When the anchor was right: imaging, histopathology, ecological rationality, and the diagnosis of culture-negative nontuberculous mycobacterial lung disease| Rassegna di Patologia dell'Apparato Respiratorio

CLINICAL HISTORY

1. 18- YEAR-OLD MALE, NEVER SMOKER, NO KNOWN ALLERGIES
2. STUDENT
3. NO DRUG ABUSE HISTORY
4. FAMILIAL CLINICAL HISTORY: not relevant
5. ASSOCIATED MEDICAL CONDITIONS: ADHD
6. PAST MEDICAL HISTORY: previous hospital admission for lung abscess at age of eleven, followed by subsequent hospital admission for pneumonia four years later
7. PHARMACOLOGICAL THERAPY: none
8. CLINICAL ONSET: subacute onset with fever and right lower lobe consolidation unresponsive to antibiotic and antifungal therapy

The patient was admitted to Pulmonology Department because of persistent, antibiotic resistant, right lower lobe consolidation associated with right pleural effusion. During a previous hospitalization, he had already undergone fiberoptic bronchoscopy with bronchoalveolar lavage (BAL) and transbronchial lung biopsy: both were negative for bacteria, fungi, mycobacteria, and non-tuberculous mycobacteria (NTM). Histopathological examination of the transbronchial biopsy was non-diagnostic.

Upon admission, blood tests and microbiological investigations were repeated.

Laboratory tests revealed mild neutrophilic leukocytosis and a marked elevation in C-reactive protein (CRP), without significant rise in procalcitonin levels. Liver and renal function tests were within normal limits. Analysis of lymphocyte subsets and immunoglobulin classes revealed no evidence of immunodeficiency. A comprehensive autoimmune panel was also negative.

Serial peripheral blood cultures and microbiological testing for the most common pathogens (Tab. I) yielded negative results.

CT SCAN

A new contrast-enhanced CT (Fig. 1) scan demonstrated extensive parenchymal consolidation with air bronchograms in right lower lobe. The consolidation was associated with multiple peribronchovascular nodules ranging in size from a few millimeters to 11 mm. On mediastinal window, a focal area of necrosis was visible within the consolidated parenchyma. Several enlarged mediastinal lymph nodes were present, the largest in the subcarinal region.

BAL

Given the nonspecific clinical, radiological, and Laboratory findings, the patient underwent bronchoscopy with bronchoalveolar lavage (BAL) and transbronchial lung cryobiopsies (TBLCB).

BAL was performed in the dorsal segment of the right lower lobe, and the recovered fluid was submitted for cytological, flow cytometric, and extensive microbiological work-up.

BAL cytology (Tab. II) showed a mild increase in total cellularity, with macrophages and lymphocytes representing the predominant cellular populations. Flow cytometric analysis (Tab. II) revealed a normal CD4⁺ T-cell count and a preserved CD4/CD8 ratio, with increased activated T lymphocytes (CD3⁺HLA-DR⁺). All microbiological investigations, including culture-based and molecular assays for viruses, fungi, bacteria, and mycobacteria, were negative.

TBLC

TBLCB (Fig. 2) performed with cone-beam CT, augmented fluoroscopy, and radial EBUS guidance, in the lateral subsegmental bronchus of the right lower lobe, enabled the collection of multiple tissue samples for histopathological and microbiological analysis. Rapid on-site examination (ROSE) of a core-roll smear prepared from the transbronchial cryobiopsy specimen identified small, non-necrotizing granulomas (Fig. 2a). Based on this finding, additional cryobiopsy samples were collected for microbiological investigations. Histopathological examination of the cryobiopsy specimens demonstrated thickened fibrotic subpleural tissue and a chronic inflammatory infiltrate composed predominantly of lymphocytes, together with multiple pale nodular aggregates corresponding to granulomas within the lung parenchyma. The surrounding parenchyma showed mildly thickened alveolar septa with a sparse lymphocytic infiltrate, while the alveolar spaces were partially filled with eosinophilic proteinaceous material, resulting in focal alveolar proteinosis-like changes. The granulomas were small, scattered, non-necrotizing, and composed predominantly of epithelioid histiocytes. Microbiological cultures for bacteria, acid-fast bacilli (AFB), and fungi (including Aspergillus), next-generation sequencing (NGS) for bacteria and fungi, and PAS, Grocott, and Ziehl-Neelsen histochemical stains were all-negative.

Despite the failure to identify an etiologic agent, empiric therapy for suspected non-tuberculous mycobacterial (NTM) disease was initiated. Given the severity of the clinical condition and the possible presence of antibiotic resistance due to previous exposure to multiple antibiotics, the chosen antimicrobial regimen included ethambutol and azithromycin together with linezolid, and moxifloxacin.

DIAGNOSIS

Empiric therapy lead to progressive clinical and laboratory improvement.

Follow-up chest CT (Fig.3), three months later, also showed marked resolution of the right lower lobe consolidation, with residual focal rounded atelectasis, consolidation, linear band-like opacities, and minimal residual ground-glass opacity.

Based on the clinical, radiological, and histopathological findings, together with the favorable response to empiric therapy,

a diagnosis of nontuberculous mycobacterial (NTM) infection was formulated.

DISCUSSION

The present case is characterized by several distinctive features: multiple pulmonary parenchymal infiltrates in a young patient with no history of underlying diseases that could before or after involve the lungs. Empirical broad-spectrum antimicrobial therapy, including antifungal agents, was ineffective. Histopathological examination demonstrated a granulomatous inflammatory process associated with focal alveolar proteinosis-like changes. Repeated microbiological investigations were consistently negative, as was the QuantiFERON test. The decision to consider nontuberculous mycobacterial (NTM) infection as the most likely diagnosis was based primarily on the radiological findings together with the distinctive histopathological features. This decision could embody all the defining features of reasoning influenced by the anchoring heuristic. Anchoring is the tendency to rely excessively on the first piece of information encountered (the anchor) when making judgments or decisions, even when that information is arbitrary, incomplete, or irrelevant. Anchoring was first described by Amos Tversky and Daniel Kahneman.

Gerd Gigerenzer, one of the leading scholars of decision-making under uncertainty, bounded rationality, risk communication, and heuristics, argues that heuristics are not merely flawed shortcuts that produce cognitive biases. Rather, in uncertain environments, simple decision rules can sometimes be more reliable than complex statistical procedures. He introduced the concept of ecological rationality, according to which a decision strategy is rational if it is well adapted to the structure of the environment in which it is applied. From Gigerenzer’s perspective, rationality cannot always be reduced to strict adherence to formal logic or probability theory, particularly when information is incomplete, time is limited, and probabilities are unknown.

The strongest evidence supporting the diagnosis of nontuberculous mycobacterial (NTM) infection was the distinctive histopathological pattern, consisting of the coexistence of non-necrotizing granulomas and focal alveolar proteinosis-like changes within the lung parenchyma. Paul Feyerabend’s seminal work against method challenges the notion of a universal scientific method, arguing that no fixed methodological rule has been consistently followed in major scientific discoveries, that many of the most significant advances have resulted from violating accepted methodological rules, and that scientific progress is too creative and historically contingent to be reduced to a single algorithm or universal methodology. This case can be analyzed and dissected also through the epistemological lens proposed by Feyerabend.

Figure e tabelle

Figure 1.CT scan: a-c) parenchymal consolidation with air bronchograms associated with multiple peribronchovascular nodules; e) enlarged mediastinal lymph nodes; f) focal area of necrosis within the parenchymal consolidation ().

Figure 2.TBLCB. a) core-roll. A small non-necrotizing granuloma (Diff-Quick); b) thickened fibrotic subpleural tissue () and lung parenchyma showing an inflammatory infiltrate consisting of lymphocytes and nodular paler areas (granulomas). Alveolar septa with mild lymphocytic infiltrate and alveolar spaces partially occupied by proteinaceous exudate (alveolar proteinosis like aspects) () (H&E, x 2); c) lymphocytic inflammation in which scattered non-necrotizing granulomas are embedded () (H&E, x 2); d) granuloma consisting mainly of epitheliod cells is evident (H&E, x 18).

Figure 3.a) resolution of right lower lobe consolidation; b-d) residual focal rounded atelectasis consolidation, linear band like opacities and residual ground-glass opacity.

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