Clinical Workup: 26-Year-Old Male, Recurrent Fever After Discharge

Clinical Summary (What We Know)

Step 1 - Think About the Top Differentials

A. Rickettsial Disease (Most Likely, Inadequately Treated)

• Subacute fever for weeks, tachycardia, hypoxia
• Bilateral consolidation / interstitial pneumonia (develops in severe cases due to vascular endothelial injury - Harrison's 22E, Section 192)
• Responds to doxycycline
• BUT: treatment duration matters - requires 7-15 days oral doxycycline; if discharged early on a short course, relapse is expected
• In severe scrub typhus, combination doxycycline + azithromycin is superior to monotherapy (Harrison's 22E); some strains (especially in South/Southeast Asia) are doxycycline-resistant and respond only to azithromycin + rifampin

B. HIV / Immunodeficiency with Opportunistic Infection

• 26-year-old male: HIV must be excluded first
• PJP (Pneumocystis jirovecii Pneumonia): bilateral diffuse infiltrates, severe hypoxia disproportionate to clinical appearance, responds to steroids acutely, relapses without adequate TMP-SMX treatment
• CMV pneumonitis, cryptococcal disease, atypical mycobacteria (MAC) - all possible in undiagnosed HIV
• The use of steroids without HIV testing/PJP treatment is potentially dangerous

C. Pulmonary Tuberculosis ± Co-infection

• 1-month fever, young male, bilateral consolidation in a TB-endemic region
• Sputum smear/GeneXpert may be negative early
• Steroid-induced immune suppression can unmask TB

D. Fungal Infection

• Pulmonary histoplasmosis, aspergillosis, or mucormycosis (especially if immunocompromised or diabetic)
• Can mimic bacterial pneumonia, respond partially to antibiotics, then relapse

E. Autoimmune / Cryptogenic

• Cryptogenic organizing pneumonia (COP): fever, patchy consolidation, good steroid response but classic relapse on steroid taper
• Hypersensitivity pneumonitis
• Eosinophilic pneumonia

Step 2 - Workup on Re-presentation

Tier 1 - MUST DO Immediately

Tier 2 - High Yield if HIV Positive or Immunocompromised

Tier 3 - If Rickettsial Relapse Suspected

Tier 4 - If Autoimmune / COP Suspected

Step 3 - Examine the Patient Again (Do Not Skip This)

• Eschar (painless black scab, often missed - axilla, groin, behind ear, hairline) - pathognomonic of scrub typhus
• Lymphadenopathy - scrub typhus, HIV, lymphoma
• Hepatosplenomegaly - rickettsial disease, HIV, lymphoma, TB
• Rash - maculopapular (rickettsial, measles); oral thrush (HIV/immunocompromise)
• Weight loss history - TB, HIV, malignancy
• Risk factors for HIV - sexual history, IV drug use, transfusion history

Step 4 - Immediate Management While Awaiting Results

1. Do NOT restart steroids blindly - if PJP or TB is possible, steroids alone will worsen the patient
2. Continue/resume doxycycline (100 mg PO BD) if rickettsial relapse is suspected, but for a full 14-day total course with azithromycin combination if severe
3. If HIV+ with CD4 <200 and PJP suspected: Start TMP-SMX (15-20 mg/kg/day in 3-4 divided doses) + adjunctive prednisolone only if PaO2 <70 mmHg
4. Empirical TB treatment only if AFB positive or strong clinical suspicion confirmed by GeneXpert
5. Repeat SpO2 and blood gas to assess current respiratory status

Diagnostic Algorithm Summary

Re-presented fever
       │
       ├── HIV test (MANDATORY FIRST)
       │        │
       │        ├── HIV+ → CD4, viral load, PJP workup, CrAg, CMV
       │        │
       │        └── HIV– → Continue below
       │
       ├── CBC: Leukopenia + thrombocytopenia? → Rickettsia/Scrub typhus serology
       │
       ├── Look for eschar → Scrub typhus PCR + serology
       │
       ├── Sputum AFB + GeneXpert → TB excluded?
       │
       ├── LDH markedly elevated → PJP even if HIV–? (consider BAL)
       │
       └── Steroid taper relapse + no infection found → COP → Lung biopsy

Key Teaching Points in This Case

1. A 5-day prednisolone course after rickettsial disease may suppress fever temporarily but does not treat the underlying infection - relapse is predictable if doxycycline was not continued for a full course (7-15 days total)
2. Severe scrub typhus with pneumonitis benefits from combination doxycycline + azithromycin, not monotherapy, per a 2023 NEJM trial cited in Harrison's 22E
3. Bilateral patchy consolidation + severe hypoxia + young male = always exclude HIV/PJP before attributing to any other cause
4. Cryptogenic organizing pneumonia is a classic steroid-taper-relapse diagnosis - but only made after infections are excluded
5. Do not discharge a febrile patient with hypoxia on short steroid course without a confirmed diagnosis - this creates exactly the scenario seen here

• Harrison's Principles of Internal Medicine 22E (2025), Chapter 192 "Rickettsial Diseases" - scrub typhus clinical features, diagnosis, and combination therapy recommendation
• Goldman-Cecil Medicine, Chapter on Pneumocystis jirovecii pneumonia
• Scrub typhus combination antibiotic therapy review (Chung et al., Infect Chemother, 2023 - PMID 37407239)
• Scrub typhus presenting as lobar pneumonia (Vihari et al., Natl Med J India, 2024 - PMID 39448532)

Clinical Evaluation: 45-Year-Old Postmenopausal Female with Generalised Swelling, Dry Skin, Constipation, Slow Speech/Gait, Hair Loss

The Core Diagnostic Problem

• Was it TSH only (the most common "thyroid test" done at peripheral hospitals)?
• Was free T4 measured?
• Was free T3 measured?
• What assay was used, and what reference range was applied?

Step 1 - Recognise the Syndrome

Step 2 - Why "Normal Thyroid Tests" Should NOT Reassure You

A. Central (Secondary/Tertiary) Hypothyroidism

• Caused by pituitary or hypothalamic failure
• TSH is low, normal, or only mildly elevated - NOT high
• Free T4 is low
• This is the most dangerous pitfall - a "normal TSH" completely misses it
• Cummings Otolaryngology table: "Pituitary hypothyroidism: Free T4 = Low; TSH = Normal, low, or slightly high"
• Harrison's 22E: "Secondary or central hypothyroidism is usually diagnosed in the context of other anterior pituitary hormone deficiencies; TSH levels may be low, normal..."

B. Subclinical (Early) Hypothyroidism - Progressed to Overt Now

• 3 months ago: TSH was borderline high but within lab "normal range" (lab normals vary widely)
• Today: disease has progressed, TSH is now clearly elevated
• The disease progressed - she has had symptoms for 4 years; 3 months ago may have been early stage

C. Euthyroid Sick Syndrome / Non-Thyroidal Illness

• Seen in patients with chronic systemic illness (nephrotic syndrome, heart failure, malignancy)
• T3 is low, T4 and TSH may be "normal" - mimics hypothyroidism clinically
• These patients have an underlying primary illness causing both the sick euthyroid picture and the oedema/symptoms

Step 3 - Structured Workup (Tier by Tier)

Tier 1 - Thyroid Panel (Repeat, Complete)

Tier 2 - Confirm/Exclude Central Hypothyroidism (If TSH is Normal/Low with Low fT4)

Tier 3 - Exclude Non-Thyroid Causes of the Same Clinical Picture

Tier 4 - Associated Autoimmune Workup (If Hashimoto's Confirmed)

• Pernicious anaemia (anti-intrinsic factor antibody, serum B12)
• Addison's disease - Schmidt's syndrome (morning cortisol, ACTH stimulation test)
• Type 1 diabetes (fasting glucose, HbA1c)
• Vitiligo (clinical exam)
• Coeliac disease (anti-tissue transglutaminase IgA, total IgA)
• Rheumatoid arthritis, SLE (ANA, anti-dsDNA, RF, anti-CCP)

Diagnostic Algorithm to Follow (from Harrison's 22E)

Step 4 - Clinical Examination Points Not to Miss

• Periorbital puffiness - characteristic myxoedematous facies
• Puffy hands and feet (non-pitting oedema - press firmly; true myxoedema does not pit)
• Madarosis - loss of outer third of eyebrows (highly specific for hypothyroidism)
• Thyroid size - goitre suggests Hashimoto's; impalpable gland = atrophic thyroiditis or central
• Delayed relaxation of Achilles tendon reflex - pathognomonic of hypothyroidism
• Bradycardia - resting HR <60 in a symptomatic patient
• Hoarse, slow, low-pitched voice - myxoedema voice
• Dry, rough, cool skin with yellowish tint (carotenaemia due to reduced conversion of beta-carotene)
• Diffuse hair thinning - check scalp, axillae, pubic area (for panhypopituitarism)
• Signs of pericardial effusion - muffled heart sounds, raised JVP
• Visual fields - bitemporal hemianopia if pituitary macroadenoma
• Signs of Addison's - hyperpigmentation, postural hypotension (autoimmune polyendocrinopathy)

Step 5 - Why She Worsened in the Last 1 Week

• Infection (any intercurrent illness)
• Cold exposure
• Unrelated medication (sedatives, diuretics)
• Non-compliance with any pre-existing thyroid therapy she may not have disclosed
• Alert: If she develops altered sensorium, hypothermia, bradycardia, hypoventilation, hyponatraemia - this is myxoedema coma, a medical emergency requiring ICU admission, IV T3 or T4, IV hydrocortisone, passive rewarming, and treatment of the precipitant.

Most Probable Diagnosis

1. Only TSH was checked and it was subclinically elevated (borderline), or
2. The test was done at a different lab with a wider "normal" range, or
3. The disease was subclinical then and has progressed to overt now

Summary of Immediate Tests to Order

1. TSH + free T4 + free T3 (repeat, complete panel - not TSH alone)
2. Anti-TPO + anti-Tg antibodies
3. Thyroid ultrasound
4. Serum albumin + urine protein (to exclude nephrotic/hypoalbuminaemic oedema)
5. CBC, LFT, RFT, lipids (hypothyroidism raises LDL and triglycerides; CPK often elevated)
6. ECG (bradycardia, low-voltage complexes if pericardial effusion)
7. Echocardiogram (pericardial effusion occurs in ~30% of hypothyroid patients)
8. Morning cortisol (if pituitary disease considered or if any suggestion of Addison's)