Idiopathic Interstitial Pneumonia: The Diagnostic Challenges with Case Presentation and Literature Review

Case Presentation:

Our patient was a 65 years old elderly female presented with history of shortness of breath, progressive from class 1to2 along with chronic nonproductive cough for 1 year. Also having whitish scanty expectoration on and off. Gave history of generalized fatigue, reflux symptoms and dryness of mouth. No hemoptysis, chest pain or giddiness. No leg swelling, fever, weight loss, loss of appetite or loss of weight. She denied history of dryness of eyes, hair falling, proximal muscle weakness, skin rash, small or large joints pain. No history of exposure to dust, biomass. No history of contact with animals or birds or environmental pollutants. She had H/O Tuberculosis at the age of 13, got treatment and cured. H/O hysterectomy 25 years back. No other symptoms related to autoimmune disorders. On examination, she was comfortable, not dyspneic pallor, icteric, lymphadenopathy, pedal edema. Vitals: BP 130/80mmHg, PR 87/mt, SPO2 98% on room air, RR 18/mt. BMI 23.3. RS: Having bilateral fine inspiratory crackles over both inter scapular/ intrascapular, intraaxillary and mammary area. No wheeze. CVS: Normal S1S2, no murmur. Abdomen: Soft, no organomegaly. CNS: No deficit, normal power and refluxes. Musculoskeletal system: Normal evaluation. Investigations: CBC: WBC 5630, Hb 10.7, Platelet 27400, RBS: 132.3mg/dl, Urea 20.6mg/dl, Creatinine 0.66mg/dl, Urine analysis: within normal limits, LFT; Within normal limits. Immunology: ANA Positive 4+(Mixed pattern), RF 12, DsDNA, Ani Histone, Sm-Ab, RNP, SSA, SSB, Scl-70, Ku-AB, PM-Scl100, Mi-2 AB, JO-1, PL-7, PL-12, ANCA: All Negative. Hepatitis and HIV serology: Negative. Spirometry: Mild restrictive pattern with FVC1.31L (77.5%), FEV11.21L (89), FEV1/FVC 92.3%. Chest Xray (Figure A) shows reticulonodular changes over bilateral lower zones with shaggy heart border. HRCT (Images B, C, D, E, F) (Ref 2-8): Anterior upper lobe predominant fibrosis -Anterior Upper Lobe (AUL) sign, Reticulations with traction bronchiectasis-Established fibrosis, Basal subpleural involvement -UIP-compatible distribution, Honeycombing present (upper and lower lobes)-Definite UIP, the distribution is atypical for IPF (anterior predominance)

Figure A(Chest Xray PA View): Bilateral reticulation with nodular changes and shaggy hear border with minimal volume reduction.

Figure B: Axial HRCT image at the level of the upper lobes demonstrates predominant anterior subpleural fibrosis with microcystic honeycombing in bilateral upper lobes (long arrows), consistent with the anterior upper lobe (AUL) sign and relative sparing of posterior lung parenchyma (short arrow).

Figure C: Axial HRCT image through the mid lung zone shows reticular interstitial thickening in both lungs with ground glass opacities interspersed within reticulations (short arrows) and associated mild traction bronchiectasis in left upper lobe (long arrow), suggestive of fibrotic ILD.

Figure D: Prone axial HRCT image of the lower lobes demonstrates subtle persistent posterior subpleural reticulations (arrows), confirming true interstitial fibrosis and excluding dependent atelectasis.

Figure E: Sagittal HRCT image of left lung demonstrates cranio-caudal distribution of fibrosis with mild anterior upper lobe predominance (arrow), highlighting the anterior upper lobe (AUL) sign and supporting a secondary UIP pattern.

Figure F: Sagittal HRCT image of right lung demonstrates cranio-caudal distribution of fibrosis with mild volume loss in anterior upper lobe (short arrow), concurrent fibrosis with microcystic honeycombing in posterior lung base (long arrow) which also highlights the anterior upper lobe (AUL) sign.

From history, clinical examination, lung functions and imaging she was diagnosed as having Interstitial lung disease with definitive UIP pattern with upper lobe predominance. As her ANA is positive and positive history of dryness of mouth, she has been categorized under IPAF-Idiopathic Pneumonitis with autoimmune features. To further narrow the diagnosis to identify the type of autoimmune disease we did minor salivary gland biopsy from lower lip. (Figure G Low power field, Figure H-High power field) (Ref 9-12)

Figure G: High power field of minor salivary gland biopsy with dense follicles lymphocytic infiltration with 2 foci.

Figure H: High power field with dense lymphocytic infiltration >50 cell/foci

Finally put all together she was diagnosed as ILD-UIP pattern secondary to Primary Sjogren syndrome. She has started on oral prednisolone 30 mg daily (tapering dose) along with Mycophenolate mofetil oral 500 mg twice daily, PPI, oral Pilocarpine and vaccinated with pneumococcal 13 vaccine. During the follow upe her cough and fatigue has improved, and she is continuously on follow up.

DISCUSSION:

The presence of clinical, radiological and serological features most of the time gives only a suggestive but not definitive diagnosis of the etiology of ILD which is a most relevant clinical occurrence in many patients (13). In 2015 the ERS and ATS together proposed the guidelines for the diagnosis of IPAF. A reasonable proportion of patients present with ILD in the presence of features suggestive of, but not confirmatory for, a defined CTD. Such patients can behave either as ILD or CTD while the disease progress. So need a definitive diagnostic pattern to identify the underlying CTD in patients with definitive UIP instead of categorizing them as IPAF. Even though several studies has been done and many literatures available still the challenges are commonly prevalent while treating such patients. The concept of IPAF has highlighted the need for multidisciplinary discussions in the field of CTD-ILD. It needs a comprehensive clinical study with extensive work up including clinical examination, radiological review, serological work up and multidisciplinary discussion among the specialists from pulmonology, radiology, pathology and rheumatology. Even though due to the paucity of symptoms and serology positivity the dilemma exists to conclude for a definitive aetiology. Most of the IPAF patients were usually having radiological patterns other than definitive UIP. The sicca symptoms are absent in the IPAF criteria as they are considered lack of specificity. But this is a controversy and need further research and review. In our patient the only symptoms present other than respiratory symptoms was dryness of mouth. Further in IPAF, a UIP pattern is excluded from the morphological domain as an IPAF criterion. In CTD-ILD, a UIP pattern is generally associated with a better survival than UIP/IPF if diagnosed and treated earlier. Our patient has definitive UIP, positive ANA and dryness of mouth and not completing the criteria for IPAF category. Treating a patient with definitive UIP with immunosuppression need more cautious approach.so need further investigation to identify the aetiology of definite UIP in a patient less than 60years old and ANA positive who did not meet the criteria of IPAP.IPF and CTD-UIP are having high mortality. As our patient has only a mild restrictive lung function and normal oxygen saturation we decided to evaluate further to identify the underlying CTD.  So we proceeded with the minor salivary gland biopsy which shows dense lymphocytic cells infiltration with more than 2 foci. The histopathological finding of focal periductal localized lymphocytic infiltrates in exocrine glandular tissue along with otherwise intact acinar units is pathognomonic for Sjögren’s syndrome (14). Minor salivary gland biopsy (MSGB) to identify the occult CTD/ILD is not well studied. Only a few cohort studies were available in the literature. The study by Essam at al(1) the data revealed among 155 patients with IIPs sixty patients (38.7%) had positive MSGB findings. Of them, the mean age was 63.3 years, 51.6% were women, usual interstitial pneumonia (UIP) was the predominant pattern (63.3%), and seronegative antibodies (61.6%) were likely. Patients with positive MSGB findings had significantly greater survival than those with negative MSGB findings (p = 0.041). After stratifying the MSGB cohort based on the presence of a UIP pattern, no significant difference in survival was noted between those with positive MSGB-UIP pattern and those with a negative MSGB-UIP pattern (p = 0.231). Multivariate analysis on all UIP patients showed that higher forced vital capacity (p = 0.010) and smoking status (p = 0.035) were independently associated with survival.  This study highlights the importance of MSGB as a potential objective tool in identifying in a subset of ILD patients with occult pSS. It’s a well-known fact that many types of CTDs manifest initial with ILD and patients who were initially negative serology and lacking symptoms become positive in a later stage. Early identification of occult CTD and managing with appropriate immunosuppressive medication can reduce the progression of lung disease and the clinical symptoms and improve the survival and quality of life.

CONCLUSION:

Our case presentation and the available literature emphasise the need of more diagnostic evaluation of ILD/Definite UIP patients with subtle clinical features and lacking significant serological positivity. Minor Gland biopsy is a minimal invasive, cost effective and minimal side effect. Doing a careful clinical assessment, radiological and serological analysis is not only enough to identify the exact underlying aetiology in occult CTD. Utilizing and maximizing the investigations like minor salivary gland biopsy like in our patient will provide the definitive aetiology for the ILD/Definite UIP and providing appropriate treatment might improve the survival and clinical symptoms of the patient.

Financial support:

Nil

Credit authorship contribution statement:

Muthurajan P Paramasivam: Case presentation and assistance in literature review

Akash A Sabapathy: Discussion and literature review

Pranav S Aravind: Discussion and literature review

Aravind K Shanmugam: Radiology interpretation and review

Brindha S Chakravarthy: MSGB interpretation and pathology review

Conflict of interest:

No conflict of interest.

REFERENCES

1. Clinical significance of minor salivary gland biopsy in patients with idiopathic interstitial pneumonia: https://doi.org/10.1016/j-med.2020.106189
2. ATS/ERS/JRS/ALAT Clinical Practice Guidelines (2018, 2022 updates)
3. Fleischner Society Guidelines (2018)
4. Palmucci S et al. J Clin Med, 2025
5. Augustine A et al. Indian J Radiol Imaging, 2023
6. Jain N et al. IJLSBPR, 2022
7. Chung JH et al. AJR, 2018
8. Palmucci S et al. Insights Imaging, 2022
9. Shiboski CH, Shiboski SC, seror R et al. 2016ACR/ EULAR classification criteria for primary Sjogren syndrome. Ann Rheum Dis. 2017,76(1): 9-16.
10. Daniels: Labial salivary gland biopsy in Sjogren’s syndrome: assessment as a diagnosis criterion.
11. Arthritis Rheum. 1984;27(2):147-156
12. Jonsson R, Brokstad KA, Jonsson MV, Delaleu N, Skarstein K. Current concepts on Sjogren’ s   syndrome. Oral Dis. 2002;8(3):130-140.
13. Mackintosh JA, Wells AU, Cottin V, et al. Interstitial pneumonia with autoimmune features: challenges and controversies. Eur Respir Rev 2021; 30: 210177 [DOI: 10.1183/16000617.0177- 2021].
14. Stefanski AL, Tomiak C, Pleyer U, Dietrich T, Burmester GR, Dörner T: The diagnosis and treatment of Sjögren’s syndrome. Dtsch Arztebl Int 2017; 114: 354–61. DOI: 10.3238/arztebl.2017.0354.