller WR & Arias CA, Nat Rev Microbiol, 2024 - PMID 38831030): K. pneumoniae is a core ESKAPE pathogen; this review comprehensively addresses novel treatment options including phage therapy and monoclonal antibodies under investigation.
• "KPC variants: the new threat to global public health" (Ding L et al., Clin Microbiol Rev, 2023 - PMID 37937997): details >200 KPC variants, some with modified spectra evading even newer β-lactam/β-lactamase inhibitor combinations.

Levels of Hypoglycemia

ADA Three-Level Classification

• Barash, Cullen & Stoelting's Clinical Anesthesia 9e; Harrison's Principles of Internal Medicine 22E (2025)

Physiological Glucose Thresholds (Sequential)

• Goodman & Gilman's Pharmacological Basis of Therapeutics; Harrison's 22E

Symptoms by Level

Neurogenic / Autonomic Symptoms (Level 1-2, higher glucose threshold)

• Catecholamine-mediated: tremor, palpitations, anxiety, tachycardia
• Acetylcholine-mediated: diaphoresis (sweating), hunger, paresthesias

Neuroglycopenic Symptoms (Level 2-3, lower glucose threshold)

• Dizziness, difficulty concentrating, blurred vision
• Behavioral changes, irritability, confusion
• Weakness, drowsiness, slurred speech
• Seizure, coma, death (if severe and untreated)

Key point: In hypoglycemia unawareness (common in long-standing type 1 diabetes), the autonomic warning symptoms are blunted or absent. This is because the glucagon secretory response to hypoglycemia becomes deficient first, followed by loss of the epinephrine response. Patients then progress directly to neuroglycopenic symptoms with no warning. This is also seen with:

• β-adrenergic blockers (mask autonomic symptoms)
• Diabetic autonomic neuropathy
• Anesthetized/sedated patients (signs of sympathetic activation mimic "light anesthesia")

• Henry's Clinical Diagnosis and Management by Laboratory Methods; Goodman & Gilman's

Whipple's Triad (Diagnosis of Hypoglycemic Disorder)

1. Symptoms consistent with hypoglycemia
2. Documented low plasma glucose (≤55 mg/dL in non-diabetics)
3. Relief of symptoms with correction of the low glucose

• Henry's Clinical Diagnosis and Management by Laboratory Methods

Counterregulatory Response Summary

• Harrison's 22E; Lippincott Illustrated Reviews Biochemistry

Treatment by Level

In patients on β-blockers: glucagon is the preferred agent because it acts downstream of the β-receptor via cAMP.

In patients with long-standing diabetes: the glucagon response is often deficient, so epinephrine/IV glucose becomes the primary rescue.

• Barash, Cullen & Stoelting's Clinical Anesthesia 9e; Goodman & Gilman's

Common Causes (by Patient Context)

• Drugs: alcohol, quinolones, pentamidine, quinine, ACE inhibitors, β-blockers, sulfonamides
• Critical illness: hepatic/renal/cardiac failure, sepsis, inanition
• Hormone deficiency: cortisol (Addison's disease), growth hormone, glucagon + epinephrine deficiency
• Endogenous hyperinsulinism: insulinoma, nesidioblastosis, post-gastric-bypass hypoglycemia, insulin autoantibodies
• Non-islet cell tumors: large retroperitoneal sarcomas, hepatocellular carcinoma (via IGF-II)
• Prolonged fasting, starvation, pregnancy

ADA Standards of Care in Diabetes - 2026: Glucose Monitoring Guidelines

Source: ADA Standards of Care in Diabetes - 2026, published January 2026 in Diabetes Care, Supplement 1. This is the most current ADA guidance. The 2026 edition represents the strongest endorsement of diabetes technology the ADA has ever issued.

What's New in 2026 vs. 2025: Key Changes

Section 7: Blood Glucose Monitoring (BGM)

Core BGM Recommendations (2025/2026, still current)

• Fasting
• Before and after meals/snacks
• At bedtime and mid-night
• Before, during, and after exercise
• When hypoglycemia is suspected
• After treating a low, until normoglycemic
• Before performing critical tasks (e.g., driving) (Grade B)

BGM remains the fallback when CGM is unavailable, inaccurate, or during rapid glucose changes (>2 mg/dL/min), CGM warm-up, transmission disruptions, or calibration needs.

Section 7: Continuous Glucose Monitoring (CGM)

2026 Headline Recommendation

• Children, adolescents, and adults with diabetes
• Anyone on any insulin therapy
• Anyone on drugs that could cause hypoglycemia (e.g., sulfonylureas)
• Anyone for whom CGM data would aid management

This marks a significant expansion from 2025's language, which tied the recommendation more narrowly to insulin users.

CGM Device Types

For T2D not on insulin: RCT data consistently show CGM superiority over BGM for improving A1C, Time in Range (TIR), Time Below Range (TBR), and Time Above Range (TAR), as well as user satisfaction.

CGM in Pregnancy (New 2026 Expansion)

• CGM indication has expanded to include pregnancy for Dexcom G7, FreeStyle Libre 2, and FreeStyle Libre 3
• Benefits demonstrated in people with type 2 diabetes and gestational diabetes (GDM)
• Section 15 updated with RCT data supporting CGM preference and benefit in GDM

CGM Metrics: Time in Range (TIR) and CGM Targets

Benefits of CGM have been shown to be consistent regardless of age, sex, education level, income, or baseline diabetes characteristics.

Automated Insulin Delivery (AID) - Closely Linked to CGM

• Youth and adults with type 1 diabetes (Grade A)
• Other types of insulin-deficient diabetes (Grade E)
• Goal: improve glycemic outcomes, reduce hypoglycemia, reduce disparities

Inpatient Glucose Monitoring (Hospital Setting)

• The 20/20 criterion applies: CGM readings should be within ±20% of POC when blood glucose is ≥70 mg/dL, or within ±20 mg/dL when <70 mg/dL.

General Device Principles

• How to interpret CGM data
• Managing skin reactions
• Understanding factors that affect accuracy

Summary: Who Should Be on CGM per ADA 2026?

Antibiotics of Choice in Urosepsis

Core Principles (Surviving Sepsis Campaign 2026 + IDSA 2025)

1. Start antibiotics immediately - within 1 hour of septic shock recognition; within 3 hours for sepsis without shock. Every 1-hour delay in bacteremic septic shock increases mortality by ~7-8%.
2. Draw blood cultures before antibiotics (2 sets) - do not delay antibiotics to wait for results.
3. Urine culture + urinalysis before or at time of antibiotic initiation.
4. Reassess and de-escalate once culture/sensitivity results are available (typically 48-72 hrs).
5. Source control - if obstruction is present (stone, stricture, stent occlusion), relieve it urgently. An infected obstructed urinary tract requires drainage - antibiotics alone will not clear it.
6. Remove indwelling urinary catheters if catheter-associated infection is suspected.

IDSA 2025 Four-Step Approach to Empiric Antibiotic Selection

Empiric Antibiotic Choices

Standard Urosepsis (No Special Resistance Risk)

Goldman-Cecil Medicine: "Empiric treatment with piperacillin/tazobactam 3.375 g IV q6h or ceftriaxone 1-2 g IV q24h should be initiated promptly. Empiric treatment need not routinely include Pseudomonas coverage."

Urosepsis with Pseudomonas Risk

Urosepsis with ESBL Risk (High-Risk Empiric Broadening)

• Prior ESBL-positive culture
• Prior antibiotic use in last 3-6 months (especially cephalosporins, fluoroquinolones)
• Recent hospitalization / LTCF residence
• Travel to high-prevalence regions (Asia, South America, Africa)
• Recurrent UTIs
• Indwelling urinary devices

Recent meta-analysis (PMID 39173739): Carbapenems are superior to piperacillin-tazobactam for ESBL-producing Enterobacterales bloodstream infections - do not use pip-tazo empirically when ESBL is likely.

Urosepsis with Carbapenem-Resistant Organisms (CRO)

These newer BL/BLI combinations (ceftazidime-avibactam, meropenem-vaborbactam) are reserved for confirmed or strongly suspected carbapenem-resistant infections. Do not use empirically unless the patient has a prior documented CRO.

Summary Table: Empiric Choice by Patient Scenario

De-escalation (When Cultures Return)

• Narrow to the most targeted effective agent based on susceptibility
• Oral step-down is appropriate once: fever resolves, vitals normalize, oral intake tolerated, patient improving
• Oral options: ciprofloxacin, levofloxacin, TMP-SMX (if susceptible), amoxicillin-clavulanate

Duration of Therapy

• Uncomplicated urosepsis (pyelonephritis with bacteremia, source controlled): 7-10 days total (IV + oral)
• Complicated urosepsis (obstruction, abscess, instrumented tract): 10-14 days after source control
• Perinephric abscess: Drainage is the primary treatment; antibiotics continued until drainage complete and patient defervesces, typically 2-3 weeks total

Source Control - Non-Negotiable

• Relieve obstruction: ureteral stent or percutaneous nephrostomy for obstructing stones or strictures
• Remove infected catheter and replace if still needed
• Drain abscesses: percutaneous drainage for perinephric or prostatic abscess

Sources: Goldman-Cecil Medicine 2V Set; Harrison's Principles of Internal Medicine 22E (2025); IDSA 2025 Guideline on Complicated UTIs; Surviving Sepsis Campaign Adult Guidelines 2026