Granulomatous-Lymphocytic Interstitial Lung Disease: A Clinician's Guide to Diagnosis and Management

Dr Neeraj Manikath , claude.ai

Introduction

Granulomatous-Lymphocytic Interstitial Lung Disease (GL-ILD) represents one of the most diagnostically challenging and therapeutically nuanced entities in modern pulmonology and immunology. This rare pulmonary complication, most commonly associated with Common Variable Immunodeficiency (CVID), affects approximately 10-20% of CVID patients and carries significant morbidity and mortality. The histopathological hallmark—a unique admixture of non-necrotizing granulomas and lymphocytic infiltration—creates a diagnostic conundrum that often mimics sarcoidosis, lymphoma, and infectious processes. For the astute clinician, recognizing the subtle clinical, radiological, and immunological clues can mean the difference between timely intervention and irreversible pulmonary fibrosis.

This review synthesizes current evidence with practical bedside wisdom accumulated over decades of managing these complex patients, offering actionable insights for post-graduate trainees and consultant physicians alike.

Common Variable Immunodeficiency (CVID) with GL-ILD: The Rituximab vs. Mycophenolate Decision

The Clinical Dilemma

When faced with a CVID patient developing GL-ILD, the therapeutic decision between rituximab and mycophenolate mofetil (MMF) represents a critical juncture. This choice isn't merely academic—it fundamentally affects disease trajectory, infection risk, and quality of life.

Pearl #1: The B-cell Paradox
Despite hypogammaglobulinemia, CVID patients with GL-ILD demonstrate paradoxical B-cell hyperactivity with lymphocytic infiltration. This is why B-cell depletion with rituximab can be remarkably effective, even in the context of apparent B-cell dysfunction (Bates et al., 2005).

Rituximab: The Mechanistic Rationale

Rituximab (375 mg/m² weekly for 4 weeks, or 1000 mg on days 1 and 15) works by depleting CD20+ B-cells, thereby reducing the lymphocytic component of GL-ILD. The evidence base, while largely retrospective, is compelling:

• Chase et al. (2013) demonstrated radiological improvement in 67% of CVID-GLILD patients treated with rituximab
• Reduction in organomegaly (splenomegaly, lymphadenopathy) often precedes pulmonary improvement
• FVC improvements of 10-15% observed in responders within 6-12 months

Clinical Hack: The Spleen Size Predictor
Before starting rituximab, measure splenic size on CT. Patients with significant splenomegaly (>13 cm in craniocaudal dimension) respond better to rituximab, as this suggests a more prominent lymphoproliferative component. This simple observation can guide your therapeutic choice.

Oyster #1: The Infection Window
The first 3-6 months post-rituximab represent the highest infection risk. Despite ongoing immunoglobulin replacement therapy (IgRT), ensure:

• Pneumocystis jirovecii prophylaxis (trimethoprim-sulfamethoxazole DS three times weekly)
• Aggressive workup of any fever (blood cultures, respiratory viral panel, fungal markers)
• Lower threshold for empiric antimicrobials

Mycophenolate Mofetil: The Alternative Path

MMF (starting 500-1000 mg twice daily, titrating to 1500 mg twice daily) offers a less aggressive immunosuppressive approach with theoretical advantages:

• Preserves residual B-cell function
• Lower risk of severe hypogammaglobulinemia worsening
• May be better tolerated in elderly patients or those with multiple comorbidities

Studies by Boursiquot et al. (2013) and Mannina et al. (2019) suggest comparable efficacy to rituximab in selected patients, with stabilization of pulmonary function in 60-70% of cases.

Bedside Nuance: The Lymphocyte Subset Analysis
Before choosing therapy, request lymphocyte subsets with B-cell enumeration. If CD19+ B-cells are already profoundly depleted (<1% of lymphocytes), rituximab offers little additional benefit—opt for MMF instead. This simple test prevents unnecessary therapy.

The Decision Matrix: A Practical Approach

Consider Rituximab when:

• Significant splenomegaly or lymphadenopathy present
• Rapid progression of pulmonary disease (FVC decline >10% in 6 months)
• Nodular lymphoid hyperplasia prominent on imaging
• Failed corticosteroid trial
• Age <60 years with reasonable infection control history

Consider MMF when:

• Minimal extrapulmonary lymphoproliferation
• B-cells already depleted (<1%)
• Elderly patients (>70 years)
• History of recurrent severe infections despite adequate IgRT
• Slower, indolent disease progression

Triple Therapy Pearl:
In severe, rapidly progressive cases, consider combination: rituximab (induction) + azathioprine or MMF (maintenance) + prednisone (0.5 mg/kg tapered over 6 months). Tauber et al. (2014) reported superior outcomes with this approach in refractory cases, though infection monitoring must be meticulous.

The Sarcoidosis-CVID Overlap: Granulomatous Disease with Hypogammaglobulinemia

Diagnostic Confusion at the Bedside

The clinical overlap between sarcoidosis and CVID with GL-ILD creates diagnostic paralysis. Both present with:

• Non-necrotizing granulomas on biopsy
• Hilar/mediastinal lymphadenopathy
• Restrictive pulmonary physiology
• Constitutional symptoms

Yet, the distinction is critical—treatment paradigms diverge dramatically.

Oyster #2: The Immunoglobulin Revelation
Always measure quantitative immunoglobulins in any patient with "sarcoidosis" before initiating treatment. Missing CVID in a presumed sarcoid patient leads to:

• Ineffective corticosteroid monotherapy
• Progressive immunodeficiency
• Preventable infections
• Missed opportunity for IgRT

The Diagnostic Algorithm: Seven Steps to Clarity

Step 1: Quantitative Immunoglobulins (Not Just Total Protein)
Request IgG, IgA, IgM. CVID criteria require:

• IgG <400 mg/dL (more than 2 SD below normal)
• Plus reduced IgA and/or IgM
• Exclude secondary causes

Step 2: Vaccination Response Testing
The pneumococcal polysaccharide vaccine (PPSV23) response test is gold. Measure pre-vaccination titers to ≥3 serotypes, vaccinate, and remeasure at 4-6 weeks. CVID patients demonstrate poor response (<50% protective titers), whereas sarcoid patients respond normally.

Clinical Hack: The Tetanus Booster Shortcut
If PPSV23 testing is unavailable or delayed, a tetanus-diphtheria booster with pre- and post-titers (4 weeks) serves as a rapid protein antigen response test. CVID patients show blunted responses, helping differentiate from sarcoidosis within a month rather than waiting months for pneumococcal testing.

Step 3: Lymphocyte Phenotyping
CVID demonstrates characteristic abnormalities:

• Reduced switched memory B-cells (CD27+IgD-IgM-) <2% of B-cells
• Expanded CD21low B-cells (>10% suggests immune dysregulation)
• Inverted CD4:CD8 ratio in some patients

Sarcoidosis typically shows normal B-cell compartments with expanded CD4+ T-cells and elevated CD4:CD8 ratio in bronchoalveolar lavage (BAL) fluid.

Step 4: Angiotensin-Converting Enzyme (ACE) Levels—Use with Caution
Elevated ACE supports sarcoidosis but lacks specificity. GL-ILD can also show mild ACE elevation (20-30% of cases).

Pearl #2: The ACE Pitfall
Don't exclude CVID based on elevated ACE alone. Conversely, normal ACE doesn't exclude sarcoidosis (40% of sarcoid patients have normal levels). Use ACE as corroborative, never definitive, evidence.

Step 5: Bronchoalveolar Lavage (BAL) Analysis
BAL in GL-ILD shows:

• Mixed lymphocytosis (both CD4+ and CD8+)
• CD4:CD8 ratio typically <3.5 (vs. >3.5 in sarcoidosis)
• Occasional plasma cells
• Exclude infection (bacterial, mycobacterial, fungal, viral PCR)

Step 6: Tissue Architecture on Biopsy
Surgical lung biopsy (VATS) remains gold standard when diagnosis is uncertain. Key differentiators:

GL-ILD:

• Granulomas less well-formed, loosely organized
• Prominent lymphoid follicles with germinal centers
• Bronchocentric distribution of lesions
• Follicular bronchiolitis component
• Lymphoid interstitial pneumonia pattern

Sarcoidosis:

• Tight, compact "naked" granulomas
• Perilymphatic distribution (along bronchovascular bundles, interlobular septa, pleura)
• Less prominent lymphoid follicles

Step 7: Extrapulmonary Manifestations
CVID patients often have:

• Chronic sinusitis/bronchiectasis (70-80%)
• Gastrointestinal disease (IBD-like, nodular lymphoid hyperplasia, malabsorption)
• Autoimmune cytopenias (ITP, AIHA)
• Hepatosplenomegaly
• Increased malignancy risk (especially lymphoma, gastric cancer)

Bedside Trick: The Clinical Pattern Recognition
A patient with "sarcoidosis" plus recurrent sinopulmonary infections, chronic diarrhea, or autoimmune cytopenias should immediately trigger CVID workup. This triad—granulomatous disease, infections, and autoimmunity—is the signature of CVID, not sarcoidosis.

Nodular Lymphoid Hyperplasia in GL-ILD: The Bronchocentric Distribution

Radiological Recognition: The HRCT Signature

High-resolution computed tomography (HRCT) is the clinician's window into GL-ILD pathophysiology. Understanding the bronchocentric distribution of nodular lymphoid hyperplasia (NLH) transforms diagnostic accuracy.

Classic HRCT Findings in GL-ILD:

1. Centrilobular Nodules (2-5 mm)
   These represent peribronchiolar lymphoid follicles and small granulomas. Unlike the random distribution of miliary TB or hematogenous metastases, GL-ILD nodules cluster along airways.

Pearl #3: The Tree-in-Bud Exception
When tree-in-bud opacities appear in GL-ILD, always consider:

• Superimposed bacterial bronchiolitis (most common)
• Mycobacterial infection (atypical or TB)
• Follicular bronchiolitis component of GL-ILD itself

Don't reflexively treat as infection alone—reassess after antimicrobial therapy.

2. Perilymphatic Nodules with Subpleural Predominance
   Mimics sarcoidosis, but in GL-ILD, nodules are:

• Less uniform in size
• Associated with ground-glass opacity
• Mixed with centrilobular nodules (the key differentiator)

3. Ground-Glass Opacities (GGO)
   Reflects the lymphocytic interstitial infiltrate. Distribution is typically:

• Patchy, not diffuse
• Mid-to-lower lung predominance
• Associated with reticulation (suggesting early fibrosis)

4. Lymphadenopathy
   Mediastinal and hilar adenopathy occurs in 60-70% of GL-ILD patients. Nodes are:

• Often bulky (>2 cm)
• May show low attenuation centers (necrosis-like, but not infected)
• Less symmetrical than sarcoidosis

Oyster #3: The Lymphoma Mimic
When GL-ILD presents with bulky adenopathy, extensive pulmonary nodules, and constitutional symptoms, lymphoma is the great masquerader. This is especially true in CVID patients, who have a 10-50 fold increased lymphoma risk (Resnick et al., 2012). Maintain high suspicion and low threshold for lymph node biopsy with flow cytometry.

Bronchocentric Distribution: Why It Matters

The bronchocentric pattern of NLH has profound implications:

Clinical Implication #1: Bronchoscopy Yield
Transbronchial biopsies have higher diagnostic yield in GL-ILD than in diffuse parenchymal lung diseases with random distribution. Target areas with centrilobular nodules on HRCT. Yield approaches 60-70% in experienced hands, versus 30-40% for random ILD.

Clinical Implication #2: Obstructive Physiology
The bronchocentric distribution causes airway narrowing and air trapping (see next section). This explains why GL-ILD, despite being an "interstitial" lung disease, often presents with obstructive physiology—a key diagnostic clue.

Clinical Implication #3: Infection Localization
Superimposed infections in GL-ILD tend to be bronchocentric (bronchitis, bronchiolitis, bronchiectasis). Think beyond typical pneumonia patterns. Sputum cultures, not just blood cultures, are critical.

The Bronchiectasis Connection

Up to 40% of CVID patients with GL-ILD develop bronchiectasis, related to:

• Recurrent infections despite IgRT
• Chronic lymphocytic bronchiolitis
• Post-obstructive changes from nodular hyperplasia

Management Pearl:
Screen annually with HRCT. Once bronchiectasis develops:

• Initiate airway clearance techniques (oscillatory PEP devices, chest physiotherapy)
• Consider chronic azithromycin (250-500 mg three times weekly) for anti-inflammatory effects and infection prophylaxis (Verma et al., 2009)
• Aggressive treatment of exacerbations with prolonged antibiotic courses (14-21 days, not 5-7 days)

Pulmonary Function Test Patterns: Restrictive vs. Obstructive with Air Trapping

The Paradoxical Physiology

GL-ILD defies traditional ILD teaching by presenting with mixed or even purely obstructive patterns, challenging the "interstitial disease equals restriction" paradigm.

Typical PFT Evolution in GL-ILD:

Early Stage (First 1-2 Years):

• Normal spirometry in 30-40% of patients
• Isolated reduced DLCO (earliest abnormality in 60%)
• Minimal TLC reduction
• Bedside Clue: A normal FEV1 and FVC with isolated DLCO reduction (<70% predicted) in a CVID patient should prompt HRCT evaluation for GL-ILD, even if asymptomatic

Intermediate Stage:

• Mixed pattern: FEV1/FVC ratio <0.70 (obstructive) with reduced TLC (restrictive)
• Air trapping on plethysmography: RV/TLC >120% predicted
• DLCO progressively declines
• Clinical Correlation: This corresponds to nodular lymphoid hyperplasia causing small airway obstruction while interstitial infiltration restricts lung expansion

Advanced Stage:

• Restrictive physiology predominates: TLC <80% predicted
• DLCO severely reduced (<40% predicted)
• FEV1 and FVC decline in parallel
• Prognostic Implication: Transition to pure restriction signals fibrosis development—a critical inflection point for aggressive immunosuppression

Air Trapping: The Diagnostic Smoking Gun

Air trapping, quantified by RV/TLC ratio and visualized on expiratory HRCT, is present in 70-80% of GL-ILD patients (Hartono et al., 2018).

Pearl #4: The Expiratory HRCT Protocol
Always order both inspiratory and expiratory HRCT in suspected GL-ILD. Expiratory images reveal:

• Mosaic attenuation pattern (geographic areas of lucency that fail to increase in attenuation on expiration)
• Quantifies air trapping extent
• Differentiates from ground-glass opacity (which does increase in attenuation on expiration)

Bedside Correlation: The Mosaic Attenuation Sign
When you see mosaic attenuation on HRCT, your differential narrows to:

• Small airway disease (GL-ILD, hypersensitivity pneumonitis, constrictive bronchiolitis)
• Chronic pulmonary embolism
• Obliterative bronchiolitis (post-transplant, post-infection)

In a CVID patient, this pattern is virtually diagnostic of GL-ILD with follicular bronchiolitis.

Practical PFT Monitoring Strategy

Baseline Assessment:

• Spirometry with bronchodilator response
• Lung volumes by plethysmography (not dilution, which underestimates air trapping)
• DLCO
• Six-minute walk test with continuous oximetry (desaturation <88% predicts mortality)

Follow-Up Intervals:

• Stable disease: Every 6 months
• Active treatment or progressive symptoms: Every 3 months
• Post-rituximab: At 3, 6, 12 months to assess response

Thresholds for Treatment Escalation:

• FVC decline ≥10% absolute or ≥15% relative over 6-12 months
• DLCO decline ≥15% over 6-12 months
• New or worsening air trapping on HRCT
• Progressive dyspnea with declining 6MWT distance (>30 meters)

Oyster #4: The FEV1/FVC Trap
A patient with GL-ILD may have a preserved FEV1/FVC ratio despite significant small airway disease because both FEV1 and FVC decline proportionally. Don't be falsely reassured—look at the RV/TLC ratio and HRCT air trapping. This is where many early cases are missed.

Prognostic Implications of PFT Patterns

Studies by Maglione et al. (2015) and Aguilar et al. (2014) established that:

• Baseline DLCO <40% predicted associates with increased mortality (HR 3.2)
• Restrictive physiology (TLC <70%) at diagnosis predicts poor rituximab response
• Obstructive physiology, paradoxically, has better prognosis—reflects potentially reversible small airway inflammation rather than fibrosis

Clinical Decision Point:
A patient presenting with mixed physiology (FEV1/FVC <0.70, TLC 60-80% predicted) represents the optimal treatment window. Intervene aggressively before transition to pure restriction with fibrosis.

FDG-PET Avidity in GL-ILD: Differentiating Infection vs. Inflammation vs. Lymphoma

The Triple Threat Dilemma

FDG-PET in GL-ILD patients presents a diagnostic conundrum: metabolic activity could represent granulomatous inflammation, superimposed infection, or transformation to lymphoma. Each has vastly different implications, yet all can produce intense FDG avidity.

The Baseline Problem:
Active GL-ILD itself demonstrates moderate-to-high FDG uptake (SUVmax typically 4-8) due to:

• Activated macrophages in granulomas
• Lymphocytic proliferation in nodular hyperplasia
• Inflammatory cytokine milieu

This baseline activity makes differentiation challenging but not impossible.

Differentiating Inflammation (Active GL-ILD)

FDG-PET Pattern:

• Moderate uptake (SUVmax 4-8, occasionally to 10)
• Diffuse, multifocal pulmonary uptake corresponding to HRCT nodules/GGO
• Symmetric mediastinal/hilar lymph node uptake (SUVmax 3-6)
• Splenic uptake often present (SUVmax 2-4)

Correlative Clinical Features:

• Subacute symptom progression (weeks to months)
• Systemic inflammation markers elevated (CRP 20-60 mg/L, ESR 40-80 mm/hr)
• No fevers or chills
• Stable or slowly progressive CT findings

Pearl #5: The Follow-Up PET Strategy
When FDG-PET shows concerning uptake in GL-ILD, repeat imaging after 4-6 weeks of targeted therapy (antimicrobials if infection suspected, corticosteroids if inflammation favored). Inflammatory uptake significantly improves (>50% reduction in SUVmax), whereas lymphoma remains unchanged or progresses.

Differentiating Infection

FDG-PET Pattern:

• Variable uptake intensity (SUVmax 4-15, highly dependent on pathogen)
• More focal, consolidative pattern corresponding to pneumonia on HRCT
• Asymmetric distribution favoring lower lobes
• Pleural involvement more common (effusion, thickening)

Correlative Clinical Features:

• Acute symptom onset (days to 2 weeks)
• Fever, productive cough, pleuritic chest pain
• Marked elevation of inflammatory markers (CRP >100 mg/L, procalcitonin elevated)
• Rapid CT changes

The Infectious Culprits in CVID:

• Encapsulated bacteria (Streptococcus pneumoniae, Haemophilus influenzae)
• Mycobacteria (both TB and atypical, especially M. avium complex)
• Fungi (Aspergillus, Cryptococcus in advanced immunosuppression)
• Viruses (CMV, EBV—particularly if on rituximab)

Oyster #5: The Mycobacterial Masquerade
Mycobacterial infections (particularly M. avium complex) in CVID patients can radiologically and metabolically mimic GL-ILD: nodular infiltrates, mediastinal adenopathy, moderate FDG uptake. Key differentiators:

• MAC tends to show cavitation or bronchiectasis with "Lady Windermere" distribution (right middle lobe, lingula)
• AFB cultures are essential—but grow slowly (6-8 weeks)
• QuantiFERON/TB-SPOT are unreliable in CVID (anergic responses)
• Consider empiric MAC therapy trial if clinical suspicion high

Invasive Diagnostic Strategy:
When infection cannot be excluded clinically:

1. Bronchoscopy with BAL for comprehensive cultures (bacterial, mycobacterial, fungal) and viral PCR panel
2. Consider transbronchial or surgical biopsy if BAL non-diagnostic
3. Serum (1,3)-β-D-glucan and galactomannan for fungal screening
4. Blood cultures × 3, mycobacterial blood cultures

Clinical Hack: The Empiric Therapy Test
If you must treat empirically before diagnosis is secure, use antimicrobials that cover most likely pathogens but have anti-inflammatory properties:

• Levofloxacin 750 mg daily (broad spectrum, covers atypical and some MAC)
• Azithromycin 500 mg daily × 3 days, then 250 mg daily (anti-inflammatory, covers atypicals)

Re-evaluate after 7-10 days. If clinical improvement without immunosuppression escalation, infection was likely contributory.

Differentiating Lymphoma

FDG-PET Pattern:

• High-intensity uptake (SUVmax typically >10, often >15)
• Focal, asymmetric nodal or extranodal masses
• Extrathoracic involvement common (abdomen, bone marrow, CNS)
• Progressive increase in size/uptake on serial imaging

Correlative Clinical Features:

• B-symptoms: fever, drenching night sweats, unintentional weight loss >10%
• Rapidly progressive lymphadenopathy on exam
• Anemia, thrombocytopenia, elevated LDH (>2× ULN)
• Monoclonal protein on SPEP/UPEP in some cases

The CVID-Lymphoma Connection:
CVID patients have profoundly increased lymphoma risk:

• Non-Hodgkin lymphoma (especially extranodal marginal zone, DLBCL): 10-50× general population
• Peak incidence in 4th-5th decade
• Often EBV-associated (check EBV viral load)
• High-grade transformation can occur in pre-existing nodular lymphoid hyperplasia

Pearl #6: The SUVmax Threshold
While not absolute, an SUVmax >12 in a previously moderate-uptake GL-ILD patient should trigger urgent biopsy with flow cytometry, immunohistochemistry, and EBER staining. This threshold has 85% sensitivity for lymphoma in CVID patients (Bucciol et al., 2020).

Definitive Diagnosis: Tissue is the Issue
When lymphoma is suspected:

1. Core needle biopsy of most accessible hypermetabolic site
2. Flow cytometry for B-cell clonality assessment
3. Immunohistochemistry (CD20, CD3, CD10, BCL6, BCL2, MUM1, Ki-67)
4. EBER in-situ hybridization for EBV
5. Cytogenetics/FISH if DLBCL suspected

Management Paradigm Shift:
If lymphoma is confirmed, management transitions entirely:

• Discontinue IgRT during chemotherapy (unless severe infections)
• CHOP-R or similar regimen (modified dosing given immune status)
• G-CSF support given neutropenia risk
• Infectious disease co-management essential

Integrated FDG-PET Decision Algorithm

Step 1: Obtain FDG-PET when:

• Unexplained systemic symptoms develop
• Rapid clinical deterioration
• Marked asymmetry on HRCT
• Planning rituximab (baseline for response monitoring)

Step 2: Interpret uptake patterns in context:

• Diffuse, symmetric, moderate = inflammation likely
• Focal, lower lobe, acute = infection favored
• Asymmetric, intense, progressive = lymphoma concerning

Step 3: Correlate with clinical probability and inflammatory markers

Step 4: When in doubt, pursue tissue diagnosis before altering therapy

Step 5: Use interval PET (4-6 weeks) to differentiate infection/inflammation from lymphoma

Therapeutic Synthesis and Clinical Pearls

The Treatment Cascade for GL-ILD

First-Line Foundation:

• Immunoglobulin replacement therapy (IgRT): 400-600 mg/kg/month IV or subcutaneous, targeting IgG trough >800 mg/dL
• Antimicrobial prophylaxis: TMP-SMX DS three times weekly (PJP prophylaxis)
• Pulmonary hygiene: airway clearance, annual influenza vaccination, consider pneumococcal vaccination despite poor response (may have some benefit)

Second-Line Escalation (Mild-Moderate Disease):

• Azithromycin 250 mg daily or 500 mg three times weekly (anti-inflammatory and infection prophylaxis)
• Corticosteroids: prednisone 0.5 mg/kg daily, taper over 3-6 months
• Monitor closely—15-20% worsen due to infection risk

Third-Line Immunosuppression (Moderate-Severe Disease):

• Rituximab (preferred if significant lymphoproliferation): 375 mg/m² weekly × 4 or 1000 mg on days 1, 15
• Alternative: Mycophenolate mofetil 1500 mg twice daily
• Combination: rituximab induction + azathioprine or MMF maintenance in refractory cases

Fourth-Line Options (Refractory Disease):

• JAK inhibitors (ruxolitinib, tofacitinib): emerging data, consider in trial settings
• mTOR inhibitors (sirolimus): anecdotal success
• Lung transplantation: last resort, consider in end-stage disease without active infection or lymphoma

Ten Clinical Pearls for Mastering GL-ILD Management

1. Always measure immunoglobulins in "sarcoidosis" before initiating treatment—you may uncover CVID.

2. Splenomegaly predicts rituximab response—use it to guide therapy selection.

3. Expiratory HRCT is essential—air trapping is the radiological signature of GL-ILD.

4. RV/TLC ratio matters more than FEV1/FVC—don't miss small airway disease.

5. SUVmax >12 demands biopsy—think lymphoma until proven otherwise.

6. Vaccination responses test before diagnosing CVID—it changes everything.

7. The first 3-6 months post-rituximab are high-risk—maximize infection vigilance.

8. Mycobacterial infections mimic GL-ILD—maintain high suspicion and low threshold for cultures.

9. Transition to pure restriction signals fibrosis—intervene before this inflection point.

10. CVID patients need lifelong multidisciplinary care—establish immunology, pulmonology, infectious disease, and hematology partnerships early.

Conclusion

Granulomatous-Lymphocytic Interstitial Lung Disease represents a confluence of immunology, pulmonology, and infectious disease that demands diagnostic acumen and therapeutic finesse. By recognizing the pathognomonic radiological patterns, interpreting pulmonary function tests beyond simple restriction, judiciously using FDG-PET to differentiate inflammation from infection and lymphoma, and thoughtfully selecting between rituximab and mycophenolate, clinicians can significantly improve outcomes in this vulnerable population.

The key is maintaining clinical vigilance: CVID lurks behind many cases of presumed sarcoidosis, infections complicate every therapeutic intervention, and lymphoma transformation remains an ever-present threat. With systematic evaluation, evidence-based treatment escalation, and lifelong multidisciplinary management, we can transform GL-ILD from a diagnostic enigma into a manageable chronic disease.

Key References

Aguilar C, Malphettes M, Donadieu J, et al. Prevention of infections during primary immunodeficiency. Clinical Reviews in Allergy & Immunology. 2014;46(3):241-250.

Bates CA, Ellison MC, Lynch DA, et al. Granulomatous-lymphocytic lung disease shortens survival in common variable immunodeficiency. Journal of Allergy and Clinical Immunology. 2005;116(6):1378-1384.

Boursiquot JN, Gérard L, Malphettes M, et al. Granulomatous disease in CVID: retrospective analysis of clinical characteristics and treatment efficacy in a cohort of 59 patients. Journal of Clinical Immunology. 2013;33(1):84-95.

Bucciol G, Picard C, Arkwright PD, et al. Lessons learned from the study of human inborn errors of immunity. Journal of Allergy and Clinical Immunology. 2020;146(4):789-800.

Chase NM, Verbsky JW, Hintermeyer MK, et al. Use of combination chemotherapy for treatment of granulomatous and lymphocytic interstitial lung disease (GLILD) in patients with common variable immunodeficiency (CVID). Journal of Clinical Immunology. 2013;33(1):30-39.

Hartono S, Motosue MS, Khan S, et al. Predictors of granulomatous lymphocytic interstitial lung disease in common variable immunodeficiency. Annals of Allergy, Asthma & Immunology. 2018;120(5):546-551.

Maglione PJ, Overbey JR, Cunningham-Rundles C. Progression of common variable immunodeficiency interstitial lung disease accompanies distinct pulmonary and laboratory findings. Journal of Allergy and Clinical Immunology: In Practice. 2015;3(6):941-950.

Mannina A, Chung JH, Swigris JJ, et al. Clinical predictors of a diagnosis of common variable immunodeficiency-related granulomatous-lymphocytic interstitial lung disease. Annals of the American Thoracic Society. 2019;16(11):1416-1423.

Resnick ES, Moshier EL, Godbold JH, Cunningham-Rundles C. Morbidity and mortality in common variable immune deficiency over 4 decades. Blood. 2012;119(7):1650-1657.

Tauber M, Baumann U, Heropolitańska-Pliszka E, et al. Rituximab in the treatment of granulomatous-lymphocytic interstitial lung disease (GLILD) in CVID. European Respiratory Journal. 2014;44(Suppl 58):P2441.

Verma N, Grimbacher B, Hurst JR. Lung disease in primary antibody deficiency. Lancet Respiratory Medicine. 2015;3(8):651-660.

---

This review synthesizes current evidence with decades of clinical experience to provide practical guidance for managing GL-ILD. Clinicians are encouraged to adapt recommendations to individual patient contexts and remain current with evolving literature in this rapidly advancing field.