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Myelodysplastic Syndromes (MDS)

Definition

1. Ineffective hematopoiesis leading to peripheral blood cytopenias
2. Dysplastic maturation of one or more myeloid cell lines
3. High risk of transformation to AML (in 10-40% of cases)

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Epidemiology & Risk Factors

• Predominantly a disease of older adults (mean age at onset ~70 years); median age at diagnosis is in the seventh to eighth decade
• Affects approximately 15,000 people per year in the US - about as common as AML
• Slight male predominance

• Environmental: radiation, benzene, smoking
• Therapy-related (t-MDS): alkylating agents (busulfan, nitrosourea, procarbazine) - latency 5-7 years; topoisomerase II inhibitors - latency 2 years
• Preceding hematologic disease: acquired aplastic anemia, Fanconi anemia, paroxysmal nocturnal hemoglobinuria (PNH)
• Constitutional/germline mutations: GATA2 (MonoMAC syndrome), RUNX1, telomere gene mutations (consider in patients <40 years)
• Clonal hematopoiesis of indeterminate prognosis (CHIP) - common precursor, progresses to MDS at ~1% per year
• Harrison's 22E, p. 859-860

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Pathogenesis

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Presentation (Clinical Features)

Symptoms

• Anemia dominates the early course: fatigue, weakness, dyspnea, pallor (most common presentation)
• At least half of patients are asymptomatic, discovered incidentally on routine blood counts
• Infections from neutropenia (functional and/or quantitative)
• Bleeding/bruising from thrombocytopenia or platelet dysfunction
• Fever and weight loss are more suggestive of a myeloproliferative rather than myelodysplastic process

Physical Examination

• Signs of anemia (pallor, tachycardia)
• ~20% of patients have splenomegaly
• Associated autoimmune manifestations (Sweet's syndrome, arthritis)
• VEXAS syndrome should be considered when MDS coexists with inflammatory disease (UBA1 somatic mutation)
• Constitutional anomalies (short stature, abnormal thumbs) point to Fanconi anemia in younger patients
• Harrison's 22E, p. 860

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Classification

ICC (International Consensus Classification, 2022) Key Subtypes:

• Harrison's 22E, p. 859

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Investigations

1. Full Blood Count and Peripheral Blood Smear

• Anemia (usually macrocytic; can be normocytic or microcytic) - present in most cases
• Thrombocytopenia - large, hypogranular platelets with functional defects
• Neutropenia - neutrophils are hypogranulated, show hyposegmented nuclei (Pseudo-Pelger-Hüet cells), contain Döhle bodies
• Circulating myeloblasts (correlate with marrow blast count)
• Total WBC usually normal or low (except in CMML where monocytosis is prominent)
• Elevated RDW, poikilocytes, macroovalocytes

2. Bone Marrow Aspirate and Trephine Biopsy (Mandatory)

• Ring sideroblasts - erythroblasts with iron-laden mitochondria visible as perinuclear granules on Prussian blue stain
• Megaloblastoid maturation
• Nuclear budding abnormalities (multilobated or multiple nuclei)

• Decreased secondary granules
• Pseudo-Pelger-Hüet cells (bilobed nuclei)
• Neutrophils without nuclear segmentation
• Döhle bodies, toxic granulations

• Small megakaryocytes with single small nuclei (micromegakaryocytes)
• Large megakaryocytes with multiple separate nuclei ("pawn-ball" megakaryocytes)

3. Cytogenetics (Conventional Karyotype + FISH)

• Conventional karyotype on bone marrow aspirate: identifies chromosomal abnormalities in ~50% of cases
• Common: del(5q), del(7q), monosomy 7, monosomy 5, trisomy 8, del(20q)
• Complex karyotype (>3 abnormalities) = very poor prognosis, predicts AML evolution
• Several cytogenetic abnormalities provide presumptive evidence of MDS even when morphologic dysplasia is insufficient
• Copy number abnormalities detected by array CGH/SNP array

4. Molecular/Genomic Testing (Next-Generation Sequencing)

• Now routinely performed in MDS workup
• Detects mutations in SF3B1, TET2, DNMT3A, ASXL1, RUNX1, EZH2, TP53, SRSF2, U2AF1, IDH1/2
• Essential for ICC/WHO 2022 classification (molecularly defined subtypes)
• Prognostic IPSS-M (2022) incorporates molecular data
• Distinguish pathogenic mutations from CHIP and variants of uncertain significance

5. Additional Laboratory Tests

• Serum B12 and folate - to exclude megaloblastic anemia (essential differential)
• Serum vitamin B6 - trial of pyridoxine if ring sideroblasts present
• Copper levels - copper deficiency can mimic MDS
• Serum ferritin, LDH, β2-microglobulin - for IPSS-R scoring
• Serum EPO - important for treatment decisions (lower EPO predicts better response to ESAs)
• Flow cytometry - reveals aberrant hematopoietic differentiation; enumerates blasts; detects PNH clone
• Iron studies - assess iron overload from transfusions
• Thyroid function - in macrocytic anemia workup

6. Differential Diagnosis to Exclude

• Vitamin B12/folate deficiency
• Copper deficiency
• Hypothyroidism
• Drug effects (methotrexate, hydroxycarbamide, alcohol)
• Aplastic anemia (hypocellular MDS vs. aplastic anemia)
• PNH
• HIV infection
• Congenital dyserythropoietic anemias (in younger patients)

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Prognosis: IPSS-R Scoring

1. Marrow blast count categories (≤2%, >2-<5%, 5-10%, >10-30%)
2. Cytogenetic risk group (5 subgroups, 16 specific abnormalities)
3. Depth of cytopenias (Hb, neutrophil count, platelet count)
4. Age, performance status, serum ferritin, LDH, β2-microglobulin

• Very low / Low risk: years (up to >5 years for MDS-5q)
• Intermediate risk: ~3 years
• High / Very high risk: months (as low as <6 months for excess blasts with complex karyotype)

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Management

A. Low-Risk MDS (IPSS-R Low/Very Low/Intermediate)

• RBC transfusions for symptomatic anemia; accompanied by iron chelation (deferoxamine or deferasirox) to prevent secondary hemochromatosis
• Platelet transfusions for bleeding
• Antibiotic prophylaxis and prompt treatment of infections
• G-CSF for severe neutropenia

• EPO alone or with G-CSF improves Hb levels, particularly in patients with low serum EPO levels and low transfusion requirements
• Survival improved by EPO through amelioration of anemia
• G-CSF alone did not improve survival in controlled trials

• Inhibits TGF-β-mediated suppression of erythropoiesis
• FDA approved for anemia in low-risk MDS, particularly those with SF3B1 mutations
• Reduces transfusion burden

• Particularly effective in del(5q) MDS: ~67% achieve transfusion independence
• Remarkably, cytogenetics also normalize in many patients
• Oral administration; response usually within 3 months
• Toxicities: worsening thrombocytopenia/neutropenia, DVT/PE risk

• For younger patients (<60 years) with hypocellular marrow and HLA-DR15 positivity
• Antithymocyte globulin (ATG) + cyclosporine: ~50% response
• Alemtuzumab (anti-CD52 monoclonal antibody) also used
• Mimics the immunosuppressive approach used in aplastic anemia

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B. High-Risk MDS (IPSS-R High/Very High)

• Azacitidine (5-azacytidine): 75 mg/m² SC for 7 days every 4 weeks
  • Improves blood counts and survival vs. best supportive care
  • ~50% of patients show improved blood counts/decreased transfusion requirements
  • Requires minimum 4 cycles to assess response; continued administration needed
  • Superior to decitabine in improving overall survival in randomized trials
• Decitabine: 30-50% response rate, duration ~1 year; IV infusion over 3-10 days in repeating cycles
• Oral decitabine-cedazuridine: FDA approved for high-risk MDS (oral formulation with bioavailability comparable to IV)

• Only known curative treatment for MDS
• Survival ~50% at 3 years in selected patients
• Indications: younger patients, higher-risk IPSS-R, earlier in disease course
• Reduced-intensity conditioning (RIC) allows transplantation in older patients with acceptable toxicity; slightly higher relapse risk
• Unrelated matched donor results comparable to sibling donors
• The "transplant conundrum": high-risk patients most need it but tolerate it worst; low-risk patients tolerate it best but may do well for years with less aggressive therapy
• In reality, only a small proportion of MDS patients actually undergo transplantation
• Goldman-Cecil Medicine, p. 1908

• Ivosidenib (IDH1 inhibitor): FDA approved for MDS with IDH1 mutations
• Venetoclax (BCL2 inhibitor): FDA approved for AML; used in combination with HMAs in high-risk MDS (investigational)
• Enasidenib (IDH2 inhibitor): used in IDH2-mutated MDS

• Considered for eligible patients as a bridge to transplant
• AML-type induction regimens (cytarabine + anthracycline) - responses are generally poor and not durable
• MDS is regarded as particularly refractory to cytotoxic regimens

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C. Novel/Emerging Therapies (Trials)

• TP53 inhibitors (targeting TP53-mutant MDS)
• Splicing factor mutation-targeted agents
• Inflammasome inhibitors / IL-1 receptor-associated kinase (IRAK) inhibitors
• Imetelstat (telomerase inhibitor) - phase III trials underway
• HMA + venetoclax combinations
• Likely future: HMA monotherapy will be replaced by HMA combination regimens

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Summary Algorithm

MDS diagnosed
      |
   Risk stratification (IPSS-R / IPSS-M)
      |
   Low/Intermediate risk          High risk
      |                                |
  - Supportive care             - Consider allo-HSCT
  - ESAs (if low EPO)             (if eligible: younger, fit,
  - Luspatercept (SF3B1+)          suitable donor)
  - Lenalidomide (5q del)                |
  - Immunosuppression             Not eligible for transplant
    (hypocellular, young)                |
                               - Hypomethylating agents
                                 (azacitidine preferred)
                               - Targeted agents (IDH1/2 i)
                               - Clinical trials
                               - Supportive care

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Key Points to Remember

1. MDS is primarily a disease of the elderly (median age 70); cytopenias with hypercellular marrow is the paradox
2. Bone marrow biopsy with cytogenetics and molecular testing is mandatory for diagnosis and classification
3. Pseudo-Pelger-Hüet cells and ring sideroblasts are classic peripheral blood/marrow findings
4. del(5q) syndrome responds strikingly to lenalidomide; SF3B1 mutations predict ring sideroblasts and favorable prognosis; TP53 mutations predict very poor outcomes
5. Azacitidine is the standard first-line disease-modifying agent for high-risk MDS ineligible for transplant
6. Allo-HSCT is the only cure; few patients are candidates
7. Most patients die from complications of pancytopenia (infection, bleeding), not AML transformation
8. Transformation to AML occurs in 10-40% of cases

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• Harrison's Principles of Internal Medicine 22E (2025), Chapter 107
• Robbins, Cotran & Kumar Pathologic Basis of Disease, Chapter 13
• Robbins & Kumar Basic Pathology, Chapter 10
• Goldman-Cecil Medicine, Chapters 167 & 168
• Henry's Clinical Diagnosis and Management by Laboratory Methods, Chapters 9 & 33

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Polyglandular Autoimmune (PGA) Deficiency Syndromes

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Overview and Classification

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APS Type 1 (APECED)

Genetics and Pathogenesis

• Caused by inactivating mutations in the AIRE gene (Autoimmune REgulator), chromosome 21q22 - over 100 mutations described
• AIRE is expressed in thymic medullary epithelial cells (mTECs), where it drives expression of tissue-specific self-antigens (e.g., insulin) to enable central T-cell tolerance (negative selection of autoreactive T cells)
• Without AIRE, autoreactive T cells escape to the periphery and destroy target organs
• Autoantibodies to type I interferons (IFN-α, IFN-ω) are a diagnostic hallmark - present in nearly 100% of cases regardless of AIRE mutation type, and not found in other autoimmune disorders
• Autoantibodies to IL-17 and IL-22 explain the susceptibility to mucocutaneous candidiasis, as these Th17 cytokines are critical for antifungal defense
• Higher frequency in Sardinians, Finns, Iranian Jews, Norwegians, and Irish (founder mutations)
• A non-classical autosomal dominant form (PHD1 domain mutations) has been described with later onset and incomplete expression
• Harrison's 22E, p. 3132; Robbins & Kumar Pathologic Basis of Disease, p. 2703

Classic Triad (diagnostic criteria: any 2 of 3)

1. Chronic mucocutaneous candidiasis (CMC) - virtually always first, affects mouth and nails > skin and esophagus
2. Hypoparathyroidism (>85% of cases) - typically second manifestation
3. Addison's disease (autoimmune adrenal insufficiency, ~80%) - typically third

Full Clinical Manifestations of APS-1

• Hypoparathyroidism: >85%
• Addison's disease: ~80%
• Gonadal failure (premature ovarian failure): 70% of women (secondary amenorrhea), 25% of men
• Dental enamel hypoplasia: 77%
• Type 1 diabetes mellitus: 23%
• Autoimmune thyroid disease: 18%

• Alopecia: 40%
• Pernicious anemia: 31%
• Vitiligo: 26%
• Intestinal malabsorption/steatorrhea: ~18-20% (caused by autoantibody-mediated destruction of enteroendocrine cells producing CCK; anti-tryptophan hydroxylase antibodies against enterochromaffin cells)
• Chronic active hepatitis: 17%
• Nail dystrophy
• Ectodermal dysplasia: enamel hypoplasia, nail dystrophy, tympanic membrane calcification
• Ocular complications: keratitis, blepharitis, corneal opacities, retinitis, ptosis
• Cerebellar ataxia
• Asplenism (Howell-Jolly bodies on peripheral blood smear) - unique to APS-1
• Autoimmune pneumonitis (up to 40% - underrecognized)
• Obstructive respiratory disease
• Vitamin B12 malabsorption (autoimmune gastritis)
• IgA deficiency
• Goldman-Cecil Medicine, p. 2502; Harrison's 22E, p. 3133

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APS Type 2 (Schmidt Syndrome)

Genetics and Pathogenesis

• Polygenic disorder - most common genetic locus: HLA B8, DR3, DR4
• Additional susceptibility genes: CTLA-4 (cytotoxic T-lymphocyte antigen-4), MICA allele 5.1, STAT4, GATA3, PTPN22 (encodes lymphoid tyrosine phosphatase - a variant is enriched in families with T1D + autoimmune thyroid disease)
• Genome-wide association studies (GWAS) have identified numerous additional susceptibility loci
• HLA associations do not predict disease absolutely, even in identical twins - environmental and other genetic factors also influence expression

Classic Components

1. Addison's disease (autoimmune adrenal insufficiency) - the anchor diagnosis
2. Autoimmune thyroid disease (Hashimoto's thyroiditis or Graves' disease)
3. Type 1 diabetes mellitus

• Addison's disease is present in APS-2 but NOT in APS-3
• Mucocutaneous candidiasis, ectodermal dysplasia, and hypoparathyroidism do NOT occur in APS-2

Additional Associations

• Primary hypogonadism
• Hypophysitis (autoimmune)
• Pernicious anemia
• Vitiligo
• Celiac disease / dermatitis herpetiformis
• Alopecia
• Myasthenia gravis (unique to APS-2; not seen in APS-1)
• IgA deficiency
• Idiopathic thrombocytopenia
• Parkinson's disease
• Goldman-Cecil Medicine, p. 2502-2503; Harrison's 22E, p. 3133

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APS Type 3

• Autoimmune thyroid disease (Hashimoto's thyroiditis or Graves') + another autoimmune condition
• BUT without Addison's disease (the key distinction from APS-2)
• Also called "Multiple Autoimmune Syndrome type 3"
• Associated non-thyroid autoimmune disorders: T1D, pernicious anemia, vitiligo, alopecia, celiac disease, myasthenia gravis, chronic active hepatitis, IgA deficiency
• An expanding category - additional autoimmune manifestations involving GI tract, pancreas, skin, heart, hepatobiliary system, nervous system, and hematologic system

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APS Type 4

• Combination of T1D, pernicious anemia, alopecia, vitiligo, or neuromuscular junction disorder
• Without Addison's disease, thyroid disease, or hypoparathyroidism
• Substantial proportion have anti-GAD (glutamic acid decarboxylase) antibodies
• Rare variant

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Comparison: APS-1 vs. APS-2

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Other Related Syndromes

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Investigations

Diagnostic Autoantibodies

Clinical Investigations

• APS-1 specific: AIRE gene mutation analysis + anti-IFN-α/ω antibodies (near 100% sensitivity)
• Endocrine workup:
  • Morning cortisol + ACTH stimulation test (Addison's)
  • Serum calcium, PTH (hypoparathyroidism)
  • TSH, free T4, T3 (thyroid disease)
  • Fasting glucose, HbA1c, C-peptide (T1D)
  • LH, FSH, oestradiol/testosterone (gonadal failure)
• Monitoring for complications:
  • FBC (pernicious anemia, asplenism)
  • Vitamin B12
  • Fecal fat / anti-tissue transglutaminase (malabsorption)
  • LFTs + anti-smooth muscle / LKM antibodies (autoimmune hepatitis)
  • Echocardiogram (cardiac involvement in POEMS)

Key Diagnostic Pitfalls

• Thyroid hormone replacement in a patient with undiagnosed Addison's disease can precipitate an adrenal crisis by accelerating cortisol metabolism - always screen for adrenal insufficiency before starting thyroxine in hypothyroid patients with autoimmune disease
• Combinations of hypothyroidism + adrenal insufficiency + hypogonadism can mimic hypopituitarism - hormonal testing easily distinguishes
• Components appear asynchronously over years - periodic re-screening is mandatory
• APS-1 siblings should be screened even if only one component disorder is detected

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Management

APS-1

• Topical ketoconazole (1-2 weeks) for mild disease
• Oral itraconazole solution for refractory or esophageal disease
• Long-term antifungal prophylaxis often required (chronic oral candidiasis risks leukoplakia and squamous carcinoma)

• Oral elemental calcium: 500-1000 mg every 6-12 hours
• Active vitamin D: calcitriol (1,25-dihydroxyvitamin D) 0.25-2 mcg/day
• Goal: serum calcium in low-normal range (8.0-8.5 mg/dL) to minimize renal stone risk
• Synthetic PTH (1-84) 50-100 mcg SC daily: reduces required doses of calcium and vitamin D
• Intestinal malabsorption complicates management

• Glucocorticoid replacement: hydrocortisone 15-25 mg/day (typically 10mg on waking + 5mg early afternoon) OR cortisone acetate
• Mineralocorticoid replacement: fludrocortisone 0.05-0.2 mg/day
• Sick-day rules: double/triple dose during illness; parenteral hydrocortisone for vomiting/surgery

• HRT (women): combined oestrogen/progesterone until age of natural menopause
• Testosterone replacement (men)

• JAK inhibitors: IFN-γ plays a role in APS-1 organ destruction; ruxolitinib (JAK1/2 inhibitor) has shown early promise in clinical studies for APS-1 (NEJM 2024, [PMID 38810185])
• Targeting the IFN-γ pathway may alter the autoimmune disease course

APS-2, 3, and 4

• Treatment of each component is identical to the sporadic disease in isolation
• No disease-modifying therapy targeting the underlying polyglandular autoimmunity exists
• Regular screening for other components is the cornerstone of management

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Screening and Surveillance Recommendations

• Annual: fasting glucose, calcium, cortisol/ACTH stimulation, thyroid function, LFTs, FBC, B12
• Antibody surveillance: anti-21-hydroxylase, anti-thyroid, anti-GAD, anti-gonadal antibodies
• Periodic ophthalmologic assessment (corneal complications)
• Upper GI endoscopy if dysphagia (esophageal candidiasis or stricture)

• Every patient with autoimmune hypothyroidism should have careful assessment for adrenal insufficiency (family history, symptoms, low-threshold testing with short Synacthen test)
• Annual screening: fasting glucose, morning cortisol, thyroid function, anti-21-hydroxylase, anti-GAD, anti-TPO antibodies
• Family members: HLA typing and antibody screening in first-degree relatives

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Prognosis

• APS-1: Prognosis of each individual component disorder is similar to its sporadic counterpart; early detection via surveillance improves outcomes. Long-term risks include oral carcinoma (from chronic candidiasis) and complications of poorly treated Addison's disease
• APS-2/3/4: Prognosis of individual components is the same as for their sporadic versions; however, cumulative burden from multiple endocrine deficiencies can reduce quality of life significantly
• Therapy-related APS (from immune checkpoint inhibitors used in cancer therapy) increasingly recognized - similar components but in a specific clinical context

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• Harrison's Principles of Internal Medicine 22E (2025), Chapter 401
• Goldman-Cecil Medicine, Chapter 212
• Robbins, Cotran & Kumar Pathologic Basis of Disease, Chapter 11
• Frameworks for Internal Medicine, Chapter on Adrenal Insufficiency
• Sleisenger & Fordtran's Gastrointestinal and Liver Disease, Chapter 104

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Biological Warfare and Bioterrorism

Definition

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Historical Context

• Plague was weaponized by the Japanese before World War II (infected fleas released in Chinese cities)
• The former Soviet Union maintained large biological weapons arsenals (including plague, smallpox, anthrax)
• The 2001 anthrax letter attacks in the United States (22 cases, 5 deaths) demonstrated the potential for mail-based delivery
• Unaccounted-for vials of variola (smallpox) found in US laboratories raise ongoing concerns
• From 1981-2018, at least 37 bioterrorist attacks occurred worldwide

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CDC Classification of Bioterrorism Agents

Category A - Highest Priority

• Can be easily disseminated or transmitted from person to person
• Cause high mortality
• Have potential to cause public panic and social disruption
• Require special public health preparedness actions
• Can be formulated as stable aerosols for efficient spread

1. Anthrax (Bacillus anthracis)
2. Smallpox (variola virus)
3. Plague (Yersinia pestis)
4. Tularemia (Francisella tularensis)
5. Botulism (botulinum toxin, Clostridium botulinum)
6. Viral hemorrhagic fevers (Ebola, Marburg, Lassa, Machupo, etc.)

Category B - Second Highest Priority

• Moderately easy to disseminate
• Cause moderate morbidity and low mortality
• Require specific diagnostic capacity and surveillance
• Examples: Brucellosis, Q fever, glanders, melioidosis, Vibrio cholerae, ricin toxin, Salmonella, E. coli O157:H7, Staphylococcal enterotoxin B, Venezuelan equine encephalitis

Category C - Emerging Threats

• Emerging pathogens that could be engineered for mass dissemination
• Available, easily produced, high potential for morbidity and mortality
• Examples: Nipah virus, hantavirus, novel influenza strains, Zika virus

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Epidemiologic Clues to a Bioterrorism Attack

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Category A Agents: Detailed Clinical Profiles

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1. ANTHRAX (Bacillus anthracis)

Three Clinical Forms:

• Painless pruritic papule → vesicle → central black eschar (anthrakis = coal in Greek) with surrounding disproportionate edema
• Case-fatality rate: 20% if untreated

• Incubation: average 1-6 days (can be up to 43 days)
• Prodrome (1-3 days): fever, profound drenching sweats, nausea, vomiting, diarrhea, cough, chest pain
• Rapid deterioration: increasing dyspnea, stridor, cyanosis, respiratory failure
• Hallmark: widened mediastinum on CXR (~60% of cases) from hemorrhagic mediastinitis
• Large hemorrhagic pleural effusions and infiltrates
• Bacteremic seeding of GI tract and meninges
• Untreated case-fatality rate: approaches 100%

• Fever, abdominal pain, diarrhea, hematochezia, hematemesis, ascites
• Paracentesis: hemorrhagic ascites
• Case-fatality rate: 50% or more

1. Ciprofloxacin 400 mg q8h IV (or levofloxacin 750 mg q24h, or moxifloxacin 400 mg q24h)
2. + Meropenem 2 g q8h IV (or imipenem 1 g q6h, or doripenem 500 mg q8h)
3. + Linezolid 600 mg q12h (or clindamycin 900 mg q8h, or rifampin 600 mg q12h)

• Fluoroquinolone or carbapenem or vancomycin + clindamycin or linezolid or doxycycline

• Raxibacumab (monoclonal antibody, 40 mg/kg IV) - also licensed for prophylaxis
• Obiltoxaximab - second licensed monoclonal antibody
• Anthrax antitoxin (equine heptavalent)
• Pleural fluid drainage (improves survival)

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2. SMALLPOX (Variola virus)

• Incubation: 7-17 days (usually 12-14)
• Prodrome (2-3 days): sudden onset fever (38-40°C), headache, backache (prominent), vomiting, prostration
• Rash (centrifugal - face and extremities > trunk): synchronous progression in ALL lesions simultaneously:
  • Macules → papules (day 1-2) → vesicles (day 4-5) → umbilicated pustules (day 7) → scabs (day 14)
  • Lesions are deep-seated, painful
  • All in same stage of development at any time point
• Contagious from onset of rash until all scabs have separated

• Hemorrhagic smallpox / flat-type smallpox: case-fatality rate approaches 100%
• Variola minor: mild variant, CFR ~1%
• Variola major (typical): CFR ~30%

• Primary: supportive care
• Tecovirimat (600 mg orally q12h × 14 days) - FDA approved for all poxvirus infections; in strategic national stockpile
• Brincidofovir (4 mg/kg once weekly × 2 doses, max 200 mg) - oral cidofovir analog; FDA approved

• Vaccinia virus-based vaccine (ACAM2000) stockpiled for entire US population
• Post-exposure vaccination within 4 days can prevent or ameliorate disease
• Ring vaccination (surveillance + containment strategy used during eradication)
• Contraindications: immunocompromised, eczema, significant exfoliative skin disease

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3. PLAGUE (Yersinia pestis)

• Swollen, extremely tender lymph nodes (bubo) - most commonly inguinal/femoral
• Fever, headache, malaise
• Can progress to septicemic plague
• Necrosis of nose, ears, digits (temperature-dependent coagulase = "Black Death" appearance)
• Untreated CFR: ~50%

• Clusters of multiple patients with hemoptysis (purulent → hemorrhagic sputum)
• Human-to-human transmission by respiratory droplets
• Untreated CFR: nearly 100%

• Streptomycin 1 g IM BD × 7-10 days (preferred if available)
• Gentamicin 5 mg/kg/day IV/IM
• Ciprofloxacin 400 mg q12h IV, or doxycycline 200 mg then 100 mg q12h, or levofloxacin 500 mg q24h

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4. TULAREMIA (Francisella tularensis)

• Incubation: 2-10 days
• Six clinical forms; most relevant after aerosol release: pneumonic and typhoidal forms (analogous to plague)
• Fever, severe exhaustion, substernal chest pain, nonproductive cough, weight loss
• Glandular form resembles bubonic plague

• Streptomycin or gentamicin × 7-10 days (drugs of choice)
• Ciprofloxacin (newer alternative)
• Doxycycline/tetracycline - second-line (higher relapse rate)
• CFR: 30% untreated; <1% with treatment

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5. BOTULISM (Botulinum toxin, Clostridium botulinum)

• Latent period: hours to several days
• Cranial nerve involvement first: ptosis, blurred vision, diplopia, photophobia, dry mouth
• Descending symmetrical flaccid paralysis (cranial → neck → arms → respiratory muscles → legs)
• Dysphonia, dysphagia
• Death from respiratory muscle failure
• Not contagious (standard precautions only)

• Supportive care (ventilatory support - may last months)
• Heptavalent botulinum antitoxin (HBAT, serotypes A-G): halts but does NOT reverse paralysis - give as soon as possible
• No antimicrobials needed (toxin-mediated, not infectious)

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6. VIRAL HEMORRHAGIC FEVERS (VHF)

• Febrile illness with malaise, myalgias, headache, vomiting, diarrhea
• Hemorrhagic features (massive hemorrhage in <50%): purpura, petechiae, mucosal bleeding
• Hypotension, shock
• Multiorgan failure

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Category B and C Agents: Summary

Key Category B Agents

Category C Examples

• Nipah virus (>75% CFR in some outbreaks)
• Hantavirus (Sin Nombre)
• Novel respiratory pathogens (engineered influenza)
• Zika virus

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General Principles of Response

Immediate Clinical Response

1. Recognize unusual presentations or disease clustering
2. Isolate the patient with appropriate precautions (see individual agent above)
3. Notify immediately:
   • Hospital infection control
   • Local/state public health department
   • CDC Emergency Operations Center: 770-488-7100
   • FBI (if criminal act suspected)
4. Collect specimens before starting treatment if possible
5. Treat empirically while awaiting results - delays are fatal

Post-Exposure Prophylaxis Overview

Decontamination

• Biological agents are generally removed by soap and water
• Remove and bag clothing
• Universal precautions during decontamination
• Pediatric decontamination with family unit where possible

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Smallpox vs. Chickenpox: Key Differentiating Points

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Principles of Preparedness

1. Maintain high clinical suspicion for unusual disease presentations
2. Know your local reporting chain - physicians are first responders
3. Laboratory notification is critical for dangerous organisms (F. tularensis, Y. pestis)
4. Strategic national stockpile (SNS) contains antibiotics, antitoxins, vaccines for mass casualty response
5. Ring vaccination remains the containment strategy of choice for smallpox
6. Infection control measures are agent-specific and must be applied rapidly

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• Goldman-Cecil Medicine, Chapter 19 (Kortepeter & Cieslak) - Primary source
• Parikh's Textbook of Medical Jurisprudence, Forensic Medicine and Toxicology, Chapter 47
• Robbins, Cotran & Kumar Pathologic Basis of Disease, Chapter 8
• Jawetz, Melnick & Adelberg's Medical Microbiology, Chapter on Bioterrorism Agents
• CDC Bioterrorism Diseases/Agents List
• USAMRIID's Medical Management of Biological Casualties Handbook, 9th ed., 2020

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Opioid-Related Disorders

Classification (DSM-5)

1. Opioid Use Disorder (OUD)
2. Opioid Intoxication
3. Opioid Withdrawal
4. Opioid-Induced Disorders (intoxication delirium, psychotic disorder, mood disorder, sleep disorder, sexual dysfunction)
5. Unspecified Opioid-Related Disorder

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Epidemiology and the Opioid Crisis

1. 1999-2010: Increased prescription opioids (peak oxycodone/hydrocodone sales in 2012); aggressive pharmaceutical marketing; overprescribing of extended-release oxycodone
2. From 2010: Rise in heroin overdose deaths (as prescription opioids became restricted)
3. From 2013: Surge in synthetic opioids - particularly fentanyl (50-100× more potent than morphine, 10× more potent than heroin) and fentanyl analogues, now the leading driver of overdose deaths

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Neuropharmacology

• Pain pathways: strong analgesia
• Reward pathway: euphoria and liability for misuse
• Respiratory center: inhibition - risk of lethal overdose
• Locus coeruleus: inhibition of noradrenergic tone (withdrawal symptoms result from rebound hyperactivity)

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1. Opioid Use Disorder (OUD)

DSM-5 Diagnostic Criteria

• Mild: 2-3 criteria
• Moderate: 4-5 criteria
• High: ≥6 criteria

• Kaplan & Sadock's Comprehensive Textbook of Psychiatry, p. 4258

Specifiers

• In early remission: 3-12 months without criteria (except craving)
• In sustained remission: ≥12 months without criteria
• On maintenance therapy (methadone/buprenorphine)
• In a controlled environment

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2. Opioid Intoxication

• Recent opioid use
• Classic triad:
  1. Miosis (pinpoint pupils) - bilateral, symmetric
  2. CNS depression - drowsiness, stupor, coma ("on the nod")
  3. Respiratory depression - reduced rate and depth, apnea
• Additional features: slurred speech, psychomotor retardation, impaired attention and memory, bradycardia, hypotension, hypothermia, decreased bowel sounds, urinary retention
• Maladaptive behavioral changes: euphoria followed by apathy, dysphoria, psychomotor retardation

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3. Opioid Withdrawal

Mechanism

Withdrawal Symptoms and Signs

Onset and Duration by Opioid

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Opioid Overdose - Clinical Emergency

Classic Triad (Toxidrome)

1. Coma / CNS depression (unresponsive, stupor)
2. Miosis (pinpoint pupils, bilateral)
3. Respiratory depression (rate <12/min, shallow, apnea)

Immediate Management

1. Airway - open airway, clear secretions; insert oral/nasal airway; intubate if needed
2. Ventilation - bag-mask ventilation until naloxone takes effect
3. Naloxone (Narcan) - competitive MOR antagonist:
   • IV: 0.4-2 mg IV, titrate to adequate respiration (not full reversal - prevents precipitated withdrawal)
   • Initial dose: ~0.8 mg per 70 kg body weight; repeat every few minutes
   • Nasal spray: 4 mg intranasal (2 mg/mL has similar efficacy to 2 mg IM)
   • Signs of response: increased respiratory rate + pupillary dilation
   • Duration of naloxone (1-2 hours) is shorter than most opioids - re-dosing or infusion required
   • If no response after 4-5 mg: consider non-opioid causes of CNS depression
   • Caution: In opioid-dependent patients, excessive naloxone precipitates severe withdrawal
4. Monitor - continue monitoring for re-narcotization (especially with long-acting opioids like methadone, fentanyl)
5. IV access - dextrose if hypoglycaemia possible; thiamine
6. Fentanyl overdose: may require multiple or higher doses of naloxone due to potency and kinetics

• History of overdose
• History of substance use disorder
• Opioid dose ≥50 morphine milligram equivalents (MME)/day
• Concurrent benzodiazepine use
• Recently released from incarceration or completed detoxification (lost tolerance)
• Miller's Anesthesia 10e, p. 2884; Kaplan & Sadock's Synopsis, p. 930

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Laboratory and Investigations

Urine Drug Testing (UDT)

• Drug metabolites first detectable 3-6 hours after use
• Saliva testing: similar sensitivity to urine; potentially shorter detection window
• Hair testing: detects longer-term use (months)
• No biomarker currently exists to diagnose OUD
• Kaplan & Sadock's Comprehensive Textbook, p. 4258

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Management of Opioid Use Disorder

Treatment Goals (not uniform - individualized)

• Protection against overdose and death
• Cessation of illicit opioid use
• Elimination of craving and withdrawal
• Improvement in physical and psychological health
• Eventual abstinence (long-term recovery goal)
• Harm reduction (immediate realistic goal)

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A. Medications for OUD (MOUD) / Medication-Assisted Treatment (MAT)

1. METHADONE (Full MOR Agonist)

• Starting dose: 20-30 mg oral (to avoid oversedation)
• Increase by 10 mg/day based on response
• Optimal maintenance dose: 60-120 mg/day (doses >60 mg show significantly improved outcomes)
• Available as: oral solution (primary), tablets, injectable

• QT prolongation - screen ECG before starting and monitor (particularly at doses >100 mg/day or with other QT-prolonging drugs)
• Constipation, excessive sweating
• Decreased libido and sexual dysfunction (reduces testosterone and FSH)
• Sleep abnormalities (insomnia, nightmares - often during first months)
• Sedation, respiratory depression (risk with rapid dose escalation)
• Drug interactions (CYP3A4): rifampin, phenytoin, carbamazepine, darunavir, efavirenz → decrease methadone levels → withdrawal; fluconazole/ketoconazole → increase levels → toxicity

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2. BUPRENORPHINE (Partial MOR Agonist)

• Partial agonist at MOR - produces agonist effects at lower doses, then ceiling effect on respiratory depression (→ safer margin than methadone)
• Very high affinity for MOR - displaces other opioids; blocks effects of heroin
• If given while patient is opioid-dependent, displaces current agonist → precipitated withdrawal
• Low dissociation from receptor → long duration of action

• Naloxone has low oral bioavailability (1-3%) - when taken sublingual, it has minimal systemic effect
• If tampered with and injected, naloxone becomes bioavailable → precipitates withdrawal in opioid-dependent users → deters diversion

• Induction: Patients must be in mild-moderate withdrawal (COWS score ≥8-12) before first dose to avoid precipitating withdrawal
• Starting dose: 2-4 mg sublingual; titrate up by 2 mg every 1-2 hours as tolerated to 8 mg on day 1
• Maintenance: typically 12-24 mg/day; max 24 mg/day (sublingual)

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3. EXTENDED-RELEASE NALTREXONE (Full MOR Antagonist)

• Oral naltrexone: 50 mg daily or 100/100/150 mg Mon/Wed/Fri (poor adherence)
• Extended-release IM naltrexone (Vivitrol): 380 mg IM every 4 weeks; more than double the success rate of oral naltrexone

• Patient must be fully opioid-free for 7-10 days (short-acting opioids) or longer (methadone 7-14 days minimum)
• Urine drug screen must be negative
• Naloxone challenge test (0.8-1.2 mg IM naloxone) to confirm no residual physical dependence before initiating full dose

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Summary Table: MOUD Comparison

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B. Management of Acute Opioid Withdrawal (Detoxification)

• Transfer to methadone 20-30 mg oral, reduce by 20%/day
• Or buprenorphine 2 mg sublingual (titrate to 8 mg day 1), then gradual taper
• Most common and effective approach

• Clonidine 0.1-0.3 mg orally every hour (up to 4 doses); off-label; reduces autonomic symptoms (rhinorrhea, lacrimation, tachycardia, hypertension) but does NOT relieve aches or craving
• Lofexidine (Lucemyra) 3.2 mg/day in 4 divided doses - FDA-approved specifically for opioid withdrawal; similar to clonidine
• Key side effect: postural hypotension
• Adjuncts for symptom relief: loperamide (diarrhea), NSAIDs/acetaminophen (myalgia), antiemetics (nausea), benzodiazepines (anxiety/insomnia - use cautiously)

• Acupuncture, transcranial magnetic stimulation, auricular vagus nerve stimulation - not yet validated for clinical use

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C. Psychosocial Interventions

• Structured, goal-oriented; addresses drug use as learned behavior
• Teaches coping skills and cognitive strategies; evidence for effectiveness in OUD
• Reduces HIV risk behaviors; particularly effective in patients with comorbid depression
• Works synergistically with pharmacotherapy

• Tangible rewards (vouchers, not cash) for positive behaviors (abstinence, treatment attendance, medication adherence)
• Requires monitored urine collection; objective index of progress

• Peer support; spirituality-based; widely available; observational evidence of benefit
• Limitation: emphasizes abstinence from all psychoactive substances → patients on opioid agonists may be ostracized
• Methadone Anonymous (MA): 12-step variant specifically for patients on methadone

• Regular counseling reduces illicit drug use; quality of counselor-patient relationship significantly impacts outcomes

• Improves medication compliance; enhances treatment outcomes

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D. Harm Reduction Strategies

• Needle/syringe exchange programs - reduce HIV, hepatitis B and C transmission
• Naloxone co-prescription and distribution to patients and families
• Supervised consumption sites (available in Canada, some European countries)
• Fentanyl test strips - allow users to test drugs for fentanyl contamination
• Treatment of infectious complications: hepatitis C (highly curable with DAA therapy), HIV treatment with ART, endocarditis management, skin abscess care

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Comorbidities

• ~70% of men and ~75% of women with lifetime OUD have an additional psychiatric disorder
• Most common: mood disorders (depression, bipolar), antisocial personality disorder, anxiety disorders, alcohol use disorder
• OUD + depression → CBT or supportive psychotherapy superior to drug counseling alone

• Infectious: HIV, hepatitis B and C, tuberculosis, endocarditis (especially tricuspid), septic arthritis, skin abscesses, necrotizing fasciitis
• Pulmonary: aspiration pneumonia, tuberculosis, pulmonary hypertension (talc granulomas)
• Vascular: deep vein thrombosis, thrombophlebitis, pseudoaneurysms
• Neurological: cerebral abscess, meningitis, myelopathy

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Opioid-Induced DSM-5 Disorders (Separate Diagnoses)

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Special Populations

• Methadone or buprenorphine (without naloxone) are recommended - do NOT abruptly withdraw (risk of fetal distress and preterm labour)
• Neonatal opioid withdrawal syndrome (NOWS/NAS) is expected and manageable - NOT an indication to withhold MOUD
• Naltrexone: insufficient safety data; generally avoided
• Breastfeeding: methadone and buprenorphine compatible with breastfeeding (minimal transfer)

• Period of extremely high overdose risk (lost tolerance to opioids)
• Naloxone rescue kits should be provided; MOUD should be initiated before release

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Prognosis and Relapse Prevention

• Detoxification alone has high relapse rates - without MOUD, most patients relapse within days to weeks
• Protracted withdrawal syndrome (anxiety, insomnia, drug craving) persists for up to 6 months after acute withdrawal
• Long-term MOUD reduces mortality (methadone reduces all-cause mortality during treatment; risk increases when treatment is stopped)
• OUD is a chronic relapsing condition - relapses are expected and should not end treatment
• 2026 JAMA review (Harris et al., PMID 41671014) provides updated guidance on medications for OUD, opioid withdrawal, and opioid overdose

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• Kaplan & Sadock's Synopsis of Psychiatry, Chapter 4
• Kaplan & Sadock's Comprehensive Textbook of Psychiatry, Chapters 11.9 and Treatment of OUD
• Goodman & Gilman's The Pharmacological Basis of Therapeutics, Chapter 28
• Tintinalli's Emergency Medicine, Chapter 24
• Miller's Anesthesia 10e, Chapter 46
• Adams & Victor's Principles of Neurology 12e

• Harris MTH et al. Medications for OUD, withdrawal, and overdose: A Review. JAMA 2026 Mar. [PMID 41671014]
• Yakovenko I et al. Management of OUD: 2024 update to the national clinical practice guideline. CMAJ 2024 Nov. [PMID 39532476]
• Englander H et al. Caring for hospitalized adults with OUD in the era of fentanyl. JAMA Intern Med 2024. [PMID 38683591]

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Oncologic Emergencies

Classification

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1. Superior Vena Cava Syndrome (SVCS)

Causes

• Malignant (~60%): Lung cancer (particularly SCLC and squamous cell histology) accounts for ~85% of malignant SVCS; lymphoma (Hodgkin's involves mediastinum more commonly but rarely causes SVCS); metastatic disease (testicular, breast)
• Benign (~40%): Intravascular devices (central venous catheters, pacemaker/defibrillator leads), aortic aneurysm, fibrosing mediastinitis, thyromegaly, Behçet's syndrome
• Young man + mediastinal mass = lymphoma vs. primary mediastinal germ cell tumor

Clinical Features

• Facial and neck swelling (especially periorbital, worsened when supine)
• Dyspnea, cough
• Dilated neck veins and collateral chest wall veins
• Cyanosis and edema of face, arms, and chest
• Hoarseness, tongue swelling, nasal congestion, epistaxis, hemoptysis, dysphagia, headache, dizziness, syncope
• Severe: proptosis, glossal/laryngeal edema, obtundation (signs of cerebral edema - poorer prognosis)
• Bending forward or lying down worsens symptoms
• Symptoms are usually progressive but may improve as collateral circulation develops

Investigations

• CXR: Widening of superior mediastinum (right side most common); pleural effusion in 25% (often exudative, right-sided)
• CT chest (contrast): Most reliable - shows mediastinal anatomy, site of obstruction, collateral vessels, identifies tissue biopsy site
• Venography: useful for planning endovascular intervention
• Tissue diagnosis (if not already established): bronchoscopy, CT-guided biopsy, mediastinoscopy, thoracotomy

Treatment

1. Airway emergency: head elevation, O2, diuretics, low-salt diet; glucocorticoids (limited role except for lymphoma)
2. Endovascular stenting: now first-line for rapid symptom relief; especially for life-threatening symptoms (cerebral edema, laryngeal edema, postural hypotension, coma); complications include hematoma, SVC perforation, stent migration, PE, heart failure post-stenting
3. Radiation therapy: primary treatment for NSCLC and solid tumor metastases
4. Chemotherapy: for SCLC, lymphoma, germ cell tumors (chemosensitive)
5. Anticoagulation ± fibrinolysis: for catheter-related thrombotic SVCS
6. SVCS recurs in 10-30%; re-palliation with repeat stenting

• Harrison's 22E, p. 629

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2. Malignant Spinal Cord Compression (MSCC)

Causes and Sites

• Most common tumors: Lung, breast, prostate (most frequent); multiple myeloma, lymphoma, melanoma, renal, GU cancers
• Sites: Thoracic spine 70% > Lumbosacral 20% > Cervical 10%
• Mechanism: vertebral body/pedicle metastases → extradural compression of dura; direct paravertebral extension through intervertebral foramen (lymphoma, myeloma); rarely intramedullary hematogenous metastasis

Clinical Features (Progressive)

1. Back pain (first symptom in most; present days to months before neurological deficit)
   • Worsens with movement, coughing, sneezing
   • Worsens when supine (distinguishes from disc disease which typically improves supine)
   • Radicular pain in cervical/lumbosacral area (unilateral or bilateral)
   • Thoracic radicular pain: tight band-like constriction around thorax and abdomen
   • Lhermitte's sign: electric sensation down back and limbs on neck flexion/extension
2. Motor weakness, spasticity, extensor plantar response (Babinski)
3. Sensory loss (pinprick and vibration); upper level of sensory loss is 1-2 vertebrae below compression
4. Autonomic dysfunction (late): bladder/bowel incontinence, decreased anal tone, distended bladder, absent bulbocavernosus reflex - poor prognostic sign
5. Ataxia of gait (spinocerebellar involvement)

Investigations

• MRI full spine (gold standard): imaging procedure of choice; multiple metastases in 25%; T1 shows cord/CSF/extradural lesions; T2 shows intramedullary pathology; Gadolinium-enhanced for intramedullary disease
• Plain radiographs: "winking owl" sign (pedicle erosion) earliest sign; insensitive overall
• CT myelography: reserved for patients who cannot undergo MRI
• Bone scan: sensitive but less specific

Treatment (NOMS Framework - Memorial Sloan Kettering)

• Neurologic: degree of epidural compression, myelopathy, radiculopathy
• Oncologic: radiosensitivity of tumor type
• Mechanical: spine stability, retropulsed bone fragments
• Systemic: extent of disease, comorbidities

• Dexamethasone (high-dose corticosteroids): 16-24 mg IV loading dose, then 4 mg q6h - reduces vasogenic edema; start immediately in all symptomatic patients
• Urgent neurosurgery and radiation oncology consultation

• Radiation therapy (RT) + glucocorticoids: initial treatment of choice for most patients with radiosensitive tumors
• Stereotactic body RT (SBRT): preferred for radioresistant tumors (renal, melanoma, sarcoma); requires 2-3mm margin from spinal cord
• Surgery (separation surgery): followed by SBRT for:
  • High-grade compression from radioresistant tumors
  • Mechanical spinal instability
  • Retropulsion of bone fragments
  • Rapid neurological deterioration
  • Unknown primary requiring histological diagnosis
• Chemotherapy: for chemosensitive tumors (e.g., lymphoma) who have had prior RT
• Vertebroplasty/Kyphoplasty: for painful pathologic compression fractures without spinal instability
• Prognosis: ambulatory status at time of treatment is the strongest predictor of outcome; rapid onset is a poor prognostic feature
• Harrison's 22E, p. 631-633

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3. Cardiac Tamponade

Causes

• Malignant pericardial disease found in 5-10% of cancer patients at autopsy
• Most common tumors: lung cancer, breast cancer, leukemia, lymphoma
• ~50% of symptomatic pericardial disease in cancer patients is NOT malignant: radiation pericarditis (acute <months or chronic up to 20 years post-RT), drug-induced (all-trans retinoic acid, arsenic trioxide, imatinib), immune checkpoint inhibitor-related, infection, hypothyroidism, autoimmune, idiopathic

Clinical Features

• Dyspnea, cough, chest pain, orthopnea, weakness
• Beck's triad (classic tamponade): hypotension, JVD, muffled heart sounds
• Pulsus paradoxus (>10 mmHg fall in systolic BP with inspiration)
• Pulsus alternans, friction rub (less common in malignant disease)
• Tachycardia, peripheral edema, hepatomegaly, cyanosis, pleural effusion

Investigations

• Echocardiography: most helpful diagnostic test; shows effusion, diastolic collapse of RV/RA
• CXR: enlarged cardiac silhouette ("water bottle heart"), 90% show abnormalities
• ECG: low voltage, electrical alternans (alternating QRS amplitude)
• Pericardial fluid: serous, serosanguineous, or hemorrhagic; cytology diagnostic in most patients for malignant etiology
• CT chest: identifies concomitant thoracic neoplasm

Treatment

• Life-threatening tamponade: immediate pericardiocentesis (may need echo-guided)
• Recurrence rate after percutaneous drainage ~20%
• Sclerotherapy (bleomycin, mitomycin C, tetracycline instillation): reduces recurrence
• Subxiphoid pericardiotomy (under local anesthesia): for drainage + biopsy
• Thoracoscopic pericardial fenestration (pericardial window): 60% of malignant effusions recur after this procedure
• Radiation/systemic chemotherapy: for underlying malignancy
• Warning: drainage can paradoxically cause worsening hemodynamic instability in ~10% ("low cardiac output syndrome")
• Harrison's 22E, p. 630

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4. Increased Intracranial Pressure / Brain Metastases

Common Primary Tumors

• 25% of cancer patients die with intracranial metastases
• Hemorrhagic metastases: melanoma, germ cell tumors, renal cell carcinoma (particularly high risk)
• NSCLC with EGFR/ALK mutations and lobular/triple-negative breast cancer: high risk

Clinical Features

• Headache (often worse in morning), nausea/vomiting, behavioral changes, focal neurological deficits, seizures
• Abrupt onset (mimicking stroke) may indicate hemorrhage into metastasis
• Papilledema, neck stiffness, visual disturbances (with raised ICP)
• Herniation syndromes with mass enlargement: uncal, transtentorial, subfalcine

Investigations

• Gadolinium-enhanced MRI brain: superior to CT; multiple enhancing lesions with surrounding edema; more sensitive for meningeal involvement, small lesions, brainstem/cerebellar lesions
• CT brain if MRI not available urgently

Treatment

1. Dexamethasone (first-line for all symptomatic patients): 10-16 mg loading dose IV, then 4 mg q6h; reduces vasogenic edema; caution - may reduce immunotherapy efficacy
2. Bevacizumab: for patients unable to wean off steroids or on immunotherapy with symptomatic edema
3. Single brain metastasis + controlled extracranial disease: surgical resection + SRS to resection cavity
4. 1-4 brain metastases + stable systemic disease: SRS preferred over WBRT (WBRT associated with cognitive dysfunction)
5. Multiple metastases: SRS increasingly used; WBRT as alternative; targeted therapy/immunotherapy for appropriate tumor types (EGFR-TKIs for NSCLC, anti-PD1 for melanoma)
6. Hydrocephalus: VP shunt placement; ventriculostomy in acute deterioration
7. Levetiracetam: seizure management (non-enzyme-inducing; does not alter chemotherapy metabolism)

• Harrison's 22E, p. 633

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5. Tumor Lysis Syndrome (TLS)

Definition and Pathophysiology

Cairo-Bishop Criteria

• Creatinine >1.5× upper limit of normal
• Cardiac dysrhythmia or sudden death
• Seizure

Clinical Manifestations

• Hyperkalemia: arrhythmias, cardiac arrest
• Hyperphosphatemia + Hypocalcemia: tetany, seizures, arrhythmias, AKI (calcium-phosphate precipitation in tubules)
• Hyperuricemia: AKI (uric acid nephropathy), oliguria, flank pain
• AKI: oliguria progressing to anuria, fluid overload

Risk Stratification

Management (Prevention and Treatment)

• Brenner & Rector's The Kidney, p. 1877-1878

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6. Febrile Neutropenia

Definition

• ANC <500/μL (or <1000/μL with predicted nadir <500)
• Temperature >38.3°C (single oral reading) or >38.0°C sustained over 1 hour

Clinical Context

• Most common oncological emergency
• Mortality if untreated: ~50%; with prompt appropriate antibiotics: <5%
• Risk of occult bacteremia is high; may have few localizing signs due to inability to mount inflammatory response

Workup

• Blood cultures ×2 (including from each lumen of central venous catheter if present)
• Urine cultures
• CXR
• Respiratory viral panel (if respiratory symptoms)
• Stool cultures if diarrhea
• Complete physical examination (including skin, mouth, perineum, catheter sites)

Empiric Antibiotic Treatment (Start within 60 minutes)

• Piperacillin-tazobactam 4.5 g IV q6-8h
• Cefepime 2 g IV q8h
• Meropenem or imipenem (if β-lactam allergic or resistant organisms suspected)

• Central venous catheter infection suspected
• Mucositis (high-grade)
• Skin/soft tissue infection
• Pneumonia
• Known MRSA colonization
• Hemodynamic instability (septic shock)

• Fever persists after 4-7 days of antibiotics
• Clinical deterioration
• Suspected invasive fungal infection
• High-risk patients (prolonged neutropenia, hematopoietic stem cell transplant)
• Options: micafungin, caspofungin, voriconazole, amphotericin B

MASCC Risk Score (identifies low-risk patients suitable for oral antibiotics/outpatient management)

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7. Hyperleukocytosis and Leukostasis

Definition

• Peripheral blast count >100,000/μL in acute leukemia (particularly AML)
• Frequency: 5-13% in AML, 10-30% in ALL; leukostasis rare in lymphoid leukemia
• High risk in: myelomonocytic AML (FAB M4/M5), 11q13/MLL abnormalities, FLT3 mutations

Pathophysiology

Clinical Features

• CNS: stupor, headache, dizziness, tinnitus, visual disturbances, ataxia, confusion, coma, sudden death; papilledema, retinal hemorrhages
• Pulmonary: dyspnea, hypoxemia, respiratory failure; diffuse bilateral infiltrates on CXR
• Other: leg ischemia, renal vein thrombosis, myocardial ischemia, priapism, bowel infarction

Treatment

1. Hydroxyurea (1-3 g orally) - rapidly reduces blast count while workup proceeds
2. Urgent induction chemotherapy once diagnosis established
3. Leukapheresis - for symptomatic leukostasis; temporizing measure
4. Avoid RBC transfusions (increases viscosity) and volume depletion
5. Monitor for DIC and TLS (common co-complications during induction)
6. Avoid platelet transfusions (may worsen leukostasis)

• Harrison's 22E, p. 635

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8. Hypercalcemia of Malignancy

Mechanisms

1. PTHrP (parathyroid hormone-related protein) secretion - most common (~80%); "humoral hypercalcemia of malignancy"; squamous cell cancers, renal, breast
2. Osteolytic metastases - direct bone destruction; breast, myeloma
3. Calcitriol (1,25-OH₂ vitamin D) production - lymphoma
4. Ectopic PTH secretion (rare)

Clinical Features (Mnemonic: Bones, Stones, Groans, Psychic Moans)

• Bones: bone pain, pathological fractures
• Stones: nephrolithiasis, nephrogenic diabetes insipidus, polyuria, polydipsia
• Groans: nausea, vomiting, constipation, anorexia, pancreatitis
• Psychic moans: confusion, lethargy, depression, psychosis, coma
• Cardiac: short QT interval, arrhythmias, heart block

Treatment

1. Aggressive IV saline hydration (3-6 L/day): first-line; promotes renal calcium excretion
2. Bisphosphonates (zoledronic acid 4 mg IV over 15 min or pamidronate 60-90 mg IV): onset 24-48h, duration 2-4 weeks; check creatinine first
3. Denosumab (RANK-L inhibitor, 120 mg SC): preferred if CrCl <30 mL/min or refractory to bisphosphonates
4. Calcitonin (4-8 IU/kg SC/IM q6-12h): rapid onset (hours), mild effect, tachyphylaxis within 48h; useful bridge while bisphosphonates take effect
5. Glucocorticoids: for lymphoma/myeloma (calcitriol-mediated)
6. Furosemide: only after adequate hydration, use cautiously
7. Dialysis: refractory severe hypercalcemia with renal failure
8. Treat underlying malignancy

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9. SIADH (Syndrome of Inappropriate ADH Secretion)

Causes in Cancer

• SCLC (most common cancer cause - ectopic ADH production)
• CNS tumors, meningeal metastases, brain irradiation
• Drugs: cyclophosphamide, vincristine, cisplatin (vomiting-associated)
• Pulmonary infections, hypothyroidism (non-malignant concurrent causes)

Clinical Features

Treatment

• Mild: fluid restriction (800-1000 mL/day)
• Moderate/Severe: 3% NaCl (hypertonic saline) - correct at max 0.5-1 mEq/L/hour (do not exceed 8-12 mEq/L in 24h - risk of central pontine myelinolysis)
• Tolvaptan (vasopressin V2 receptor antagonist): for refractory cases; monitor Na closely
• Demeclocycline: alternative; causes nephrogenic DI
• Treat underlying malignancy

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10. Neoplastic Meningitis (Leptomeningeal Disease)

Causes

• Melanoma, breast (lobular/triple-negative), lung (NSCLC with EGFR/ALK), lymphoma, acute leukemia
• Incidence 3-8% of cancer patients

Clinical Features

• Multifocal neurological signs/symptoms: headache, gait abnormality, mental changes, nausea, vomiting, back/radicular pain, seizures
• Cranial nerve palsies (CN VI, VII most common), limb weakness, paresthesias, decreased DTRs

Investigations

• LP (CSF): malignant cells on cytology (40% false-negative on first tap - repeat at least once); elevated protein; low glucose; elevated CSF pressure
• Gadolinium-enhanced MRI brain + spine (full neuroaxis): leptomeningeal/subependymal/dural/cranial nerve enhancement; intradural nodules; communicating hydrocephalus; 20% have cord abnormalities
• CSF flow studies: abnormal in 70%; important for intrathecal chemotherapy planning

Treatment

• Intrathecal chemotherapy: methotrexate, cytarabine, or thiotepa via lumbar puncture or Ommaya reservoir
• Systemic chemotherapy: CNS-penetrant agents (e.g., high-dose methotrexate, temozolomide, targeted therapy for EGFR/ALK mutations in NSCLC)
• Focal RT: for bulky disease, symptomatic or obstructive lesions, cranial nerve involvement
• VP shunt: for hydrocephalus
• Prognosis: poor (median survival 10-12 weeks); leukemia/lymphoma may be cured if systemic disease controlled
• Harrison's 22E, p. 634

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11. Airway Obstruction

Causes

Management

• Humidified oxygen, glucocorticoids
• Heliox (helium-oxygen mixture): reduces turbulent flow, buys time
• Proximal obstruction (larynx/trachea): emergency tracheostomy
• Intrinsic distal obstruction: bronchoscopy + laser (Nd:YAG), argon plasma coagulation, electrocautery, mechanical debulking, intraluminal stenting, photodynamic therapy
• Extrinsic compression: endobronchial stenting, radiation therapy
• Resectable primary airway tumors: surgery
• Harrison's 22E, p. 635

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12. Disseminated Intravascular Coagulation (DIC) in Cancer

Common Triggers

• Acute promyelocytic leukemia (APL/AML-M3) - most classic
• Mucin-secreting adenocarcinomas (pancreatic, gastric, lung)
• Massive tumor lysis, sepsis

Treatment

• APL: all-trans retinoic acid (ATRA) is definitive; ATRA itself can be a trigger - treat underlying leukemia promptly
• FFP (clotting factor replacement), cryoprecipitate (fibrinogen/Factor VIII), platelet transfusions
• Heparin: controversial; may be used in chronic DIC from solid tumors

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Quick Reference: Key Points per Emergency

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• Harrison's Principles of Internal Medicine 22E (2025), Chapter 80 - Oncologic Emergencies (primary comprehensive source)
• The Washington Manual of Medical Therapeutics, Chapter 22
• Brenner & Rector's The Kidney, Chapter 42 (Tumor Lysis Syndrome)
• Tintinalli's Emergency Medicine, Chapter - Oncologic Emergencies

• Wright K et al. Malignant Superior Vena Cava Syndrome: A Scoping Review. J Thorac Oncol 2023. [PMID 37146753]
• Maciel CB & Busl KM. Neuro-oncologic Emergencies. Continuum 2024. [PMID 38830073]

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Thyroiditis - Clinical Features, Diagnosis, and Management

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Classification Overview

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1. Acute (Suppurative) Thyroiditis

Epidemiology and Etiology

• Rare (<1% of all thyroid disease); most common in children and young adults
• Most common predisposing condition: pyriform sinus fistula (4th branchial pouch remnant, predominantly left-sided)
• In the elderly: long-standing goiter or degeneration in thyroid malignancy
• Immunocompromised patients (HIV): atypical organisms - fungi, mycobacteria, Pneumocystis
• Common organisms: Staphylococcus aureus and Streptococcus pyogenes (~40% of adults); α- and β-hemolytic streptococcus and anaerobes (children)

Clinical Features

• Thyroid pain - often referred to the throat or ears
• Small, tender, asymmetric goiter
• Fever, dysphagia, erythema over thyroid
• Systemic illness: malaise, cervical lymphadenopathy
• Rapid onset rarely causes diagnostic confusion

Investigations

• Elevated ESR and leukocytosis (left shift)
• Thyroid function usually normal
• FNA biopsy: PMN infiltration; culture identifies organism
• Ultrasound/CT: identifies abscess formation; localizes anatomy
• Thyroid function tests rarely diagnostic

Management

• Antibiotics guided by Gram stain, then cultures from FNA
• Abscess drainage: percutaneous (image-guided) or surgical
• Surgery for abscess or if malignancy cannot be excluded
• Treat predisposing cause (e.g., piriform sinus fistula excision)
• Complications (uncommon with prompt treatment): tracheal obstruction, septicemia, retropharyngeal abscess, mediastinitis, jugular venous thrombosis
• Does not typically result in long-term hypothyroidism

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2. Subacute (Granulomatous / de Quervain's) Thyroiditis

Epidemiology

• Most common cause of a painful thyroid gland
• Accounts for up to 5% of clinical thyroid disorders
• Peak incidence: 4th-5th decade; female:male = 3-5:1
• Occurs seasonally (peaks with enterovirus season)

Etiology and Pathophysiology

• Viral or post-viral inflammatory disorder (mumps, coxsackie, influenza, adenovirus, echovirus); also reported after SARS-CoV-2 infection and COVID-19 vaccination
• Pathology: Patchy infiltrate with follicular disruption → multinucleated giant cells → granulomas → fibrosis → recovery
• Triphasic thyroid function due to follicular destruction:
  1. Thyrotoxic phase: stored hormone leaks from damaged follicles → ↑T4/T3, ↓TSH, LOW radioiodine uptake (<5%)
  2. Hypothyroid phase: stores depleted; gland not yet recovered → ↓T4, ↑TSH
  3. Recovery phase: TSH-driven regeneration → normalization

Clinical Features

• Presentation typically 2-3 weeks after upper respiratory illness
• Neck pain, exquisitely tender thyroid - often radiates to jaw, ear, or anterior chest
• Pain may start unilateral and migrate to opposite lobe
• Fever, malaise, myalgias, fatigue
• ~50% of patients have symptoms of thyrotoxicosis during initial phase
• Complete resolution is the usual outcome
• Permanent hypothyroidism in 15% (especially those with coincidental thyroid autoimmunity)
• Prolonged course with relapses in a small percentage

Investigations

Management

1. Mild-moderate pain: NSAIDs (e.g., aspirin 600 mg q4-6h) + PPI gastroprotection
2. Severe symptoms or inadequate NSAID response: Oral prednisone 15-40 mg/day (taper over 6-8 weeks guided by symptoms and ESR); if relapse during taper, increase dose and taper more slowly
3. Thyrotoxic symptoms: β-blockers (propranolol 20-40 mg tid-qid or atenolol 25-50 mg daily) - symptomatic only; antithyroid drugs (PTU/methimazole) are NOT indicated (synthesis is not increased - hormone is released from damaged follicles)
4. Hypothyroid phase: Levothyroxine replacement (50-100 μg daily) if prolonged or symptomatic; use low enough dose to allow TSH-mediated recovery
5. Monitoring: TSH and free T4 every 2-4 weeks

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3. Silent (Painless) Thyroiditis and Postpartum Thyroiditis

Definition and Epidemiology

• Painless thyroiditis = silent thyroiditis; postpartum thyroiditis = occurs within 12 months after delivery (essentially the same disorder)
• Postpartum thyroiditis: up to 10% of pregnancies; recurs after ~70% of subsequent pregnancies
• 3× more common in women with type 1 diabetes mellitus
• More frequent with personal/family history of autoimmunity
• In the postpartum setting, 20× more common than Graves' hyperthyroidism

Pathogenesis

• Autoimmune destruction-induced thyroiditis
• Associated with positive TPO antibodies (present antepartum)
• Unlike subacute thyroiditis, the immune response CAN be self-perpetuating → risk of permanent hypothyroidism

Clinical Features (Classic Triphasic Sequence)

1. Thyrotoxic phase (1-3 months): tachycardia, palpitations, heat intolerance, nontender goiter; symptoms milder than Graves' disease; substantial weight loss is rare
2. Brief euthyroid period (1-2 months) (may be absent)
3. Hypothyroid phase (up to 12 months): fatigue, impaired concentration, constipation, cold intolerance

• ~25% have only the thyrotoxic phase; ~50% have only the hypothyroid phase
• Some patients never develop clinically apparent thyrotoxicosis

Investigations

Management

1. Thyrotoxic phase: β-blockers (atenolol 25-50 mg daily) until hormone levels normalize; antithyroid drugs NOT useful (synthesis not increased)
2. Hypothyroid phase: Levothyroxine if symptomatic or if pregnant/attempting conception; taper after 6-12 months to assess recovery
3. Long-term: Annual thyroid function follow-up; up to 50% develop permanent hypothyroidism (higher risk with: high-titer TPO antibodies, missed thyrotoxic phase, severe hypothyroidism)
4. Glucocorticoids NOT indicated in silent thyroiditis

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4. Drug-Induced Thyroiditis

Causes

• Immune checkpoint inhibitors (ICIs): pembrolizumab, nivolumab - thyroiditis in 5-20% of treated cancer patients; painless thyroiditis pattern
• Interferon-α (IFN-α): used in hepatitis B/C, hematologic malignancies; thyroid dysfunction in up to 5%; commonest in women with pre-existing TPO antibodies; can cause painless thyroiditis, hypothyroidism, or Graves' disease
• Tyrosine kinase inhibitors (TKIs): sorafenib and others
• Amiodarone: can cause thyroiditis or thyrotoxicosis (two distinct types: iodine-excess thyrotoxicosis = type 1; destructive thyroiditis = type 2); may be acute, subacute, or chronic

Management

• Same approach as silent thyroiditis: β-blockers for thyrotoxicosis, levothyroxine for hypothyroidism
• ASCO recommends routine TFT monitoring during ICI therapy
• For amiodarone-induced destructive thyroiditis (type 2): glucocorticoids (prednisone 40 mg/day); consider discontinuation of amiodarone if clinically feasible

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5. Hashimoto's Thyroiditis (Chronic Lymphocytic Thyroiditis)

Epidemiology

• Most common cause of hypothyroidism in iodine-sufficient regions of the world
• Most prevalent 45-65 years; female:male = 10-20:1
• Strong genetic component: CTLA4 polymorphisms; 40% concordance in monozygotic twins; 50% of asymptomatic siblings have antithyroid antibodies

Pathogenesis (Autoimmune Destruction)

• Multiple immunological mechanisms:
  1. CD8+ cytotoxic T cells kill thyroid epithelial cells
  2. CD4+ Th1 cells release IFN-γ → macrophage activation → follicular destruction
  3. Anti-TPO and anti-thyroglobulin antibodies → antibody-dependent cytotoxicity and complement activation

Pathology (Robbins)

• Diffuse, symmetric thyroid enlargement
• Dense lymphocytic infiltrate with prominent germinal centers
• Hürthle (oxyphil) cells - follicular cells with abundant eosinophilic granular cytoplasm (mitochondria-rich metaplasia in response to injury)
• Atrophic follicles; increased fibrous stroma

Clinical Features

• Painless, diffuse, firm/rubbery goiter of variable size - most common presentation
• Slowly progressive hypothyroidism (most common clinical outcome): fatigue, cold intolerance, weight gain, constipation, dry skin, hair loss, bradycardia, periorbital puffiness
• Hashitoxicosis: transient thyrotoxicosis due to follicular disruption releasing stored hormone; precedes hypothyroidism in some patients; elevated T4/T3, suppressed TSH, decreased RAIU
• Associated with other autoimmune conditions (Type 1 DM, vitiligo, pernicious anemia, Addison's disease, Sjögren's, lupus)
• Increased risk of B-cell non-Hodgkin lymphoma (primary thyroid lymphoma)
• Possible increased risk of papillary thyroid carcinoma (controversial)
• Focal thyroiditis: present in 20-40% of euthyroid patients at autopsy (subclinical autoimmunity)

Investigations

Management

1. Confirmed hypothyroidism: Levothyroxine (LT4) replacement - starting dose 1.6 μg/kg/day; titrate to normalize TSH; check TSH 6-8 weeks after dose change
2. Subclinical hypothyroidism (elevated TSH, normal T4): treat if TSH >10 mIU/L, or if symptomatic, or if pregnant (or attempting)
3. Euthyroid Hashimoto's: no treatment needed; monitor TSH annually
4. Goiter causing compressive symptoms: LT4 suppression rarely effective; surgical resection if significant compression
5. Selenium supplementation: may reduce TPO antibody titers (evidence limited)
6. Annual monitoring: TFTs; screen for associated autoimmune conditions
7. Thyroid lymphoma suspected: urgent CT + FNA/core biopsy

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6. Riedel's Thyroiditis (Invasive Fibrous Thyroiditis)

Overview

• Rare, poorly understood fibroinflammatory disorder causing progressive fibrosis of the thyroid with extension into surrounding structures
• Predominantly affects middle-aged women
• Strong association with IgG4-related disease (idiopathic fibrosis at multiple sites: retroperitoneum, mediastinum, biliary tree, lung, orbit)

Clinical Features

• Insidious, painless goiter
• Rock-hard, fixed, non-tender thyroid - clinically mimics malignancy (anaplastic carcinoma, lymphoma)
• Compressive symptoms due to fibrosis extending beyond thyroid capsule:
  • Dysphagia (esophageal compression)
  • Dyspnea/stridor (tracheal compression)
  • Dysphonia/hoarseness (recurrent laryngeal nerve involvement)
  • Venous congestion (neck vein compression)

Investigations

• TSH/T4: hypothyroidism when significant gland destruction; may be normal early
• Ultrasound: diffusely hypoechoic with ill-defined borders
• CT/MRI: defines extent; evaluates tracheal narrowing
• FNA: dense fibrotic changes - cannot reliably exclude anaplastic thyroid carcinoma
• Open (surgical) biopsy required for definitive diagnosis (FNA inadequate)
• Serum IgG4 levels may be elevated

Management

1. Medical (inflammatory component):
   • Glucocorticoids (prednisone): first-line anti-inflammatory
   • Tamoxifen (antifibrotic): widely used; may have independent benefit via TGF-β suppression
   • Other agents: mycophenolate mofetil, rituximab
2. Hypothyroidism: levothyroxine replacement
3. Surgery: indicated for:
   • Exclude malignancy (ATC or thyroid lymphoma cannot be excluded by FNA)
   • Relieve aerodigestive tract compression (isthmus wedge resection most common)
   • Surgery is technically challenging due to obliterated tissue planes; only partial resection recommended
4. Not associated with increased risk of thyroid malignancy

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Differential Diagnosis: Painful vs. Painless Thyroiditis

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Key Distinguishing Point: Painless Thyrotoxicosis

• Silent/postpartum thyroiditis
• Subacute thyroiditis (if painful)
• Drug-induced thyroiditis (ICI, IFN-α)
• Factitious thyrotoxicosis (exogenous T4/T3 ingestion - also low RAIU, low Tg)
• Struma ovarii (ectopic thyroid tissue)

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• Harrison's Principles of Internal Medicine 22E (2025), Chapter 396 - Thyroiditis (primary source, all types)
• Goldman-Cecil Medicine, Chapter 207 - Postpartum and Sporadic Painless Thyroiditis; Subacute Thyroiditis
• Robbins & Kumar Basic Pathology (Robbins Pathology) - Hashimoto's and de Quervain's pathology and morphology
• Sabiston Textbook of Surgery - Riedel's thyroiditis and acute suppurative thyroiditis