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Investigations in Common Fever & Infectious Conditions - Quick Reference
Below is a structured reference covering the key investigations used in fever workup, their normal values, and how they change across conditions - from simple viral fever through advanced bacterial and parasitic infections.
CORE INVESTIGATIONS - NORMAL VALUES
| Investigation | Normal Value |
|---|---|
| Temperature | 36.1 - 37.2°C (97 - 99°F) |
| WBC (Total Leukocytes) | 4,000 - 11,000 cells/µL |
| Neutrophils | 50 - 70% (2,500 - 7,500/µL absolute) |
| Lymphocytes | 20 - 40% (1,000 - 4,800/µL) |
| Eosinophils | 1 - 4% (100 - 400/µL) |
| Monocytes | 2 - 8% |
| Basophils | 0 - 1% |
| Hemoglobin (Male) | 13.5 - 17.5 g/dL |
| Hemoglobin (Female) | 12.0 - 15.5 g/dL |
| Hematocrit (Male) | 41 - 53% |
| Hematocrit (Female) | 36 - 46% |
| Platelets | 150,000 - 400,000/µL |
| MCV | 80 - 100 fL |
| ESR (Male) | < 15 mm/hr (Westergren) |
| ESR (Female) | < 20 mm/hr |
| CRP | < 0.5 - 1.0 mg/dL (< 10 mg/L) |
| Procalcitonin (PCT) | < 0.1 ng/mL |
| Serum Sodium | 135 - 145 mEq/L |
| Serum Potassium | 3.5 - 5.0 mEq/L |
| Serum Creatinine | 0.7 - 1.2 mg/dL (male); 0.5 - 1.0 (female) |
| BUN | 7 - 20 mg/dL |
| ALT (SGPT) | 7 - 56 U/L |
| AST (SGOT) | 10 - 40 U/L |
| Total Bilirubin | 0.3 - 1.2 mg/dL |
| Serum Albumin | 3.5 - 5.0 g/dL |
| Blood Glucose (fasting) | 70 - 100 mg/dL |
| Urine Specific Gravity | 1.005 - 1.030 |
| Urine WBC | 0 - 4 cells/HPF |
CONDITION-BY-CONDITION INVESTIGATION GUIDE
1. SIMPLE VIRAL FEVER (e.g., Common Cold, Influenza, Adenovirus)
| Investigation | Expected Finding | Significance |
|---|---|---|
| WBC | Normal or low (3,000 - 8,000) | Viral-induced leukopenia is common |
| Differential | Lymphocytosis (>40%), neutropenia | Classic viral pattern |
| Platelets | Normal or mildly decreased | Non-specific |
| CRP | Mildly elevated (1 - 20 mg/L) | Non-specific inflammation |
| ESR | Mildly elevated | Non-specific |
| Procalcitonin (PCT) | < 0.5 ng/mL - KEY FINDING | Low PCT strongly argues against bacterial sepsis |
| LFTs | Normal | |
| Urine | Normal | |
| Throat swab / Rapid Ag test | Positive (e.g., Flu A/B antigen) | Confirms influenza |
Pattern to remember: WBC normal or LOW + lymphocytosis + low PCT = viral fever
2. BACTERIAL FEVER / SEPSIS (e.g., Pneumonia, UTI, Cellulitis)
| Investigation | Expected Finding | Significance |
|---|---|---|
| WBC | Elevated (>11,000), often 15,000 - 25,000+ | Leukocytosis |
| Neutrophils | >70-80% with left shift (band forms >10%) | Bands = immature neutrophils, severe infection |
| Toxic granulations / Döhle bodies | Present on blood film | Marker of severe bacterial infection |
| CRP | Markedly elevated (>50 - 200+ mg/L) | Rises within 6 hrs, peaks at 48 hrs |
| ESR | Elevated (often >40 mm/hr) | Lags behind CRP |
| Procalcitonin (PCT) | >0.5 - 2.0 ng/mL (moderate); >2.0 (severe sepsis) | Best biomarker for bacterial vs. viral |
| Blood Culture | Positive organism in bacteremia | Gold standard - collect BEFORE antibiotics |
| Urine C&S | Bacteria + WBCs if UTI | |
| Chest X-ray | Consolidation/infiltrate in pneumonia | |
| Lactate | >2 mmol/L = sepsis; >4 = septic shock | Tissue hypoperfusion marker |
| Serum Creatinine | May rise if organ dysfunction |
PCT cut-offs: < 0.1 = unlikely bacterial | 0.1 - 0.5 = possible | 0.5 - 2.0 = probable | >2.0 = severe sepsis/bacteremia
3. TYPHOID FEVER (Salmonella typhi)
| Investigation | Week 1 | Week 2 | Week 3-4 |
|---|---|---|---|
| WBC | Low-normal (2,000 - 6,000) | Leukopenia continues | Leukopenia |
| Neutrophils | Normal or low | Relatively low | Low |
| Eosinophils | Absent (eosinopenia) - classic finding | Absent | Returning eosinophils = recovery sign |
| Platelets | Mildly low | May drop further | Normalizing |
| Blood Culture | Positive (80% sensitivity) | 50% sensitivity | 30% sensitivity |
| Urine Culture | 25% positive | Higher yield | |
| Stool Culture | Lower yield | Higher yield (week 2-3) | |
| Widal Test (Felix-Widal) | Usually negative | O antibodies rise (day 6-8); H antibodies (day 10-12) | Significant titer |
| Significant Widal titer | O ≥1:80, H ≥1:160 (endemic area); O ≥1:40 (non-endemic) | Fourfold rise in paired sera = definitive | |
| CRP | Elevated | Elevated | |
| LFTs | Mildly elevated ALT/AST (~2-3x ULN) | Hepatomegaly | |
| Rapid tests (Typhidot, Tubex) | IgM positive from day 4-5 | More reliable |
Key: Blood culture is gold standard (highest yield in Week 1). Widal test has 30% false-negative rate and cross-reacts with malaria, typhus, cirrhosis - so use with caution. Park's Textbook of Preventive and Social Medicine, p. 278
4. MALARIA
| Parameter | P. vivax / P. ovale | P. falciparum | P. malariae |
|---|---|---|---|
| WBC | Normal or mildly low | Normal or low | Normal |
| Platelets | Low (<150,000) - often 50,000-100,000 | Severely low (<50,000 in severe disease) | Mildly low |
| Hemoglobin | Mildly low (anemia develops) | Severely low (hemolytic anemia) | Mild anemia |
| Bilirubin (indirect) | Elevated (hemolysis) | Markedly elevated | Mild rise |
| LDH | Elevated | Very high | Elevated |
| Blood film (thick + thin smear) | Ring forms + Schuffner's dots | Ring forms + banana-shaped gametocytes, multiple rings/cell | Basket/band trophozoites |
| RDT (HRP-2 antigen) | Negative for falciparum | Positive (HRP-2) | Negative (use pan-Ag) |
| Parasite density (thin smear) | % parasitized RBCs; >5% = severe in falciparum | ||
| Serum creatinine | Usually normal | May rise (blackwater fever, acute kidney injury) | Nephrotic syndrome (chronic) |
| Blood glucose | Normal | Hypoglycemia in severe falciparum | Normal |
| CSF | Normal | Abnormal in cerebral malaria | Normal |
| Urine | Normal | Hemoglobinuria (blackwater fever - dark urine) | Proteinuria in P. malariae nephropathy |
Harrison's 22E, Diagnosis of Malaria block: "If the blood smear is negative when examined by an experienced microscopist, the patient does not have malaria."
5. DENGUE FEVER
| Phase | Day 1-3 (Febrile) | Day 4-6 (Critical) | Day 7-10 (Recovery) |
|---|---|---|---|
| WBC | Normal or mildly low | Leukopenia (often 2,000-4,000) | Rising back to normal |
| Neutrophils | Low | Very low | Normalizing |
| Lymphocytes | Increasing | Atypical lymphocytes | High |
| Platelets | Borderline low | Severely low (<100,000 = dengue fever; <20,000 = dengue hemorrhagic) | Rising - recovery sign |
| Hematocrit | Normal | Rising >20% from baseline = plasma leakage (dengue hemorrhagic fever) | Falls as plasma re-absorbed |
| NS1 Antigen | Positive (days 1-5) - high sensitivity early | Becoming negative | Negative |
| IgM antibody | Negative | Positive from day 5 | Persists weeks |
| IgG antibody | Negative (primary infection) or positive early (secondary infection) | Rising | High |
| AST/ALT | Mildly elevated | Can be markedly elevated | Normalizing |
| PT/aPTT | Normal | Prolonged in DHF/DSS | |
| Fibrinogen | Normal | Low in DIC (severe DHF) |
WHO dengue criteria: Thrombocytopenia (<100,000) + hemoconcentration (hematocrit rise >20%) = dengue hemorrhagic fever (DHF). Platelet <20,000 + spontaneous bleeding = dengue shock syndrome (DSS). Dermatology 5e / Harrison's
6. LEPTOSPIROSIS
| Investigation | Leptospiremic Phase (days 1-7) | Immune Phase (days 7-14) |
|---|---|---|
| WBC | Elevated (10,000-15,000), neutrophilia | Elevated, then normalizing |
| Platelets | Mildly low | Low-normal |
| Creatinine | Rising | Markedly elevated (Weil's disease = AKI) |
| Bilirubin | Rising | Markedly elevated - conjugated (jaundice) |
| CPK (creatine kinase) | Markedly elevated | Elevated - myalgia/myositis |
| Urinalysis | Proteinuria, hematuria, casts | Worse - acute tubular necrosis pattern |
| LFTs | AST/ALT elevated | ALT may normalize; bilirubin very high |
| Dark-field microscopy of blood | Can see leptospires (rarely used) | Negative |
| MAT (Microscopic Agglutination Test) | Negative early | Positive (titer >1:100 significant, >1:400 diagnostic) |
| ELISA IgM | Positive from day 5-7 | Highly positive |
| Blood culture (EMJH medium) | Positive in first 5-7 days | Negative |
| Urine culture | Negative | Positive (weeks 2-4) |
Weil's disease triad: Jaundice + acute kidney injury + bleeding tendency
7. URINARY TRACT INFECTION (UTI)
| Investigation | Simple Cystitis | Pyelonephritis | Urosepsis |
|---|---|---|---|
| Urinalysis | WBC >5/HPF, bacteria, nitrite positive | WBC casts (pathognomonic), WBC >10/HPF | Same + may be dilute |
| Urine culture | >100,000 CFU/mL (symptomatic: >1,000) | >100,000 CFU/mL | Blood culture also positive |
| WBC | Normal or mildly elevated | 12,000-20,000 | >20,000 with left shift |
| CRP | Normal or mildly elevated | Elevated (>50 mg/L) | Very high |
| PCT | < 0.5 ng/mL | 0.5-2.0 ng/mL | >2.0 ng/mL |
| Creatinine | Normal | May rise | Rising (septic AKI) |
| Blood culture | Negative | Usually negative | Positive (E. coli most common) |
8. PNEUMONIA
| Investigation | Viral Pneumonia | Typical Bacterial (Pneumococcal) | Atypical (Mycoplasma, Legionella) |
|---|---|---|---|
| WBC | Normal or low | 15,000-30,000, neutrophilia | Normal or mildly elevated |
| CRP | Mild-moderate elevation | Very high (>100 mg/L) | Moderate elevation |
| PCT | < 0.25 ng/mL | >0.5 - 2.0 ng/mL | Variable (0.1 - 0.5) |
| Chest X-ray | Bilateral interstitial/ground-glass | Lobar consolidation, air bronchograms | Patchy bilateral infiltrates, worse than exam suggests |
| Sputum Gram stain | No bacteria (or normal flora) | Gram-positive cocci in pairs (diplococci) | No typical organism on Gram stain |
| Sputum culture | Viral PCR if needed | S. pneumoniae | Culture or serology |
| Urine Legionella Ag | Negative | Negative | Positive in Legionella pneumophila type 1 |
| Urine Pneumococcal Ag | Negative | Positive | Negative |
| Cold agglutinins | Normal | Normal | Elevated in Mycoplasma (>1:32) |
| Mycoplasma IgM | Negative | Negative | Positive (>1:16 significant) |
| Sodium | Normal | Hyponatremia common in severe pneumonia | Hyponatremia classic in Legionella |
| LFTs | Normal | Mildly elevated | Elevated in Legionella (hepatitis) |
| LDH | Mildly elevated in viral | Very elevated in Legionella/PCP |
9. MENINGITIS
| Investigation | Viral (Aseptic) | Bacterial | Tuberculous | Fungal (Cryptococcal) |
|---|---|---|---|---|
| WBC (CSF) | 10-500, mostly lymphocytes | >500 - 2,000+, mostly neutrophils (>80%) | 100-500, mostly lymphocytes | 10-200, lymphocytes |
| CSF Glucose | Normal (>45 mg/dL; >60% serum) | Very low (<40 mg/dL) | Low (20-45 mg/dL) | Very low |
| CSF Protein | Normal-mildly high (45-100 mg/dL) | Very high (>100-500 mg/dL) | High (100-500 mg/dL) | High (100-500 mg/dL) |
| CSF appearance | Clear | Turbid/cloudy | Clear (xanthochromic) | Clear, viscous |
| CSF Gram stain | Negative | Positive in ~70% (bacteria seen) | Negative (AFB rarely seen on ZN) | Negative; India ink positive |
| CSF Culture | Viral PCR | Bacterial culture | LJ medium (slow - 6-8 weeks) | Fungal culture; CrAg positive |
| Opening pressure | Normal (7-18 cmH2O) | Markedly elevated | Mildly-moderately elevated | Very high |
| Blood WBC | Normal | High with neutrophilia | Normal or mildly elevated | Low (immunocompromised) |
| Serum CRP | Mild | Very high | Elevated | Low-moderate |
| Serum PCT | Low | High (>2.0 ng/mL) | Low-moderate | Low |
| CSF Lactate | <3.5 mmol/L | >3.5 mmol/L (high) | Elevated | Elevated |
CSF glucose normal = 45-80 mg/dL; should be >2/3 of blood glucose
10. INFECTIVE ENDOCARDITIS
| Investigation | Expected Finding |
|---|---|
| Blood cultures (3 sets) | Positive in >90% (gold standard); S. viridans most common |
| WBC | 12,000-20,000, neutrophilia |
| ESR | Very high (>60-100 mm/hr) |
| CRP | Very high |
| Hemoglobin | Low (normochromic normocytic anemia of chronic inflammation) |
| Rheumatoid factor | Positive in ~50% of subacute IE |
| Urinalysis | Microscopic hematuria, RBC casts (immune complex glomerulonephritis) |
| Echocardiography (TTE/TEE) | Vegetations, valve incompetence - major Duke criterion |
| ECG | PR interval prolongation = aortic root abscess |
| Complement (C3/C4) | Low (immune complex consumption) |
11. TUBERCULOSIS (TB)
| Investigation | Primary TB | Active Pulmonary TB | Miliary TB |
|---|---|---|---|
| WBC | Normal | Normal or mildly elevated, lymphocytosis | Elevated; pancytopenia in bone marrow involvement |
| Hemoglobin | Normal | Mildly low (anemia of chronic disease) | Low |
| ESR | Elevated | Very high (>80-100 mm/hr) | Very high |
| CRP | Elevated | Elevated | Very high |
| Sputum AFB smear | Negative | Positive in ~60% (ZN stain; require ≥5,000 bacilli/mL) | Usually negative |
| Sputum culture (LJ) | Gold standard | Positive in 80-85% | May need BAL or bone marrow |
| GeneXpert MTB/RIF | Detects M. tuberculosis + rifampicin resistance within 2 hrs | Sensitivity ~88% smear+, ~67% smear- | |
| Tuberculin test (Mantoux) | >10 mm induration after 48-72 hrs (5 mm in HIV+) | Positive | May be negative (anergy in miliary) |
| IGRA (Quantiferon Gold) | Positive | Positive | May be negative |
| Chest X-ray | Ghon complex, hilar lymphadenopathy | Cavitation, upper lobe infiltrates | Miliary shadowing (1-3 mm nodules throughout) |
| Serum Sodium | Normal | SIADH in advanced disease (hyponatremia) | |
| LFTs | Normal | Mildly elevated (drug monitoring during treatment) | |
| Serum Albumin | Normal | Low in chronic disease | Very low |
| ADA (Adenosine Deaminase) | - | Elevated in TB pleural effusion (>40 U/L) | Elevated in CSF/ascites TB |
SUMMARY PATTERN CHEAT SHEET
| Pattern | Think Of |
|---|---|
| WBC low + lymphocytosis + low PCT | Viral fever (influenza, EBV, dengue early) |
| WBC high + neutrophilia + high PCT (>0.5) | Bacterial infection / sepsis |
| WBC low + eosinopenia + low-normal CRP | Typhoid fever |
| Thrombocytopenia + rising hematocrit | Dengue hemorrhagic fever |
| Thrombocytopenia + hemolytic anemia + blood film parasites | Malaria |
| Jaundice + AKI + elevated CPK + fever | Leptospirosis (Weil's disease) |
| CSF: high neutrophils + low glucose + high protein | Bacterial meningitis |
| CSF: lymphocytes + low glucose + high protein (weeks) | TB meningitis |
| Persistent bacteremia + new murmur + hematuria | Infective endocarditis |
| ESR very high + low albumin + upper lobe cavitation | Active pulmonary TB |
| Lobar consolidation + urine Legionella Ag + hyponatremia | Legionella pneumonia |
KEY BIOMARKER CUT-OFFS AT A GLANCE
| Biomarker | Normal | Viral Infection | Bacterial Infection | Sepsis |
|---|---|---|---|---|
| PCT | <0.1 ng/mL | <0.25 ng/mL | 0.5-2.0 ng/mL | >2.0 ng/mL (>10 = severe) |
| CRP | <10 mg/L | 10-40 mg/L | 40-200 mg/L | >200 mg/L |
| WBC | 4-11 x10³/µL | 3-8 (low-normal) | 12-25 (high) | >25 or <4 (SIRS extremes) |
| Lactate | <2.0 mmol/L | Normal | Normal-mildly elevated | >2 mmol/L (sepsis); >4 (shock) |
| Neutrophil % | 50-70% | Low (<50%) | High (>80%) | >80% with bands |
Sources: Park's Textbook of Preventive and Social Medicine (typhoid, p. 278) | Harrison's Principles of Internal Medicine 22E (malaria diagnosis) | Tintinalli's Emergency Medicine (malaria blood smear) | Henry's Clinical Diagnosis and Management by Laboratory Methods (CBC, reference ranges) | Goldman-Cecil Medicine | Rosen's Emergency Medicine
Explore advanced pathology: investigations in chronic infections & immune complications
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Here is the complete advanced pathology reference, organized from chronic infections through immune system complications:
Advanced Pathology: Investigations in Chronic Infections & Immune Complications
MASTER REFERENCE - ADVANCED NORMAL VALUES
| Investigation | Normal Value | Clinical Significance |
|---|---|---|
| CD4+ T-cell count | 500 - 1,500 cells/µL | Immune competence marker |
| CD8+ T-cell count | 300 - 1,000 cells/µL | Cytotoxic T-cells |
| CD4:CD8 ratio | 1.5 - 2.5 | Inverted (<1.0) in HIV/immunosuppression |
| HIV RNA viral load | Undetectable (0 copies/mL) in treated patients | >1,000 = replicating virus; >100,000 = high risk |
| HBsAg | Negative | Positive = HBV infection |
| Anti-HBs | Negative (or >10 IU/L = immune) | Protective after vaccination/recovery |
| HCV RNA | Undetectable | Any detectable = active HCV |
| Serum IgG | 700 - 1,600 mg/dL | |
| Serum IgA | 70 - 400 mg/dL | |
| Serum IgM | 40 - 230 mg/dL | |
| Serum IgE | < 100 IU/mL | |
| Complement C3 | 90 - 180 mg/dL | |
| Complement C4 | 16 - 47 mg/dL | |
| CH50 (total complement) | 41 - 90 U/mL | |
| ANA (antinuclear Ab) | Negative (<1:40 titer) | |
| Anti-dsDNA | < 7 IU/mL (negative) | |
| RF (Rheumatoid Factor) | < 14 IU/mL | |
| Anti-CCP | < 20 U/mL (negative) | |
| Ferritin | 12 - 300 ng/mL (male); 12 - 150 (female) | |
| LDH | 140 - 280 U/L | |
| Beta-2 microglobulin | 0.8 - 2.4 mg/L | |
| Fibrinogen | 200 - 400 mg/dL | |
| D-dimer | < 0.5 µg/mL (< 500 ng/mL) | |
| PT | 11 - 13 seconds (INR 0.9 - 1.1) | |
| aPTT | 25 - 35 seconds | |
| ADA (Adenosine Deaminase) | Serum: < 20 U/L | Elevated in TB, lymphoma, hemolysis |
PART 1 - HIV/AIDS: STAGING & MONITORING
HIV Disease Progression by CD4 Count
| CD4 Count | Stage | OI Risk | Prophylaxis Needed |
|---|---|---|---|
| > 500 cells/µL | Asymptomatic HIV | None significant | None |
| 200 - 500 cells/µL | Symptomatic HIV (Category B) | TB, Herpes Zoster, oral thrush, bacterial pneumonia | TB screening; pneumococcal vaccine |
| < 200 cells/µL | AIDS-defining | PCP (Pneumocystis jirovecii) | TMP-SMX prophylaxis |
| < 150 cells/µL | Advanced AIDS | Histoplasmosis, Cryptococcal meningitis | |
| < 100 cells/µL | Severe AIDS | Toxoplasmosis, MAC (Mycobacterium avium complex) | Azithromycin prophylaxis for MAC |
| < 50 cells/µL | End-stage AIDS | CMV retinitis, PML (JC virus), disseminated MAC | Valganciclovir for CMV |
HIV Monitoring Panel (per Harriet Lane / Harrison's)
| Investigation | At Diagnosis | Every 3-6 Months on ART | Target on ART |
|---|---|---|---|
| CD4+ count | Baseline | Every 3-6 months | >500 cells/µL |
| HIV RNA viral load | Baseline | Monitor suppression | <50 copies/mL (undetectable) |
| Genotype resistance testing | At diagnosis | If virologic failure | - |
| CBC with differential | Baseline | Monitor (ART toxicity) | Normal |
| LFTs (ALT, AST, bilirubin) | Baseline | Monitor | Normal |
| Serum creatinine / GFR | Baseline | Monitor (tenofovir nephrotoxicity) | Normal |
| Fasting lipids | Baseline | Annually (ART-related dyslipidemia) | LDL <100 mg/dL |
| Fasting glucose | Baseline | Monitor (protease inhibitor-related DM) | <100 mg/dL |
| HLA-B*5701 | Before abacavir | Once only | Negative = safe to use |
| HBsAg, HBsAb, HBcAb | At diagnosis | Recheck if negative and at-risk | - |
| HCV antibody | At diagnosis | Recheck if at-risk | - |
| VDRL / RPR (syphilis) | At diagnosis | Annually if sexually active | Non-reactive |
| Toxoplasma IgG | At diagnosis | If CD4 <100 | - |
| CMV IgG | At diagnosis | If CD4 <50, add CMV PCR | - |
| Urinalysis | Baseline | Monitor | Normal |
Opportunistic Infections by CD4 - Specific Investigations
| OI | CD4 Threshold | Key Investigation | Diagnostic Value |
|---|---|---|---|
| PCP (Pneumocystis) | <200 | BAL with GMS/immunofluorescence; serum LDH; Beta-D-glucan | LDH >300 U/L; BDG positive; LDH rises with severity |
| Cryptococcal Meningitis | <100 | CSF India ink; serum/CSF CrAg (cryptococcal Ag); CSF culture | CrAg sensitivity >95% |
| CMV Retinitis | <50 | CMV PCR (blood); fundoscopy; CMV pp65 antigenemia | >500 copies/mL significant |
| MAC (M. avium complex) | <50 | Blood culture (lysis-centrifugation); blood AFB culture | Takes weeks; high-volume bacteremia |
| Toxoplasmosis | <100 | Serum Toxoplasma IgG (if negative, low risk); MRI brain (ring-enhancing lesions) | IgG positive + CD4<100 + ring lesions = treat empirically |
| PML (JC virus) | <50 | CSF JC virus PCR; MRI (T2 white matter lesions no mass effect) | JC PCR positive in CSF |
| Histoplasmosis | <150 | Urine/serum Histoplasma Ag; blood culture; bone marrow biopsy | Urine Ag sensitivity >90% in disseminated disease |
| Kaposi Sarcoma | Any (AIDS) | Clinical + skin/mucosal biopsy; HHV-8 PCR | HHV-8 DNA confirmed by PCR |
IRIS (Immune Reconstitution Inflammatory Syndrome)
| Feature | Finding |
|---|---|
| Trigger | ART initiation when CD4 <100 |
| Timing | Weeks to months after ART start |
| CD4 trend | Rising (paradox: worsening despite immunological improvement) |
| HIV viral load | Falling |
| CRP / ESR | Markedly elevated |
| Ferritin | Often very high (>500-1,000 ng/mL) |
| Common presentations | TB-IRIS, Cryptococcal IRIS, Herpes Zoster IRIS |
| TB-IRIS | New lymphadenopathy, fever, pulmonary infiltrates after ART start |
Sources: Harriet Lane Handbook 23e, p. 625; Firestein & Kelley's Rheumatology; Goldman-Cecil Medicine
PART 2 - VIRAL HEPATITIS: CHRONIC DISEASE MARKERS
Hepatitis B - Complete Serology Map
| Marker | Acute HBV | Chronic HBV (Active) | Chronic HBV (Inactive Carrier) | Resolved HBV | Vaccinated |
|---|---|---|---|---|---|
| HBsAg | + | + | + | - | - |
| Anti-HBs | - | - | - | + | + |
| Anti-HBc IgM | + (high titer) | - (or low) | - | - | - |
| Anti-HBc IgG | - | + | + | + | - |
| HBeAg | + | + | - | - | - |
| Anti-HBe | - | - | + | + | - |
| HBV DNA (PCR) | High (>200,000 IU/mL) | High (>2,000 IU/mL) | Low (<2,000 IU/mL) | Undetectable | Undetectable |
| ALT | Very high (>10x ULN) | Elevated or fluctuating | Normal | Normal | Normal |
| Interpretation | Active acute infection | Active chronic, infectious | Carrier state | Past infection, immune | Immune (vaccine) |
Window period: HBsAg cleared but anti-HBs not yet detectable - ONLY anti-HBc IgM is positive. This is the sole serologic marker during the window period. Henry's Clinical Diagnosis, p. 1477
Hepatitis B - Liver Disease Staging
| Investigation | Normal | Chronic Hepatitis B | Cirrhosis | HCC |
|---|---|---|---|---|
| HBV DNA | Undetectable | >2,000 IU/mL | May be low or high | Variable |
| ALT | 7-56 U/L | Elevated (1.5-5x ULN) | May normalize (burnt out) | May rise again |
| AST:ALT ratio | <1.0 | Usually <1.0 | >1.0 (AST>ALT = cirrhosis pattern) | >2.0 |
| GGT | 9-48 U/L | Mildly elevated | Elevated | High |
| Bilirubin | <1.2 mg/dL | Mildly elevated | Elevated (>2.5 mg/dL in decompensation) | High |
| Albumin | 3.5-5.0 g/dL | Normal | Low (<3.0 g/dL decompensated) | Very low |
| PT/INR | INR <1.2 | Normal | Prolonged INR >1.5 | Prolonged |
| Platelet count | 150,000-400,000 | Normal | Low (<100,000 = portal hypertension) | Low |
| AFP (alpha-fetoprotein) | <10 ng/mL | Mildly elevated | 10-100 ng/mL (watch) | >400 ng/mL strongly suggestive |
| Liver biopsy (Metavir) | F0 | F1-F2 | F3-F4 | N/A |
| FibroScan (kPa) | <7 kPa | 7-10 kPa | >12 kPa (F3-F4) | >17 kPa (cirrhosis) |
Hepatitis C - Diagnosis & Treatment Monitoring
| Investigation | Initial Screening | Confirmation | Pre-Treatment | SVR (Cure) |
|---|---|---|---|---|
| Anti-HCV antibody | Positive (ELISA) | Must do RNA next | - | Stays positive for life (not useful) |
| HCV RNA (PCR) | - | Positive = active infection | Quantify viral load | Undetectable at 12 weeks post-Rx = SVR |
| HCV Genotype | - | - | Types 1-6; guides DAA selection | - |
| ALT | Elevated | - | Severity of inflammation | Normal (cure) |
| Platelet count | - | - | Low = cirrhosis/portal HTN | Rising after cure |
| Cryoglobulins | - | - | Positive in 40-50% chronic HCV | Resolve after SVR |
| Serum IgM | - | - | Elevated (cryoglobulinemic vasculitis) | Falls after SVR |
| Rheumatoid Factor | - | - | May be positive (cryoglobulin-related) | Falls after SVR |
| Urinalysis | - | - | Proteinuria + hematuria = MPGN | Resolves after SVR |
Henry's Clinical Diagnosis (Hepatitis B & C, p. 1477-1882)
PART 3 - FUNGAL & PARASITIC CHRONIC INFECTIONS
Aspergillosis (in Immunocompromised)
| Investigation | Normal | Invasive Aspergillosis | Chronic Pulmonary | Allergic (ABPA) |
|---|---|---|---|---|
| Serum Galactomannan (GM) | <0.5 ODI | >0.5-1.0 (positive, two consecutive) | May be positive | Usually negative |
| Beta-D-glucan (BDG) | <60-80 pg/mL | Positive (>80 pg/mL) | Positive | Negative |
| Serum Aspergillus IgG | Negative | May be low (immunocompromised) | Positive | Positive |
| Serum Aspergillus IgE (specific) | <0.35 kU/L | - | - | Elevated (>0.35) |
| Total IgE | <100 IU/mL | Normal | Normal | Very high (>1,000 IU/mL) |
| Eosinophils | 1-4% | Normal | Normal | Elevated (>500/µL) |
| BAL GM | <1.0 | >1.0 (high sensitivity) | - | - |
| CT chest | Normal | "Halo sign" (early), "air-crescent sign" (late), cavitation | Cavitation + aspergilloma | Mucoid impaction, central bronchiectasis |
| WBC | Normal | Often low (neutropenic patient) | Normal | Normal-high |
Cryptococcosis
| Investigation | Normal | Cryptococcal Meningitis | Disseminated |
|---|---|---|---|
| Serum CrAg (cryptococcal Ag) | Negative | Positive (sensitivity >95%) | Positive |
| CSF CrAg | Negative | Very high titer (1:1,024 or more) | - |
| CSF India ink | Negative | Encapsulated yeast with clear halo | - |
| CSF Opening pressure | 7-18 cmH2O | Very high (>25-40 cmH2O) | - |
| CSF WBC | <5 cells/µL | Mild lymphocytosis (10-50) or even normal in severe AIDS | - |
| CSF Glucose | 45-80 mg/dL | Low to normal | - |
| CSF protein | 15-45 mg/dL | Elevated | - |
| CD4 count | >500 | Usually <100 cells/µL | <50 cells/µL |
| Urine Ag | Negative | Positive (disseminated) | Positive |
Leishmaniasis (Visceral / Kala-azar)
| Investigation | Finding |
|---|---|
| WBC | Very low (leukopenia 1,000-3,000) |
| Hemoglobin | Low (<8 g/dL, normochromic normocytic) |
| Platelets | Very low (<50,000) - pancytopenia pattern |
| ESR | Very high (>100 mm/hr) |
| Serum globulins (IgG) | Markedly elevated (hypergammaglobulinemia - reversed A:G ratio) |
| Serum albumin | Low (<3.0 g/dL) |
| LFTs | AST/ALT elevated, bilirubin elevated |
| Bone marrow / splenic aspirate | Leishman-Donovan (LD) bodies (intracellular amastigotes) - gold standard |
| rK39 rapid antibody test | Positive (sensitivity ~97% in South Asia) |
| Aldehyde test (Napier's) | Positive (gel-like coagulation due to hypergammaglobulinemia) - historical |
PART 4 - SEPSIS & ADVANCED ORGAN DYSFUNCTION
SOFA Score - Laboratory Components
| Organ System | Investigation | SOFA 0 (Normal) | SOFA 1 | SOFA 2 | SOFA 3 | SOFA 4 |
|---|---|---|---|---|---|---|
| Respiration | PaO2/FiO2 ratio | >400 | 300-400 | 200-300 | 100-200 | <100 |
| Coagulation | Platelets (/µL) | >150,000 | 100-150k | 50-100k | 20-50k | <20,000 |
| Liver | Bilirubin (mg/dL) | <1.2 | 1.2-2.0 | 2.0-6.0 | 6.0-12.0 | >12.0 |
| Cardiovascular | MAP / vasopressors | MAP >70 | MAP <70 | Low-dose dopamine | High-dose dopamine | Norepinephrine + |
| Renal | Creatinine (mg/dL) | <1.2 | 1.2-2.0 | 2.0-3.5 | 3.5-5.0 | >5.0 |
| CNS | GCS | 15 | 13-14 | 10-12 | 6-9 | <6 |
SOFA ≥2 = organ dysfunction. SOFA rise >2 = sepsis (Sepsis-3 criteria, 2016).
Disseminated Intravascular Coagulation (DIC)
| Investigation | Normal | DIC (Active/Overt) | DIC (Chronic/Low-grade) |
|---|---|---|---|
| PT | 11-13 sec | Prolonged (>14 sec) | Mildly prolonged |
| aPTT | 25-35 sec | Prolonged (>40 sec) | Normal or mildly prolonged |
| Fibrinogen | 200-400 mg/dL | Very low (<150 mg/dL) | Normal-low (compensated) |
| D-dimer | <0.5 µg/mL | Very high (>4-10 µg/mL) | Elevated (>1-2 µg/mL) |
| FDPs (fibrin degradation products) | <5 µg/mL | Very high | Elevated |
| Platelets | 150,000-400,000 | Rapidly falling (<50,000 in severe) | Low-normal |
| Schistocytes (blood film) | 0-<1% | >1% (microangiopathic hemolysis) | May be present |
| Antithrombin III | 80-120% | Very low (<50%) | Moderately low |
| Factor V / VIII levels | 50-150% | Very low | Low |
| Common causes | - | Gram-negative sepsis, trauma, obstetric crises, AML-M3 | Malignancy, chronic infection |
Symptom to Diagnosis 4th Ed: DIC = thrombocytopenia + prolonged PT + reduced fibrinogen + elevated D-dimer
PART 5 - IMMUNE COMPLICATIONS: AUTOIMMUNITY
Systemic Lupus Erythematosus (SLE) - EULAR/ACR 2019
| Investigation | Normal | SLE (Active) | SLE (Remission) | Clinical Weight (EULAR score) |
|---|---|---|---|---|
| ANA (ELISA/IIF) | Negative (<1:40) | Positive ≥1:80 (>95% sensitivity - entry criterion) | May stay positive | Entry criterion |
| Anti-dsDNA | Negative (<7 IU/mL) | Highly positive; titre correlates with disease activity | Falls in remission | +6 points |
| Anti-Sm (Smith) | Negative | Positive in ~30% - highly specific (>99%) | Persists | +6 points |
| Anti-Ro/SSA | Negative | Positive in ~50-70% | Persists | - |
| Anti-La/SSB | Negative | Positive in ~30-40% | Persists | - |
| Anti-phospholipid Ab (aCL, LAC, anti-B2GP1) | Negative | Positive in ~40% | Variable | +2 points each |
| C3 | 90-180 mg/dL | Low (<90 mg/dL) - active nephritis | Normalizes with treatment | +3 points (low C3 or C4) |
| C4 | 16-47 mg/dL | Very low (<16 mg/dL) | Normalizes | +4 points (both low) |
| CH50 | 41-90 U/mL | Very low or undetectable | Normalizes | - |
| CBC | Normal | Hemolytic anemia (+4), leukopenia <4,000 (+3), thrombocytopenia <100,000 (+4) | May normalize | +3 to +4 |
| Direct Coombs test | Negative | Positive (autoimmune hemolytic anemia) | - | +4 |
| Urinalysis | Normal | Proteinuria >0.5g/day, RBC casts = lupus nephritis | Minimal protein | +4-8 |
| ESR | <20 mm/hr | Very high (>60-100 mm/hr) during flare | Mildly elevated | - |
| CRP | <10 mg/L | Notably: CRP is often NORMAL or only mildly elevated in SLE flare (unlike RA) | - | Key differentiator |
Clue: High ESR + normal/low CRP in a febrile patient = think SLE flare (not sepsis, where CRP is always high) Goldman-Cecil Medicine; Fuster & Hurst's The Heart 15e
Rheumatoid Arthritis (RA)
| Investigation | Normal | Early RA | Established RA | Severe/Extra-articular RA |
|---|---|---|---|---|
| RF (IgM Rheumatoid Factor) | <14 IU/mL | Positive in ~70% | Positive | Very high titers |
| Anti-CCP (ACPA) | <20 U/mL | Positive in ~70-80% - more specific than RF | Positive | High |
| CRP | <10 mg/L | Elevated (20-100 mg/L) | Elevated correlates with activity | Very high in flare |
| ESR | <20 mm/hr | Elevated | Elevated (50-100 mm/hr) | Very high |
| CBC - Anemia | Hb 12-17 g/dL | Normal early | Normochromic normocytic (ACD) | Severe ACD; also drug-related |
| Platelet count | 150-400k | Normal | Elevated (reactive thrombocytosis) | Elevated |
| WBC | 4-11k | Normal or mildly elevated | Normal | Low (Felty syndrome: RA + splenomegaly + neutropenia) |
| ANA | Negative | May be weakly positive (30%) | - | - |
| Complement | Normal | Normal (RA = normocomplementemic) | Normal | Consumed in RA vasculitis |
| Synovial fluid WBC | <200 cells/µL | 2,000-50,000 (inflammatory) | Inflammatory | >50,000 = septic arthritis must be ruled out |
| X-ray | Normal | Periarticular osteopenia, soft tissue swelling | Juxta-articular erosions | Severe erosions, joint destruction |
Sjögren's Syndrome
| Investigation | Finding |
|---|---|
| Anti-Ro/SSA | Positive in ~70-80% (most specific) |
| Anti-La/SSB | Positive in ~40-60% |
| ANA | Positive in ~80% |
| RF | Positive in ~75% (high levels - cryoglobulin-associated) |
| Serum IgG | Elevated (hypergammaglobulinemia) |
| Serum IgM | Elevated (cryoglobulins) |
| Complement (C3, C4) | Low in those with cryoglobulinemia |
| CBC | Mild lymphopenia, mild anemia |
| ESR | Elevated |
| CRP | Mildly elevated |
| Schirmer's test | <5 mm wetting in 5 min = dry eyes |
| Salivary gland biopsy | Focal lymphocytic sialadenitis (focus score >1) |
| Serum protein electrophoresis | Polyclonal hypergammaglobulinemia |
PART 6 - PRIMARY IMMUNODEFICIENCIES
Antibody Deficiency Disorders
| Condition | IgG | IgA | IgM | B-cells | Key Investigation | Clinical Pattern |
|---|---|---|---|---|---|---|
| XLA (Bruton's agammaglobulinemia) | Very low (<2 g/dL) | Very low | Very low | Absent | BTK gene mutation; absent B-cells (flow cytometry) | Recurrent bacterial infections from infancy; no viral susceptibility |
| CVID (Common Variable ID) | Low (<7 g/dL; <2 SD below mean) | Low | Low or normal | Normal or low number, dysfunctional | Vaccine response absent; B-cell phenotyping | Presents in 2nd-3rd decade; also autoimmunity, lymphoma risk |
| IgA Deficiency | Normal | Very low (<7 mg/dL) | Normal | Normal | Serum IgA level | Recurrent sinopulmonary infections; anaphylaxis to blood products |
| Hyper-IgM Syndrome | Very low | Very low | Normal or elevated | Normal | CD40L expression (flow cytometry); gene testing | Pneumocystis, Cryptosporidium infections; neutropenia |
| Steroid-induced hypogammaglobulinemia | Moderately low (>400 mg/dL) | May be low | Normal | Normal | Clinical context; dose-dependent | Dose and duration-dependent |
Goldman-Cecil Medicine (Common Variable ID); Murray & Nadel's Respiratory Medicine (antibody deficiencies)
T-Cell / Combined Immunodeficiency
| Condition | CD4 | CD8 | B-cells | NK cells | Ig Levels | Key Test |
|---|---|---|---|---|---|---|
| SCID (Severe Combined ID) | Absent or very low | Absent or very low | Present or absent | Variable | Very low all | Absent thymic shadow on CXR; lymphocyte proliferation assay - absent |
| DiGeorge Syndrome | Very low | Very low | Normal | Normal | Normal or low | FISH for 22q11.2 deletion; low PTH + hypocalcemia |
| Wiskott-Aldrich | Progressively low | Normal | Normal | Low | IgM low; IgA/E elevated; IgG normal | WASp protein by flow cytometry; WAS gene |
| Ataxia-Telangiectasia | Low | Normal | Normal | Normal | IgA very low; IgE low; IgG may be low | AFP very high (>10 ng/mL) - hallmark; chromosomal breakage studies |
| Chronic Granulomatous Disease (CGD) | Normal | Normal | Normal | Normal | Normal | DHR (dihydrorhodamine) flow cytometry - absent oxidative burst; NBT test |
PART 7 - HAEMATOLOGICAL IMMUNE COMPLICATIONS
Haemophagocytic Lymphohistiocytosis (HLH)
This is a life-threatening hyperinflammatory syndrome triggered by infections (EBV most common), malignancy, or autoimmune disease.
| Investigation | Normal | HLH (HScore/HLH-2004 criteria) | Significance |
|---|---|---|---|
| Ferritin | 12-300 ng/mL | >500 ng/mL (>10,000 = highly specific) | Most sensitive marker; tracks disease activity |
| Temperature | 36.1-37.2°C | >38.5°C (persistent) | Criterion |
| Spleen | Normal | Splenomegaly | Criterion |
| CBC - Cytopenia | Normal | ≥2 cell lines low (Hb <9g/dL; Plt <100k; Neutrophils <1,000) | Criterion |
| Triglycerides (fasting) | <150 mg/dL | >265 mg/dL (≥3 mmol/L) | Criterion |
| Fibrinogen | 200-400 mg/dL | Low (<150 mg/dL) | Criterion |
| Bone marrow biopsy | Normal | Haemophagocytosis (macrophages engulfing RBCs, WBCs, platelets) | Criterion |
| NK cell activity | Normal | Very low or absent | Criterion |
| sCD25 (soluble IL-2 receptor) | <2,400 U/mL | Very high (>2,400 U/mL; often >10,000) | Criterion; correlates with T-cell activation |
| LDH | 140-280 U/L | Very high (>600-1,000 U/L) | Tissue destruction |
| CRP | <10 mg/L | Very high (>100-300 mg/L) | Inflammation |
| EBV PCR | Undetectable | Positive in EBV-HLH | Identifies trigger |
| AST/ALT | <40 U/L | Markedly elevated | Hepatitis from haemophagocytosis |
5 of 8 HLH-2004 criteria = diagnosis. Ferritin >10,000 + cytopenia + high triglycerides = strong suspicion.
Macrophage Activation Syndrome (MAS) - Overlap with HLH in Rheumatic Disease
| Investigation | Normal | MAS (complicating SLE/sJIA) |
|---|---|---|
| Ferritin | <300 ng/mL | Rapid rise >500 ng/mL; often >10,000 |
| ESR | <20 mm/hr | Paradoxically FALLS (fibrinogen being consumed) - key differentiator from SLE flare |
| CRP | <10 mg/L | Markedly elevated |
| Platelets | >150k | Rapidly falling |
| Fibrinogen | 200-400 | Falling |
| D-dimer | <0.5 | Rising |
| WBC | 4-11k | Falling (leukopenia) |
| LDH | 140-280 | Very high |
| AST/ALT | Normal | Elevated |
Clinical clue: A patient with active autoimmune disease who develops FALLING ESR + RISING ferritin + pancytopenia = think MAS before thinking disease flare.
MASTER PATTERN RECOGNITION TABLE
| Lab Pattern | Think First | Also Consider |
|---|---|---|
| CD4 <200 + lymphocytosis (atypical) + LDH very high + BDG positive | PCP pneumonia | Cryptosporidiosis |
| Pancytopenia + very high ferritin (>10,000) + splenomegaly + haemophagocytes on BM | HLH | MAS, disseminated TB |
| HBsAg+ >6 months + HBeAg+ + high HBV DNA + elevated ALT | Active chronic hepatitis B | Needs antiviral therapy |
| Anti-HCV+ but HCV RNA undetectable | Cleared/resolved HCV (no treatment needed) | False-positive Ab screen |
| High ANA + high anti-dsDNA + low C3/C4 + proteinuria + normal CRP | Active SLE (nephritis) | Drug-induced lupus (no low complement) |
| High RF + high anti-CCP + high CRP + elevated platelet | Rheumatoid Arthritis | - |
| Reversed albumin:globulin ratio + pancytopenia + splenomegaly + fever in endemic area | Visceral Leishmaniasis | |
| Rising CD4 + falling viral load + NEW fever/lymphadenopathy + high CRP | IRIS (immune reconstitution) | ART drug reaction |
| PT prolonged + aPTT prolonged + fibrinogen very low + D-dimer very high + schistocytes | DIC (sepsis, trauma, obstetric) | TTP (normal PT/fibrinogen; schistocytes + very low platelets) |
| IgG very low + IgA very low + IgM very low + absent B-cells in male infant | XLA (Bruton's) | SCID |
| IgA isolated low + recurrent sinopulmonary infections + normal other Ig | Selective IgA deficiency | - |
| AFP very high + cerebellar ataxia + telangiectasias | Ataxia-Telangiectasia | - |
BIOMARKER SEVERITY LADDER - AT A GLANCE
| Biomarker | Mild Disease | Moderate | Severe | Life-Threatening |
|---|---|---|---|---|
| Ferritin | 300-1,000 | 1,000-5,000 | 5,000-10,000 | >10,000 (HLH/MAS) |
| D-dimer | 0.5-1.0 µg/mL | 1-4 µg/mL | >4 µg/mL | >10 µg/mL (overt DIC) |
| LDH | 280-500 | 500-1,000 | 1,000-2,000 | >2,000 (HLH, PCP, severe hemolysis) |
| Beta-2 microglobulin | 2.5-4 mg/L | 4-6 mg/L | >6 mg/L | (lymphoma, CKD staging, HIV severity) |
| sCD25 (IL-2R) | Mildly elevated | 2,400-5,000 U/mL | 5,000-10,000 | >10,000 (HLH) |
| CD4 count | 200-500 (HIV) | 100-200 | 50-100 | <50 (end-stage AIDS) |
Sources: Harrison's Principles of Internal Medicine 22E | Goldman-Cecil Medicine | Harriet Lane Handbook 23e | Henry's Clinical Diagnosis and Management by Laboratory Methods | Firestein & Kelley's Textbook of Rheumatology | Murray & Nadel's Respiratory Medicine | Dermatology 5e (EULAR/ACR SLE criteria) | Symptom to Diagnosis 4th Ed | Tietz Textbook of Laboratory Medicine 7e
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