Diagnosing Sepsis

Step 1: Bedside Screening - qSOFA

Step 2: Confirm with SOFA Score

Step 3: Diagnose Septic Shock (if applicable)

• Vasopressor requirement to maintain MAP ≥ 65 mmHg PLUS
• Serum lactate > 2 mmol/L (> 18 mg/dL) despite adequate fluid resuscitation

Step 4: Initial Laboratory Workup

• Complete blood count with differential (leukocytosis, leukopenia, bandemia)
• Basic metabolic panel (creatinine, electrolytes)
• Liver function tests
• Coagulation panel (PT/INR, aPTT - screen for DIC)
• Serum lactate (elevated in tissue hypoperfusion; key for shock diagnosis)
• Urinalysis

• At least 2 sets of blood cultures (aerobic + anaerobic) - positive in only ~1/3 of septic shock cases
• Urine culture
• Sputum culture if pneumonia suspected
• Wound/other site cultures as clinically indicated

• Chest X-ray (pneumonia is the cause in ~50% of septic shock cases)
• CT abdomen/pelvis if intra-abdominal source suspected
• Ultrasound for focused assessment
• Harrison's Principles of Internal Medicine 22E, p. 2363

Step 5: Biomarkers

Step 6: Rule Out Sepsis Mimics

• Heart failure / cardiogenic shock
• Pulmonary embolism
• Adrenal insufficiency
• Connective tissue disease / vasculitis
• Mesenteric ischemia
• Pancreatitis (causes SIRS without infection)
• Noninfectious ARDS

Summary Diagnostic Pathway

Suspected infection
        ↓
qSOFA ≥ 2?  →  (Yes) → High suspicion → Full SOFA score
        ↓ (No)
  Continue monitoring      SOFA increase ≥ 2 from baseline?
                                    ↓ (Yes)
                               SEPSIS CONFIRMED
                                    ↓
                     Serum lactate > 2 mmol/L + vasopressors needed?
                                    ↓ (Yes)
                              SEPTIC SHOCK

Key Points

• The Sepsis-3 definition replaced the old SIRS-based criteria because SIRS alone was too nonspecific
• Blood cultures are positive in only ~1/3 of septic shock patients; culture negativity does not exclude sepsis
• Proof of infection is not required to diagnose sepsis at onset - clinical suspicion is sufficient to initiate workup and treatment
• Early recognition is critical: appropriate antibiotic therapy started early is associated with significantly reduced mortality

Good's Syndrome - A Complete Overview

What Is It?

Epidemiology

• Occurs almost exclusively in adults, most often after age 40 (mean diagnosis age ~61 years in one cohort)
• Affects both sexes, with a slight female predominance (~57% female in recent series)
• Rare overall - exact prevalence is unknown; accounts for a small fraction of all primary immunodeficiencies
• Represents approximately 5-10% of all thymoma patients (not all thymoma patients develop Good's syndrome)

Pathophysiology

• Profound reduction or complete absence of B cells and pre-B cells in peripheral blood (undetectable levels in ~89% of patients in one study)
• This leads to failure of antibody production → agammaglobulinemia or hypogammaglobulinemia across all isotypes (IgG, IgA, IgM)

• Reduced CD4+ T cells, including naive, central memory, and T follicular helper cells
• Reduced T regulatory cells (Tregs)
• Paradoxically, expanded TCRγδ+ T cells
• Reduced NK cells, neutrophils, basophils, and dendritic cells

Clinical Presentation

1. Recurrent Infections (most prominent feature)

• Bronchiectasis develops in ~57% of patients due to chronic/recurrent respiratory infections
• Sinusitis in ~24% of patients
• CMV retinitis is a well-recognized and potentially blinding opportunistic complication
• Fatal opportunistic pulmonary infections with fungi and Pneumocystis can occur

2. Autoimmune Manifestations (~47% of patients)

• Myasthenia gravis (well-known thymoma association)
• Pure red cell aplasia (PRCA)
• Myelodysplastic syndrome (MDS)
• Lichen planus (oral, vulvovaginal-gingival)
• Polymyositis
• Vasculitis
• Inflammatory bowel disease / ulcerative colitis
• Aplastic anemia

3. Thymoma

• Usually benign (most commonly WHO type A or AB) but can be malignant
• May not be visible on plain chest X-ray - HRCT of the chest is essential as thymoma can be occult on standard radiograph
• The thymoma and hypogammaglobulinemia often appear simultaneously, but in some patients the hypogammaglobulinemia develops years after thymoma diagnosis

Diagnosis

• HRCT chest - mandatory in all patients with suspected antibody deficiency (plain CXR misses many thymomas)
• CT is the modality of choice for characterizing the anterior mediastinal mass

• Serum immunoglobulins (IgG, IgA, IgM) - low or absent across all isotypes
• B-cell count by flow cytometry - absent or severely reduced (<1% of lymphocytes; often undetectable)
• Vaccine antibody titers (anti-tetanus, anti-pneumococcal) - typically absent or very low
• T-cell subsets - often reduced CD4+ T cells; CD8+ T cells may be relatively preserved; expanded γδ T cells

Complications & Prognosis

• High morbidity and mortality: in one cohort (n=21), 9 patients (43%) died at a median of 4.2 years after diagnosis
• Secondary malignancy occurs in ~24% (excluding the thymoma itself)
• Untreated recurrent bronchial infections lead to bronchiectasis → cor pulmonale → death
• The immunodeficiency does not resolve after thymectomy - it is essentially permanent

Treatment

1. Thymectomy

• Recommended when the thymoma is resectable
• Removes the neoplasm and prevents tumor progression/malignant transformation
• Does NOT reverse the immunodeficiency or autoimmunity
• Surgery should not be delayed hoping it will resolve the immune defect

2. Immunoglobulin Replacement (cornerstone of treatment)

• IVIG (intravenous immunoglobulin) or SCIG (subcutaneous immunoglobulin) given lifelong
• Goal: maintain trough IgG levels ≥ 500-700 mg/dL (higher targets in patients with bronchiectasis or ongoing infections)
• Reduces frequency and severity of bacterial infections
• Response may be less robust in patients with deeper combined immune defects

3. Antimicrobial Prophylaxis

• PCP prophylaxis (trimethoprim-sulfamethoxazole or alternatives) given the risk of Pneumocystis jirovecii pneumonia
• Antifungal prophylaxis in selected patients
• Some patients may need antiviral prophylaxis (e.g., acyclovir/valacyclovir for recurrent HSV)

4. Supportive Measures

• GM-CSF (granulocyte-macrophage colony-stimulating factor) for neutropenia if present
• Blood transfusions for pure red cell aplasia
• Prompt treatment of infections with appropriate antimicrobials
• Monitoring and management of autoimmune complications (e.g., pyridostigmine/thymectomy for myasthenia gravis)
• Pulmonary rehabilitation for bronchiectasis

Key Takeaways

1. Good's syndrome = thymoma + hypogammaglobulinemia in an adult
2. It is a combined B- and T-cell immunodeficiency, not purely humoral
3. Thymoma may be occult on plain CXR - always get HRCT in suspected antibody deficiency
4. Thymectomy is recommended but does not cure the immunodeficiency
5. Lifelong IVIG replacement is the mainstay of treatment
6. Watch for opportunistic infections (PCP, CMV, Candida) and autoimmune complications
7. Prognosis is guarded - significant mortality from infections and complications