Bilateral diffuse micronodularchanges of radiographicpresentation in a 42-year-oldwomanCase report

A 42-year-old woman was found to haveabnormal shadow on a chest radiograph ob-tained during a periodic health examination. Shehad a history of chronic nonproductive coughon effort for several months. The patient wasadmitted for investigation. Her past medicalhistory was unremarkable and there were noallergies or occupational exposure. She rarelysmoked and consumed little alcohol. During herchildhood years, her father had been on chronictreatment for pulmonary tuberculosis.

The patient looked well with a blood pressureof 120/64 mmHg, heart rate of 64 beats?min-1,regular respiratory rate of 14 breaths?min-1 anda temperature of 36.8uC. Examination of abdo-men, nervous systems and cardiovascular andrespiratory system were within normal limits.Finger clubbing wasn’t noted on either handand lymph nodes were not palpable. Her chestradiography and high-resolution CT (HRCT)scans are shown in figure 1.

Statement of interestNone declared.

HERMES syllabus links:B. 4.1, B. 4.2, D. 3.1

Task 1

How would you interpret thechest radiography and HRCT?

a)

b)

Figure 1a) Plain radiograph showsmicronodular lesions through-out both lungs, which are moreprominent in the upper andmiddle zones. b) High-resolu-tion CT scans of the chest at thelevel of the right upper lobarbronchus.

Breathe | September 2012 | Volume 9 | No 1 63DOI: 10.1183/20734735.016112

Kyoko Yagyu1,Tomoyo Morita1,Munetake Takata1,Yae Yoshida1,Daijiro Nabeya1,Takao Kamimori1,Mayumi Inaba2,Hiroshi Fujiwara1

1Depart. Of RespiratoryMedicine, YodogawaChristian Hospital2Depart. Of Pathology,Osaka City UniversityGraduate School OfMedicine, Osaka, Japan

Kyoko Yagyu: Department ofRespiratory Medicine, YodogawaChristian Hospital, 2-9-26, AwajiHigashi-Yodogawa, Osaka,533-0032 Japan

qqbn43ng9@alpha.ocn.ne.jp

Serological studies for HIV, chlamydia andmycoplasma were negative, as were antinuc-lear antibody, angiotensin-converting enzymeand tumour makers.

The exception was a slightly elevated C-reactive protein level (0.76 mg?dL-1). Haemat-ology tests revealed a white blood cell count of7,600 cells?mm-3, haemoglobin of 13.4 g?dL-1

and platelet count of 264,000 cells?mm-3. Thetuberculin skin test was negative. Bacteriologicalcultures of sputum and gastric aspirate for acid-fast bacillus were negative.

Arterial blood gas analysis while breathingroom air showed hypoxaemia. Lung functiontests revealed a normal flow rate and a slightdecrease in diffusion capacity for carbon mon-oxide to 40.6% of the predicted value.

Bacteriological and cytological examina-tion of washings and lung specimens obtainedby transbronchial biopsy did not provide aspecific diagnosis. Open lung biopsy was per-formed, targeting the left upper and lowerlobes (fig. 2).

Answer 1

The chest radiograph (fig. 1a) showsextensive diffuse shadowing in the upperand middle zones predominately and theHRCT (fig. 1b) revealed extensive diffuselesions in the upper and middle lobeswithout cavitation, effusion, infiltration orsuspicious scattering resource. There wereextensive well-demarcated centriacinarnodules and peripheral branching linearstructures that formed small Y- and V-shaped lesions. These abnormalities werenot present within 5–10 mm of the pleura.

a) b)

c)

Figure 2Histological examinations of open lung biopsy specimens from the upper and lowerlobes. a) In a whole-mount section, necrotising granulomas are relatively small, roundedand well defined, but sometimes fuse to form large nodules (arrow). Haematoxylin andeosin staining 610; Scale bar: 10 mm. b) Epithelioid granulomas with caseatingnecrosis involve the respiratory bronchioles and spread into the surrounding alveoli.Haematoxylin and eosin staining 640; scale bar: 100 mm. c) Respiratory bronchioleshows stenosis due to proliferation of epithelioid granulomas. Healing lesions arereplaced by fibrous tissue. There is airspace enlargement in the adjacent areas.Haematoxylin and eosin staining 640; scale bar: 100 mm.

Task 2

How would you interpret thepathology?

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The necrotising granulomas were rela-tively small, round and well demarcated, butsometimes fused to create larger nodules.These lesions invaded the alveoli around therespiratory bronchioles, suggesting the spreadof infection via the airways. Endobronchialgrowth of the granulomas was also seen. Inthe pulmonary acini, some of the granulomashad progressed to fibrosis and healed com-pletely (fig. 2).

DiscussionClassically, reactivation of pulmonary tubercu-losis in adults affects the apical or posteriorsegments of the upper lobe, or else the superiorsegment of the lower lobe [1]. However, a varietyof radiographic findings have become morefrequent in recent years. This phenomenon,thought to be related to the increased use ofsteroid therapy, immunosuppressive therapyand anticancer drugs, as well as the growth ofthe elderly population. According to HADLOCK

et al. [2], who reported unusual radiographicfinding of pulmonary tuberculosis in adults, theincidence of a miliary pattern in 270 patientswas 0.4% [2]. The incidence of similar casesamong 100 patients was 3.0% in a series byMILLER and MACGREGOR [3].

A diffuse micronodular pattern on chestradiographs is not only seen in pulmonarytuberculosis, but also in diffuse panbronchio-litis, infectious bronchiolitis, hypersensitivitypneumonitis, pneumoconiosis, sarcoidosis,primary lymphoma, alveolar cell lung cancerand amyloidosis. Several authors have investi-gated diffuse micronodular changes on radio-graphs to assess the correlations with HRCTand pathological findings and it has been shownthat a micronodular pattern of pulmonarytuberculosis comprises miliary tuberculosis

combined with endobronchial spread of infec-tion [4, 5]. On HRCT, miliary tuberculosis isseen as tiny nodules randomly distributedthroughout the lung parenchyma. These nodulesare uniform and are distributed without any rela-tion to the airways. In the present case withdisseminated endobronchial pulmonary tuber-culosis, HRCT revealed well-demarcated cen-triacinar opacities and peripheral branchinglinear structures (2–5 mm in diameter) in theupper and middle lobes. These lesions weresmall and irregular (Y- and V-shaped) with highattenuation, and showed a dense segmentaldistribution in the upper and middle lobes,while being sparse in the lower lobe (fig. 1b).According to COLLINS et al. [6], bronchiolesfilled by tuberculous inflammatory exudates orgranulation tissue are seen as centrilobularand linear branching opacities, which weredescribed as acino-nodular lesions. This pat-tern is analogous to the ‘‘tree-in-bud’’ appear-ance of the airways in patients with bronchialimpaction. However, the lesions seem toinvolve much more distal airways than thosecreating the tree-in-bud appearance. Pathologi-cal examination revealed compact nodules ofcaseating necrosis that filled the terminalbronchioles. These lesions corresponded tothe centriacinar and linear branching changes

Answer 2

Pathological examination revealedepithelioid granulomas with caseatingnecrosis.

Answer 3

The diagnosis of pulmonary tuberculosiswas made.

Task 3

What is your diagnosis?

Acid-fast bacilli were detected by Ziehl–Neelsen staining in this pathological examina-tion. Culture of the biopsy material grew Myco-bacterium tuberculosis without any resistance toantituberculous drugs.

Immediately, the patient started on ther-apy with isoniazid, rifampicin, pyrazinamideand etambutol. Follow-up CT and chest radio-graphy showed improvement after 6 monthsof antituberculous chemotherapy. Her symp-toms and hypoxaemia also resolved.

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on CT scans. In whole-mount sections, fibroticalveoli were scattered among normal lung tissue.Each focus of fibrotic change was associated withlocalised emphysema in the adjacent lung tissuethat might lead to bronchiolar distortion oremphysema in the future (fig. 2). Generally, thelesions of pulmonary tuberculosis have variousstages, including the proliferative, sclerosing,and fibrosing phases. However, the lesions inthis particular case maintained the mild anduniform stage of progression. Furthermore,these lesions preferentially involved the periph-eral airways or the acini.

SCHMIDT [7] originally reported this type ofbronchogenic pulmonary tuberculosis as ‘‘dieacinos-nodose Lungentuberkulose’’. Additonally,chronic disseminated acinar pulmonary tuber-culosis has been elucidated as Oka’s classifica-tion of pulmonary tuberculosis type IIB in Japan[8], but it may be considered as an extensivetree-in-bud appearance.

It seems that the progression of tubercu-losis is more complex than that of otherbacterial pulmonary infections. An uncommonmode of progression like this case presumablyarises from the interplay between bacterialvirulence factors and the cell-mediated immu-nity of the host. Recently, dendritic cells in theperipheral airways have been recognised asprofessional antigen-presenting cells ratherthan alveolar macrophages in association withthe primary immune response [9]. Cytokinessecreted by dendritic cells and macrophages, aswell as interferon-c produced by natural killer T-cells and cd T-cells in the early period of

infection, strongly induce macrophage activa-tion and the development of antigen-specificinterferon-c-producing CD4+ T-cells [10]. In thisprocess, dendritic cells play an important role asantigen-presenting cells.

In the present case, we were unable todiagnose pulmonary tuberculosis initially. Itseems that the number of bacilli in the spu-tum was relatively small. Considering the otherdiffuse micronodular lung diseases that producesimilar acino-nodular lesions as those seen inthis case of pulmonary tuberculosis, we shouldhave listed the differential diagnosis morecarefully because interferon-c released assay byT-cell (QuantiFERON TB-2G; Cellestis, Carnegie,Australia) was unavailable at that time.

In conclusion, this case illustrates the radi-ological and pathological correlates of diffusemicronodular pulmonary tuberculosis. HRCTdemonstrated well-defined centriacinar lesionsand extensive peripheral branching linear struc-tures. Pathological examination revealed com-pact epithelioid granulomas with caseatingnecrosis extending from the respiratory bronch-ioles to the surrounding alveoli. It is importantto diagnose carefully such cases and not confusetuberculosis with other types of diffuse lungdisease.

Acknowledgements

The authors would like to thank A.Hebisawa (Division of Clinical Laboratory,Tokyo Hospital, Japan) for advice about thepathological findings.

References

1. Farman DP, Speir WA. Initial roentgenographic mani-festations of bacteriologically proven Mycobacteriumtuberculosis: typical or atypical? Chest 1986; 89: 75–77.

2. Hadlock FP, Park SK, Awe RJ, et al. Unusualradiographic findings in adult pulmonary tuberculo-sis. Am J Roentgenol 1980; 134: 1015–1018.

3. Miller WT, Macgregor RR. Tuberculosis: frequency ofunusual radiographic findings. Am J Roentgenol 1978;130: 867–875.

4. Rossi SE, Franquet T, Volpacchio M, et al. Tree-in-bud pattern at thin-section CT of the lungs:radiologic-pathologic overview. RadioGraphics 2005;25: 789–801.

5. Lee KS, Kim TS, Ham J, et al. Diffuse micro-nodular lung Disease; HRCT and pathologicfindings. J Comput Assist Tomogr 1999; 23:99–106.

6. Collins J, Blankenbaker D, Stern EJ. CT patterns ofbronchiolar disease: What is ‘‘tree-in-bud’’? Am JRoentgenol 1998; 171: 365–370.

7. Schmidt PG. [Differentialdiagnose der Lungenkrank-heiten mit besonderer Berucksichtingung derTuberklose.]. Tuberkulose-Bibliothek 1936; 60: 44–47.

8. Tokuda H. Pathogenesis of chronic disseminated acinarpulmonary tuberculosis: Oka’s classification of pul-monary tuberculosis type IIB discussion through ananalysis of two typical cases. Kekkaku 2007; 82: 507–513.

9. Wolf AJ, Linas B, Trevejo-Nunez GJ, et al.Mycobacterium tuberculosis infects dendritic cells withhigh frequency and impairs their function in vivo.J Immnol 2007; 179: 2509–2519.

10. Kaufmann SHE. Protection against tuberculosis:cytokines, T cell, and macrophages. Ann Rheum Dis2002; 61: ii54–ii58.

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