Pulmonary Histoplasmosis: Clinical and Imagistic Characteristics

Abstract

Histoplasmosis is a condition caused by infection with a fungus, called Histoplasma capsulatum. The fungus can be found in the environment in an inactive form (spores), particularly in soil with great amount of bird or bat droppings. Infection occurs when a person inhales the spores and sometimes it can become aggressive especially when the immunity is low or the person has been in contact with a very high amount of fungi. The magnitude of symptoms correlates with the amount of fungi in contact with the patient. About 90% of patients are usually asymptomatic or presenting very few symptoms. However, in immunosuppressed patients, the infection can spread and affect several organs and systems like eyes, liver, spleen, central nervous system, hematological manifestations, joint manifestations. In patients with pre-existing lung disease chronic pulmonary histoplasmosis is not uncommon.

1. Introduction

The fungus incriminated in pulmonary histoplasmosis is Histoplasma Capsulatum (H. Capsulatum), a dimorphic organism. Having two forms, the mycelial one is observed at ambient temperatures, while at body temperatures, the inhaled microorganism converts to yeast, which is the case of terminal bronchioles and alveoli [1]. Regarding the epidemiology, the most endemic zones of the world are those with temperate climates such as eastern and southern Europe, eastern Asia, Australia, regions of Africa and in the river valleys of the north and central part of the United States [2].

The immunity to H. Capsulatum is cell-mediated by IFN-g production from CD4 T lymphocytes and activated macrophages. The macrophages containing the infection lead to granuloma formation. The immune response is given mainly by IL 12, IFN-g, and tumor factor necrosis (TNF)-a [1].

2. Methodology

The PubMed platform was used as a search tool to collect medical information about histoplasmosis, and “histoplasmosis, clinical, and imaging features” as keywords. We found several articles from which the proper information was selected.

3. Pulmonary histoplasmosis-framework

Most people exposed to H. Capsulatum infection will have a mild, even asymptomatic form of the disease, with up to 90% of cases going undiagnosed. However, those under 2 years old and over 50, considered extreme ages, may develop more severe symptoms, with a febrile syndrome, dyspnea, cough, chest pain, and abdominal pain, approximately 2 weeks after exposure. Frequently, the disease is self-limiting, but in case of inhalation of a large inoculum, diffuse histoplasmosis can occur, with severe manifestations, especially dyspnea [3].

The spectrum of imaging changes found in histoplasmosis shows substantial variability, depending on the patient’s immunological status, the amount of inoculum at the time of infection, and the organs or systems involved. The radiological lesion pattern can mimic pathologies much more frequently encountered in medical practice, such as community-acquired pneumonia, tuberculosis, and bronchopulmonary neoplasm, but also other pulmonary fungal diseases, which underlines the difficulty of a prompt and certain diagnosis [4].

At the two opposite poles in terms of imaging diagnosis, we identify cases of subclinical histoplasmosis, in which the chest x-ray is present within normal limits, going up to the acute disseminated form with nodular miliary pattern and diffuse pulmonary distribution, such as systemic damage.

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

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.

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].

Figure 2.

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

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, non-specific rales are present on auscultation, according to the level of lung damage.

Chronic cavitary histoplasmosis is defined from an imaging point of view by fibro-cavitating 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 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].

Figure 3.

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

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].

4.2 Chronic progressive disseminated histoplasmosis

It is a severe form, which occurs in immunosuppressed people, for example, patients with HIV, in the AIDS stage with CD4 below 150 cells/μL, and transplant patients, with malignant hematological pathology. Also, patients who follow various immunosuppressive therapies, such as systemic corticosteroids, tumor necrosis factor antagonists (infliximab, etanercept), or patients exposed to fungi in childhood, are more prone to this severe form. H. Capsulatum can remain latent after the initial exposure, and the reactivation can occur years after the initial exposure. The organism can even be transmitted through donated organs [12].

The disseminated progressive form presents the following CT characteristics (see Figure 4): diffuse pulmonary infiltrates in both lung fields, nodular miliary pattern, or aspect of acute respiratory distress syndrome (ARDS) representing the consequence of uncontrolled fungal proliferation at the level of the reticuloendothelial system with secondary dissemination at the pulmonary, hepato-splenic, gastrointestinal tract and at the hematogenous bone marrow level [9].

Figure 4.

CT image in the axial plane demonstrates a generalized miliary pattern in both lung fields, with associated ground-glass areas showing a tendency to multifocal condensations.

4.3 Pulmonary nodules

Pulmonary nodules (see Figure 5) from histoplasmosis are frequently detected incidentally, most of them representing the primary healed granulomatous lesion. Histoplasmosis is actually the most common cause of non-cancerous granulomatous nodules and masses in endemic regions [13].

Figure 5.

CT images in the axial plane: (left) solitary pulmonary tissue nodule located in the periphery of the right lower lobe, with central calcification—pathognomonic appearance for histoplasmoma; (right) nodular appearance evident on the lung window.

More often, additional investigations are necessary to establish a diagnosis of certainty; the differential diagnosis is made mainly with nodules of malignant etiology; these lesions can mimic bronchopulmonary neoplasm or lung metastases. The differential diagnosis may require the performance of PET CT with 18F-FDG (fluorodeoxyglucose), which will highlight in the subacute phase of the infection lung nodules or masses with a faster reduction of affinity for 18F-FDG compared to associated adenopathies in contrast to proliferative lesions-malignant. Thus, in smoking or ex-smoking patients with nodules over 1 cm, it is necessary to perform a biopsy, either by transthoracic biopsy with a fine needle or by surgical excision. In the case of subcentrimetric nodules, imaging monitoring is recommended. Anti-Histoplasma antibodies can be detected in some patients, but the titers are usually low (1:8–1:16), and antigen tests are mostly negative. In the histopathological examination, both casefied and non-casefied granulomas can be detected. Cultures, even on special media for fungi, are often negative because the organisms are not viable [14, 15].

The histoplasmoma represents the solitary healed nodular lesion, with central calcification determining the appearance of a “target” lesion, pathognomonic for histoplasmosis (see Figure 6) [16].

Figure 6.

CT image in the axial plane highlights a lung nodule with soft tissue density, approximately 1 cm in size, with a homogeneous, well-defined, round-oval shape located in the periphery of the left upper lobe.

4.4 Mediastinal histoplasmosis

It can take several forms: mediastinal adenitis, mediastinal granuloma, and fibrosing mediastinitis. The type of damage influences the symptomatology.

4.4.1 Mediastinal adenitis

Most of the time, it is asymptomatic or paucisymptomatic, the most common symptoms being fever and pleuritic chest pain [17, 18]. However, an increase in the ganglia size can cause local obstruction through extrinsic compression, affecting the airways, the superior vena cava, or the esophagus, thus causing different symptoms: dyspnea, swallowing disorders, or cape edema. The radiological image is often suggestive. From an imaging point of view, mediastinal adenitis presents the appearance of mediastinal formation with solid density and homogeneous appearance on CT, in contrast to the heterogeneous appearance of granulomatous mediastinitis.

In isolated cases, pericarditis can also occur. Although this form is often self-limiting, a complete resolution of symptoms occurs after an extended period, from weeks to months. Imaging shows maintenance of the increased dimensions, and their calcification is frequent. Serology is often positive, thus confirming the diagnosis.

In the case of mediastinal adenitis, no specific treatment is recommended, but non-steroidal anti-inflammatory therapy is indicated to reduce pain or fever. However, if the clinical impact is important, specific antifungal treatment with Itraconazole is recommended to prevent disease progression and corticosteroids.

The differential diagnosis is most frequently made with mediastinal granuloma; in mediastinal adenitis, the characteristic is the homogeneous appearance, while in mediastinal granuloma, we have an enlargement of the ganglion with an inhomogeneous appearance [8].

4.4.2 Mediastinal granuloma

It is characterized by forming a semi-liquid adenopathy block, formed by the union of a group of necrotic lymph nodes, most frequently subcarinal and paratracheal. Macroscopically, the necrotic material has the appearance and consistency of a paste, surrounded by a thin capsule (2–3 mm).

As in the case of mediastinal adenitis, mediastinal granuloma can be an accidental discovery, often asymptomatic. Very rarely, in small children, between 2 and 5 years old, it can compress the central airways, the esophagus, or the superior vena cava, as it is known that in these children, the vessels and airways are more flexible [18, 19].

Clinically, it can manifest early after the acute infection, after a few weeks or months, but it can remain subclinical for years when calcifications are detected.

Most of the time, the symptomatology is determined by complications, with adhesion to the neighboring structures and fistulization, with the drainage of the content in the bronchi, pulmonary parenchyma, or esophagus [20]. This liquid usually has a purulent appearance. After the drainage takes place, a new latent phase may appear. The reappearance of symptoms after a certain period can predict an unfavorable evolution over time. Sometimes, drainage to the esophagus can determine the evolution toward sepsis due to the occurrence of retrograde bacterial enteric infection [21, p. 39]. Also, sometimes a fistulization can occur in the pulmonary parenchyma, with the appearance of pneumonic infiltrate or drainage in the pleural or pericardial space, which is extremely rare but urgently requires a surgical pericardial window [22].

Symptomatic mediastinal granuloma requires surgical treatment, but the approach must be made selectively, in the case of adhesions, precisely so as not to cause damage to the surrounding organs. In the case of bacterial superinfections due to fistulization, broad-spectrum antibiotic therapy is necessary in addition to the usual recommended antifungal therapy. Treatment of patients with mediastinal granuloma with itraconazole 200 mg once or twice daily for 6 to 12 weeks in symptomatic patients is reasonable, especially in early mediastinal granuloma, shortly after infection. In the case of asymptomatic mediastinal granuloma, surgical treatment is not recommended [23].

Granulomatous mediastinitis can be the first presentation of histoplasmosis in the form of a mediastinal mass detected on chest X-ray. The CT appearance is of a heterogeneous formation with paratracheal or subcarinal localization, secondary to caseous necrosis at the level of granulomas; internal calcifications may be present [8]. Also, the CT examination can highlight the occurrence of complications: for example, extrinsic compression of the trachea, esophagus, or superior vena cava, respectively fistulization at the mediastinal level, confirmed by the presence of air inclusions at the level of the granuloma. Fistulization at the pulmonary level can be highlighted by a parenchymal infiltrate of the pneumonic type [24].

Fibrosing mediastinitis appears secondary to a chronic inflammatory process with excessive deposits of fibrous tissue at the mediastinal level, which can obstruct the upper respiratory tract and pulmonary vessels. It can be focal (80% of cases, frequently in the case of histoplasmosis) or diffuse (20%). We are thinking of fibrosing mediastinitis in the case of people aged between 20 and 30 years. Although the prevalence is 1 in 100,000 infected patients, it is significant in endemic areas because there are millions of people affected [3]. The symptomatology is determined by the degree of damage to the adjacent structures. The most common symptom is hemoptysis, but the complications can vary depending on the neighboring structures affected [25]. Thus, in unilateral occlusion of the pulmonary artery, pulmonary infarction can be associated with damage to the entire lung. In the case of slow onset of the occlusion, we can have superior vena cava syndrome as a consequence. Most of the time, the damage is unilateral, but patients with fibrosing mediastinitis must be monitored periodically. The CT appearance is variable, with the appearance of a hilar or mediastinal mass (in localized form) or with a fibrosing infiltrative appearance (in diffuse form) with soft tissue density, which obliterates the mediastinal fatty atmosphere and determines the cuffing of the main vessels, with the risk of pulmonary hypertension or obstruction of the superior vena cava [26].

4.5 Forms of extrapulmonary histoplasmosis

In addition to pulmonary manifestations, in some cases (5%) cardiac (pericarditis) [27], skin (erythema multiforme, erythema nodosum) [7], rheumatological (arthritis), ocular manifestations may appear, but these represent a sterile inflammation as part of a systemic response, rather than a disseminated disease.

4.5.1 Progressive disseminated histoplasmosis and meningitis

Approximately 5–20% of patients have CNS involvement. This could include a mass lesion, encephalopathy, and meningitis. Medical therapy is initiated for all patients with progressive disseminated histoplasmosis and meningitis [2].

4.5.2 Cardiac histoplasmosis

Immediate procedural intervention is practiced when there is hemodynamic and respiratory decompensation due to pericardial or pleural damage. In severe cases, thoracocentesis or pericardiocentesis is performed in patients with large pleural effusions, respectively, cardiac tamponade [2].

If the pericardiocentesis is insufficient to alleviate the cardiac tamponade, it may be necessary to place the pericardial window.

Endovascular histoplasmosis can lead to valve infection and aneurysm formation, requiring surgical excision of the infected valves and aneurysm repair. In most cases, endovascular histoplasmosis cannot be cured with medical therapy alone.

4.5.3 Cutaneous and rheumatological histoplasmosis

The lesions are self-limiting. Therapy is indicated only in the case of prolonged episodes or in immunosuppressed patients.

4.5.4 Ocular histoplasmosis

It occurs in 1 to 10% of cases [5]. Extensive maculopathy in suspected ocular histoplasmosis requires steroid treatment. Laser photocoagulation treatment may be necessary for patients with the active formation of neovascular membranes due to choroiditis. Excessive growth can lead to progressive vision loss.

Figure 7 summarizes the histoplasmosis clinical classification and high-resolution computer tomography (HRCT) findings.

Figure 7.

Histoplasmosis clinical classification and high resolution computer tomography (HRCT) findings.