**4. Clinical and imaging classification**

Pulmonary histoplasmosis can take several forms:

### **4.1 Acute, subacute, and chronic pulmonary histoplasmosis**

If symptoms develop, onset occurs 3–14 days after exposure [5]. Acute is defined as less than 1 month of symptoms, while subacute refers to more than 1 month of symptoms but less than three [6]. Fever, headache, malaise, myalgia, abdominal pain, and chills are common symptoms. Joint pain and skin lesions can occur in 5–6% of patients, mostly in women [7]. Enlarged hilar and mediastinal lymph nodes may present in 5–10% of patients. Broncholithiasis can occur if these nodes calcify and may sometimes erode into the airways, leading to possible hemoptysis, obstructive pneumonia, and the expectoration of stones [6]. Cough, hemoptysis, dyspnea, and/or chest pain may be present and are related to the degree of pulmonary airway compression and circulation. Paratracheal involvement may cause coughing or dyspnea due to compression of the trachea or bronchi. Esophageal compression occurs rarely, causing dysphagia.

*Acute pulmonary histoplasmosis* characterized by imaging (see **Figure 1**) through pulmonary condensations with peribronchovascular distribution and unsystematized lobar, segmental, or multifocal localization in association with mediastinal and hilar adenopathies, reflects the granulomatous reaction and acute alveolar lesions [8].

#### **Figure 1.**

*CT images in the axial plane highlight: (left) the presence of bilateral peribronchovascular infiltrates with associated ground-glass areas; (right) focal centrilobular nodules in the posterior segment of the right upper lobe.*

The "tree-in-bud" pattern may be present. Pleural effusion is not characteristic of this disease and does not often appear [4].

Differential diagnoses: Most often, an erroneous diagnosis is established and is often confused with community-acquired or viral pneumonia, which is why antibiotic and antiviral treatment is often administered. Only when the response to this therapy is not expected the clinician raises the suspicion of acute histoplasmosis. It can also be misdiagnosed as other granulomatous pulmonary processes, including mycobacterial, lymphoma, and sarcoidosis.

Within *subacute pulmonary histoplasmosis*, which represents the most frequent form of manifestation of the disease, the chest X-ray can demonstrate a focal area of pulmonary consolidation in association with mediastino-hilar lymphadenopathy (see **Figure 2**). Healing may occur with the formation of a histoplasmoma [9].

*Chronic pulmonary histoplasmosis* occurs in elderly patients, more often men and smokers. Other risk factors include race (white), pre-existing lung disease, and immunosuppression. It has a slowly progressive nature, and, clinically, it is characterized by symptoms present for over 3 months [3], with an affected general condition, cough, weight loss, dyspnea, and pleuritic chest pain. To these symptoms, increased production of sputum and hemoptysis can be added if the pre-existing lesions are extensive and cavities are present. The objective examination is not specific, nonspecific rales are present on auscultation, according to the level of lung damage.

*Chronic cavitary histoplasmosis* is defined from an imaging point of view by fibrocavitating lesions located in the upper lobes, most frequently on the background of an emphysematous lung or with underlying structural damage (see **Figure 3**). It can associate the appearance of a "bump," secondary to the mycotic infiltrate superimposed on the level of pre-existing emphysematous bubbles, with a pseudocavitary appearance. The differential diagnosis includes, first of all, pulmonary tuberculosis

**Figure 2.** *Chest X-ray (PA) showing a pulmonary opacity in the projection of the right lung base.*

#### **Figure 3.**

*Axial CT image demonstrates the presence of fibro-cavitation lesions in the apico-posterior segment of the left upper lobe.*

with a chronic appearance [8]. This can also be done with other chronic cases of pneumonia, including infections with tuberculous or non-tuberculous mycobacteria, or with other fungal infections: chronic invasive pulmonary aspergillosis, chronic pulmonary coccidioidomycosis or blastomycosis [10].

The *mediastinal and hilar lymph nodes* can often be calcified without necessarily being enlarged. Due to the chronic inflammation, over time, there will be a decrease in lung volume and hilar retraction, with the appearance of fibrosis, loss of parenchyma, and necrosis [10]. The mechanism seems to be immune, through an inadequate response to fungal antigens, rather than through direct fungal aggression [11].
