Kant’s thought retains its relevance even when clinical reasoning is the subject of analysis | Rassegna di Patologia dell'Apparato Respiratorio

Article

1. 60-YEAR-OLD MALE, NEVER SMOKER
2. FARMER WITH MODERATE EXPOSURE TO BIRDS AND HAY
3. FAMILIAL CLINICAL HISTORY: not relevant
4. PAST MEDICAL HISTORY: allergic rhino-sinusitis, paroxysmal atrial fibrillation
5. PHARMACOLOGICAL THERAPY: apixaban
6. CLINICAL ONSET: exertional dyspnoea and low grade fever

Due to the progressive worsening of symptoms, the patient was admitted to a pulmonology department.

Chest CT and bronchoalveolar lavage (neutrophils 70% - eosinophils 20%) were interpreted as possibly consistent with the

CLINICAL HISTORY

Diagnosis of Eosinophilic Pneumonia.

After one month of corticosteroid therapy, both low-grade fever and dyspnea resolved and a follow-up chest CT was reported as negative. Consequently, corticosteroid treatment was discontinuated.

One month after discharge, the patient was again admitted for respiratory failure. CT scan showed bilateral ground glass attenuation mainly in peribronchovascular fashion (Fig.1). A bronchoalveolar lavage (BAL) was performed again, revealing 80% macrophages, 8% lymphocytes and 12% neutrophils. On suspicion of a recurrence of eosinophilic pneumonia, corticosteroid therapy was restarted.

Despite corticosteroid therapy, the patient showed progressive clinical worsening and after a few weeks was admitted to our unit for progressive respiratory failure.

Upon admission, additional blood investigations, including arterial blood gas analysis were carried out. Laboratory tests (Tab.I) revealed a mild neutrophilia, associated with an increase in inflammatory markers and positivity for beta-D-glucan.

The arterial blood gas analysis (Tab. I) performed on room air shows severe type 1 respiratory failure, improving with oxygen at high flows through nasal cannulae (HFNC).

HRCT

The CT scan performed upon admission (Fig. 2) revealed an increase of the bilateral ground-glass opacities, with newly developed areas of crazy paving, particularly evident in the anterior segment of the right upper lobe, and increased extent of the pre-existing attenuation in both lower lobes. Scattered bronchial dilatation was observed in the lingula and the right upper lobe.

LABORATORY TESTS

ARTERIAL BLOOD GAS ANALYSIS:

pH 7.40 pO2 37 mmHg pCO2 21 mmHg HCO313 mmol/l

BAL

A bronchoscopy under general anesthesis with BAL and transbronchial cryobiopsies under fluoroscopic guidance was carried out.

BAL cytological profile (Tab. II) revealed neutrophilia and PCR-based assays documented DNA of Pneumocystis Jierovecii>10000000 copies /ml and of Cytomegalovirus<890 copies/ml.

TBLCB

The hematoxylin-eosin staining (Fig 2 a-b) of the lung parenchyma samples, retrieved from the right lower lobe with transbronchial cryobiopsy, revealed interstitial pneumonia with frothy, foamy exudate within alveolar spaces. Grocott methenamine staining (GMS) (Fig 2 c) documented clusters of round and sometimes indented or helmet shaped cysts, with a central dot, within the alveolar exudate (Pneumocystis).

DIAGNOSIS

Additional laboratory tests on peripheral blood samples identified positivity for anti-HBc and anti-Treponema pallidum antibodies, along with the presence of HIV RNA (403 copies/ml).

The integration of clinical, radiological, and histopathological data allowed for the diagnosis of:

Subacute lung injury due to Pneumocystis Jierovecii pneumonia in a subject with HIV infection and latent syphils.

The diagnosis of eosinophilic pneumonia was formulated on the basis of a mild eosinophilia in BAL fluid and of the CT scan interpretation. However eosinophis in BAL fluid can be found in a wide range of pulmonary disorders: from classic eosinophilic pneumonia (both acute and chronic), to sarcoidosis, desquamative interstitial pneumonia (DIP), drug-induced pneumonitis, neoplastic processes, and many infectious conditions. Furthermore the hyopothesis of eosinophilic pneumonia was not corroborated by CT scan aspects. CT may be very helpful in suggesting the diagnosis of acute eosinophilic pneumonia, showing the typical findings of septal lines, pleural effusions, and areas of consolidative and ground-glass opacity. Pleural effusions may be small or large. About 30% of cases have an upper lung predominance of abnormality. The distribution of consolidation and ground-glass abnormality is peripheral in more than 50% of cases, but may be central or random, CT is often unnecessary to confirm the diagnosis of chronic eosinophilic pneumonia (CEP), if typical imaging findings are associated with blood eosinophilia. In general, CT studies confirm the chest radiographic findings, showing strikingly peripheral, multifocal consolidation or ground-glass abnormality. The bilateral subpleural distribution is universal in patients who are scanned within 1 month of the onset of symptoms. Patients with CEP who are imaged more than 1 month after onset of symptoms have a different pattern on CT. The consolidation tends to be more patchy, and though the opacities remain peripheral, the subpleural zone is often relatively clear. A characteristic feature in these more chronic cases is the presence of a dense bandlike structure parallel and about 1-2 cm deep to the chest wall, which may traverse the fissures. In chronic cases of CEP, dense fibrosis and lung distortion may rarely be seen.

DISCUSSION

In our patient the total lymphocytes count in peripheral blood was always within normal range (but without documentation of the lymphocytes subsets) and a blood eosinophilia was never documented. Eventually a decision to swiftly proceed with bronchoscopy was taken. Rapid onsite analysis of BAL (using Diff Quick, a very rapid staining procedure) revealed clusters of typical Pneumocystis micro-organisms and this was cofirmed hours later by detections of a huge number of DNA copies of the organism in the same fluid. Transbronchial lung cryobiopsy documented an interstitial pneumonia with frothy, foamy exudate within alveolar spaces. Grocott methenamine staining documented round and sometimes indented or helmet shaped organisms within the alveolar exudate (Fig 3). A final diagnosis of Pneumocystis pneumonia (PCP) was formulated. Immunodeficiency due to HIV infection was confirmed by blood tests. Pneumocystis jierovecii is an ascomycete fungus of the subphylum Taphrinomycotina, most closely related to Schizosaccharomyces, Taphrina, and Saitoella species of fungi.

There are two easily recognized forms of the organism: trophic forms (≈2 to 6 μm in diameter) and cysts (≈6 to 8 μm in diameter), which can contain up to eight intracystic bodies (ascospores); additional intermediate forms are also seen. Trophic forms, which have an amorphous shape, are estimated to outnumber cysts, which are spherical, by approximately 10:1 in an infected lung. For many years, development of PCP was thought to result from a reactivation of latent infection by organisms that remained viable following infection at an early age, similar to tuberculosis. However, recent molecular epidemiologic studies based on the detection of mutations in the dihydropteroate synthase (DHPS) gene of Pneumocystis, as well as genotyping of isolates from outbreaks of PCP primarily in renal transplant patients, have provided compelling evidence that the infecting strain is often recently acquired. Molecular studies have further documented that in the majority of non-outbreak cases of PCP, multiple strains can be identified in respiratory samples. In patients who develop recurrent PCP, this recurrence can be due to relapse, especially for early recurrences, or to reinfection with a novel strain. Recurrent PCP occurs almost exclusively in HIV-infected patients, in whom the risk was greater than 50% early in the AIDS epidemic, before the availability of combination antiretroviral therapy (cART) and the broad use of anti-Pneumocystis prevention. Animal studies have provided important insights into the pathogenesis of Pneumocystis infection. Exposure for as little as 1 day to a Pneumocystis-infected animal results in transmission of infection. In healthy animals, an adaptive immune response develops by approximately 5 to 6 weeks, which leads to control and clearance before the organism burden produces symptoms. CD4 cells are critical to this control, although other populations, including B cells and macrophages, are also important. CD8 cells can contribute to the associated inflammation. Lung epithelial cells play an important role in interacting with pneumocystis and providing vital innate immune responses. Limited human data suggest a similar time course. Host inflammatory responses, in part attributable to organism-derived β-glucans, appear to play a critical role in the development of pulmonary symptoms, and this might explain why patients with PCP have a mild improvement in the first days after steroids assumption. Among HIV-infected patients the incidence of PCP is inversely related to the CD4+ T cell count: at least 80% of cases occur at counts <200/micronL. The patient herein discussed had <100 CD4+ lymphocytes/micronL in peripheral blood. HIV load (very high in this case) is another factor that predisposes to PCP. The CT findings of PCP include scattered or diffuse ground-glass opacities, consolidation, and thickening of interlobular septa The CT findings are characterized by ground-glass opacities predominating in the early stages of the disease and with linear opacities predominating in cases of more chronic, repetitive, or undertreated infection. Cysts in the areas of ground glass attenuation or nodules have been reported as well. This case highlights how the pulmonary manifestations in a context of HIV infection, and in particular when PCP is the first manifestation, are less readily and promptly recognized and diagnosed today compared to the past, when these conditions were more frequently encountered. Finally, this case can provide educational value concerning the potential errors that might be committed by physicians. Immanuel Kant in his renowed work “Kritik der reinen Vermunft” (“Critique of Pure Reason”) (1781-1787), asserts that “thoughts without content are empty, intuitions without concepts are blind”. So observations in medical practice need to be guided by knowledge and thougths or diagnostic hypotesis should always be verified collecting, in a objective way, empirical data.

Figure e tabelle

Figure 1.(a-f) bilateral ground glass attenuation mainly in peribronchovascular fashion().

Figure 2.(a-f) increase of the bilateral ground-glass opacities; (b) crazy paving in the anterior segment of the right upper lobe (); (e, f) extent of the pre-existing attenuation in both lower lobes; (b,c,d) Scattered bronchial dilatation in the lingula and the right upper lobe.

Figure 3.TBLCB: a) interstitial pneumonia with frothy, foamy exudate within alveolar spaces (H&E, x10); b) higher magnification view showing the characteristic frothy appearance of the intra-alveolar exudate (H&E, x20); c) GMS stain showing intraalveolar clusters of the organism (GMS stain, x20).

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