Current Concepts in the Epidemiology, Diagnosis, and Management of Histoplasmosis Syndromes

Marwan M. Azar, MD; James L. Loyd, MD; Ryan F. Relich, PhD; L. Joseph Wheat, MD; Chadi A. Hage, MD

Disclosures

Semin Respir Crit Care Med. 2020;41(1):13-30. 

In This Article

Mediastinal Histoplasmosis

Mediastinal Adenitis

Clinical Findings. Mediastinal histoplasmosis is most commonly asymptomatic (Table 5). In symptomatic cases, the characteristic syndrome is one of fever and enlarged mediastinal lymph nodes, often in a young adult from an endemic area presenting with pleuritic-like chest pain.[82,83] Very rarely, inflamed nodes may even cause local obstruction by impinging on airways, esophagus, or superior vena cava (SVC). This is more common in children than adults since the trachea or major bronchi of children are more pliable. The pain is typically severe, often prompting hospitalization due to concern for pulmonary embolism, pleurodynia, or pericarditis. The latter can accompany acute histoplasmosis and mediastinal adenitis (MA). Although symptomatic MA is usually self-limited, total resolution of symptoms may take weeks to months. Despite resolution of symptoms, lymph node enlargement usually persists, and ectopic calcification typically develops during the ensuing years.

Diagnosis. Unlike pulmonary and disseminated histoplasmosis, in which symptoms are nonspecific, the clinical syndrome of symptomatic MA is quite typical, though it sometimes may be difficult to distinguish the clinical syndromes of MA from an early presentation of mediastinal granuloma (MG). The most distinctive feature is the appearance on computed imaging (CT). Whereas the necrotic contents in MG demonstrate a heterogeneous density on CT, adenitis appears as a solid homogeneous density (Figure 9). Although antigen testing is usually negative, serology is usually positive so further diagnostic testing is generally not necessary.

Figure 9.

Mediastinal adenitis. A 31-year-old female admitted for inspiratory central chest pain and fever for 2 days. Chest CT showed a 2 × 3.5 cm subcarinal mass without calcification. There was also a 1 cm rounded infiltrate in RLL and right hilar adenopathy (not shown). Aspiration of the subcarinal node showed lymphocytes with no evidence of malignancy. She improved with nonsteroidal anti-inflammatory treatment. Histoplasma serology via complication fixation was 1:256. CT, computed tomography; RLL, right lower lobe.

Management. Symptomatic MA is typically a self-limited illness. There is no evidence that therapy for adenitis has any impact on subsequent late complications but nonsteroidal anti-inflammatory treatment is appropriate for symptomatic management of pain or fever. For persistent or severe cases, such as airway compromise, steroids may be prescribed. In those cases, concurrent itraconazole therapy is recommended to prevent progression of disease.

Mediastinal Granuloma

MG is defined as a cluster of necrotic lymph nodes often paratracheal or subcarinal that are coalesced into a semiliquid conglomerate mass. MG is predominantly composed of necrotic material, with an appearance and consistency similar to toothpaste and surrounded by a thin (2–3 mm) capsule,[84] which is not distinguishable by current imaging. The diagnosis of MG does not require the finding of granulomas on histopathologic sections, as MG is defined by its gross pathology.

Clinical Findings. For most patients, MG is asymptomatic and is found incidentally. In very young (2–5 years) children, it may rarely compress compliant central airways or the SVC.[83,85] Unlike fibrosing mediastinitis (FM), MG does not invade adjacent vessels or airways, but may compress the esophagus or SVC. MG may manifest either early (a few weeks or months) after acute infection or may remain subclinical for years, before becoming symptomatic, at which time calcification is usually identifiable. New onset chest pain, in a patient with a pre-existing but asymptomatic MG, may be a sentinel symptom for a future complicated course. Complications include attachment to nearby structures, fistulization, with subsequent drainage of semiliquid, purulent-appearing contents into adjacent structures, including bronchi, lung parenchyma, esophagus, or surgical tracts if mediastinoscopy was performed.[86] In some cases, MG may fistulize and empty most or all of their contents and then remain dormant. Alternatively, a quiescent MG may also become symptomatic at regular intervals, often a few months, heralded by low-grade fever, malaise, and night sweats. When such MGs incompletely drain their overall contents, interval flares and recurrences may ensue, typically through the original fistulous site. Drainage is most obvious when it can be visualized through an external site such as a mediastinoscopy scar. The presence of air within an MG confirms fistulization, which can manifest as productive cough in the case of a bronchial fistula. Fistulization and drainage to the esophagus can be completely subclinical[87] but can rarely be complicated by retrograde bacterial enteric infection of the MG, sometimes leading to sepsis.[88] Drainage to lung parenchyma, such as from right paratracheal MG directly across pleura to right upper lobe, may be clinically deceptive as its manifestation is a parenchymal lung infiltrate like pneumonia. MG drainage into the pericardial space is quite rare, but very important because an urgent surgical pericardial window may be needed.[89]

Diagnosis. MG is characterized on CT imaging by calcifications, either in a patchy distribution or a subcapsular rim, as well as by heterogeneous density of the contents (Figure 10). In contrast to FM, which is always a late complication, MG may also develop early (a few months after infection; noncalcified on imaging), so biopsy may be needed to distinguish early MG from necrotizing lymphoma or other granulomatous conditions. EBUS with transbronchial needle aspiration is progressively more widely utilized for cytologic analysis of mediastinal nodes or masses, but may have special risk in MG, as many patients have developed bacterial superinfection of MG after EBUS.[90]

Figure 10.

Mediastinal granuloma. Axial chest CT image of a 5 × 6 cm right paratracheal mediastinal granuloma in a 32-year-old female. She was asymptomatic, but a year later developed chest pain and was found to have an MG that fistulized and drained to the RUL. CT, computed tomography; MG, mediastinal granuloma.

Serology is positive in most MG patients, but not universally. Nonviable organisms are usually present in MG tissue, but locating them requires a large sample with an exhaustive review of a Gomori methenamine silver (GMS) stain, as organisms are often scarce and scattered. Small samples such as needle aspirates or excisional biopsy commonly do not sample or may overlook the organisms, and cultures are typically negative. Since mycobacteria are also known to cause MG, they should be considered in appropriate circumstances.

Management. Surgical resection is required for definitive therapy of symptomatic MG. Portions of the MG adherent to critical structures should be left in place to reduce chances of injury. The surgical approach may be complex so close coordination with the thoracic surgeon is needed. As the contents of an MG are not proinflammatory, intraoperative spillage of contents is not of concern. The efficacy of resection for symptomatic MG is in stark contrast to FM where surgery carries high risk and is rarely therapeutic. When MG is characterized incorrectly as FM, that may cause treatment delay or prevent resection. In the event of bacterial superinfection as a result of an esophageal fistula, broad-spectrum antibiotics with activity against enteric flora are required. Treatment of MG patients with a course of itraconazole 200 mg once or twice daily for 6 to 12 weeks in symptomatic patients is reasonable, especially in early MG soon after the infection. Spontaneous resolution of MG does occur, and is suspected to be due to silent fistulization and discharge of contents into the esophagus, which may be erroneously attributed to response to medical therapy. On occasion, spontaneous drainage of MG contents is demonstrated by a decrease in the number of internal calcifications. MG does not progress to FM as previously thought,[91] so resection of asymptomatic MG is not warranted.

Fibrosing Mediastinitis

In FM, a solid, dense, and invasive fibrotic mass leads to invasion across adjacent tissue planes and causes obstruction of pulmonary vessels or airways.

Clinical Findings. Symptoms of FM occur due to critical obstruction of adjacent vessels or airways and the resulting effects. Unilateral pulmonary artery occlusion, which is sometimes associated with clinical infarction, often leads to autoamputation of one lung,[83,85,92] most often the right. SVC obstruction may lead to SVC syndrome or may have surprisingly few signs as a result of gradual development of sufficient collateral veins. Hemoptysis is the most common symptom of FM.[92] In contrast to MG, which occurs across the entire age spectrum, including children as young as 2 years, FM typically presents in 20 or 30 year olds. The underlying mechanisms and risk factors for FM are unknown. Although only 1 in 100,000 infected patients develop FM, the prevalence of FM is significant because several million people are infected annually. One referral center in an endemic area has evaluated more than 300 FM patients during the past 30 years (personal communication, J. Loyd). Recent widespread use of CT imaging has led to greater recognition of FM. MA and FM are syndromes unique to histoplasmosis, whereas MG is also caused by mycobacteria.

Although FM tissue growth and vascular occlusion progress slowly (~1 mm/year) and silently,[85] symptoms are typically surprisingly acute, after vascular narrowing reaches a threshold sufficient to cause infarction (more commonly the right lung) or SVC syndrome. Significant morbidity is typical, including chest pain, hemoptysis, dyspnea, or SVC syndrome, but long-term survival after unilateral loss of lung function is generally favorable. Extension from unilateral to bilateral FM during follow-up is unusual (~1 in 50), but serial imaging is recommended to monitor for possible progression. Bilateral disease is uncommon (~20%) but is usually life-threatening when it occurs.

Diagnosis. In a young adult from an endemic area with no obvious alternative diagnosis, the imaging findings for FM are nearly pathognomonic. Chest X-rays often show few abnormalities, especially in the case of subcarinal FM, which is hidden by cardiac structures. Pulmonary infiltrates related to infarction may be incorrectly attributed to common conditions such as pneumonia. CT imaging demonstrates characteristic abnormal mediastinal proliferation along with heavy calcification, localized at lymph node sites (Figure 11). Characteristic diagnostic features including occlusion of pulmonary arteries, pulmonary veins, SVC, or airways are highlighted by use of vascular contrast. Nuclear medicine perfusion lung scanning can be useful either as a global assessment or to evaluate suspected abnormalities of the artery, vein, or airway of specific lung zones. When symmetrical narrowing of all pulmonary veins by FM is present (pseudomitral stenosis syndrome), the relatively normal distribution of perfusion may conceal the severity of the disease. A CT of the chest without contrast can distinguish calcifications from radiographic contrast. When typical CT findings are present in the correct clinical setting and when alternative diagnoses are unlikely, a confirmatory tissue diagnosis may not be needed. Almost any combination of affected structures has been seen, but a few typical presentations occur. One typical syndrome is right pulmonary artery occlusion, followed a few years later by narrowing of left pulmonary veins. In general, pulmonary vein narrowing may be cryptic and easily missed until cardiac catheterization. Right paratracheal FM causing SVC syndrome, in association with right pulmonary artery or right superior pulmonary vein obstruction, is another common presentation. Another is subcarinal FM obstructing the right pulmonary artery, followed years later in the left main bronchus. Serology is positive in most cases, but not always, and antigen testing is mostly negative. Nonviable organisms are rarely present on pathologic samples from needle or biopsy acquisition. Organisms are usually localized in small central caseous areas (2–4 mm) not typically identified on imaging or accessible for tissue sampling, but they may be identified from large en bloc samples from surgical resection or postmortem, after an intense search was conducted.

Figure 11.

Mediastinal fibrosis. Axial chest CT image in a 44-year-old woman with bilateral FM, demonstrating a calcified subcarinal mass with total obstruction of the right pulmonary artery. She had also developed obstruction of both left pulmonary veins (not shown), which were successfully stented with subsequent dramatic improvement in her clinical functional status. CT, computed tomography; FM, fibrosing mediastinitis.

Management. Antifungal or anti-inflammatory treatments do not improve FM symptoms or outcomes. After B lymphocyte presence was demonstrated in FM tissue,[93] a follow-up intervention in three patients using rituximab was conducted and showed decreased metabolic activity by PET imaging.[94] There are no reports to date of regression of disease or alteration of FM course by rituximab. In the event of massive hemoptysis, bronchial artery embolization (BAE) by an interventional radiologist is the preferred approach. When unilateral FM is associated with hemoptysis, bronchial artery hypertrophy invariably occurs on the occluded side, and may be associated with marked friability of the airway mucosa, known as "bleed on touch," which may increase risk of bronchoscopy. In a single-center anecdotal experience, FM-related massive hemoptysis requiring BAE has been less common than in the previous two decades, perhaps due to increased use of pulmonary artery and vein stents, which might minimize development of bronchial artery collaterals. Indeed, intravascular stents can successfully manage FM-related vascular obstruction,[95] and should be considered whenever critical structures are affected, especially with bilateral involvement. The arterial, venous, and airway structures for each lung zone should be assessed prior to stenting, because adequate lung function is contingent on the function of all three. Due to extremely dense fibrosis associated with FM, stenting obstructed pulmonary vessels often requires specialized interventionalists with prior FM experience. In a small series, four of eight patients died within a few weeks of pulmonary vein stenting, emphasizing the high mortality of bilateral involvement.[96] Feasibility for stenting is best assessed at catheterization by interventional cardiologists experienced with FM, who perform atrial transeptal puncture to access pulmonary veins and then interrogate each obstruction to assess pressure gradients and relevant physiologic data. Stenting is not technically feasible for all FM patients.

Stenting of the SVC is recommended for symptomatic SVC obstruction. Aortic injury caused by SVC stenting is a rare but recognized life-threatening complication.[97] In the long term, restenosis develops in a significant minority, so patients should be monitored for recurrent symptoms.

Airway involvement is less common than vascular involvement by FM but can be difficult to manage because the effectiveness of airway stents for FM is historically poor, due to reocclusion within weeks by airway tissue growth. Patients with bilateral mainstem bronchus obstruction are among the most challenging problems and should be managed by interventional bronchoscopy specialists.[98]

Because of fused tissue planes and hypervascular tissues leading to hemorrhage, surgery for FM is high in risk. Surgery should be reserved for life-threatening circumstances such as pneumonectomy to rescue a patient from life-threatening hemoptysis not controlled by BAE. Pneumonectomy for unilateral FM is associated with an estimated risk for major complication or death of at least 20 percent. Lung transplantation is not considered at most centers, because native lung explantation without injury to phrenic nerves is extremely unlikely.

Progressive Disseminated Histoplasmosis

Epidemiology. Certain populations are at increased risk for developing PDH. These include patients at extremes of age (≥55 and ≤1 years)[68] and immunocompromised patients, including those with HIV/AIDS, recipients of solid organ or bone marrow transplantation, and those receiving TNF-α inhibitors and other biologics. Other less common but important risk factors include CD4 lymphopenia,[99] common variable immunodeficiency,[100] hyper IgE syndrome (Job's syndrome),[101,102] and defects in the interleukin 12 or interferon gamma pathways.[103] Immunocompromised patients are at least 10 times more likely to develop PDH than the general population.[68] The occurrence of PDH in a seemingly immunocompetent patient may be indicative of an underlying undiagnosed immunodeficiency. However, PDH has been described in immunocompetent patients, presumably due to exposure to large inocula.[104] Histoplasmosis in the setting of solid-organ transplantation is rare (<1%) even in endemic areas and most cases occur within 1 to 2 years of transplantation.[105] Donor-derived infection has been described but occurs only in 1:10,000 transplants.[106] Histoplasmosis is similarly infrequent in the bone marrow transplant population but appears to be more common in those with graft-versus-host disease.[107] In contrast, histoplasmosis is the most common invasive fungal infection in patients on TNF-α inhibitors. Despite the fact that histoplasmosis is well recognized in this population, diagnosis is often delayed and infection is associated with a mortality rate of 20%.[45]

Clinical. The clinical syndrome consists of fever, constitutional symptoms such as fatigue, night sweats, and weight loss, and respiratory symptoms. Due to a nonspecific presentation, a high index of suspicion should be maintained in immunocompromised patients living in endemic areas or with recent epidemiologic exposures. Pulmonary involvement develops in the majority (50–90%) of patients (Figure 12), and is characterized by diffuse reticulonodular, interstitial, or miliary infiltrates.[108] The most common sites of extrapulmonary dissemination are the liver, spleen, gastrointestinal tract, and bone marrow; dissemination to these sites occurs in 33 to 66% of cases (Table 6).[47] Less common sites include skin, adrenal glands, central nervous system, and heart,[109] in 10 to 20% of cases.[47]

Figure 12.

Progressive disseminated histoplasmosis. A 38-year-old man with Crohn's disease on infliximab presented with fever, dyspnea, hypoxia, and abdominal pain. Chest radiograph showed bilateral reticulonodular infiltrates. A bronchoscopy was performed with BAL GMS stains showing yeast consistent with H. capsulatum. Urinary Histoplasma antigen was highly positive. BAL, bronchoalveolar lavage.

Diagnosis. The diagnostic approach to PDH consists of a multitude of testing modalities including bronchoscopy with BAL for cytopathology/histopathology and culture, as well as antigen detection (preferably on urine). These methods provide the basis for diagnosis in most cases in the United States including 70% of nonimmunocompromised to 95% in immunocompromised patients.[44–46,109] In patients with HIV/AIDS, blood cultures may be positive in up to 50%. Although no longer routinely used in most clinical laboratories, lysis centrifugation tubes are more sensitive than conventional and Bactec MYCO/F Lytic blood cultures for the recovery of H. capsulatum.[110–112] If suspicion for PDH is high, testing both urine and serum should be considered as 15% of patients may have false-negative results if testing on only one specimen type is done. Similarly, antigen testing on BAL should also be considered and may be the only evidence for positivity in one-tenth of cases.[51] Serology is less sensitive in immunocompromised patients but may have a role if the pretest probability is high and initial testing is negative. Detection of antibody may serve as the sole basis for diagnosis in rare cases.[45]

Management. Treatment is recommended in all cases of PDH. Liposomal amphotericin B should be instituted as initial therapy for 1 to 2 weeks (Table 4), except when there is CNS involvement when the induction phase is extended to 4 to 6 weeks. Liposomal amphotericin B is preferred over deoxycholate due to better clinical response (88 vs. 64%) and a trend toward improved mortality (2 vs. 13%).[70] Following the induction phase, step down to itraconazole for at least 1 year is recommended. In selected cases of mild disease, itraconazole alone for 1 year has been effective. Alternatives to itraconazole for oral therapy include fluconazole[113] and voriconazole,[114] but the preferred choice is posaconazole due to increased in-vitro activity.[115] If posaconazole is selected, tablet or intravenous formulations should be used as the therapeutic blood concentrations are hard to achieve using the suspension formulation.[116,117] Immunocompromised patients with histoplasmosis should be managed as if they have PDH and treated for at least 12 months, since shorter courses in these cases have been associated with relapse.

Another mainstay of treatment for PDH is immunosuppression reduction. This includes reduction of maintenance immunosuppression in recipients of solid-organ transplants, discontinuation of TNF-α inhibitors and other biological agents when possible, and resumption of antiretroviral therapy in nonadherent patients with HIV/AIDS. In patients with interferon gamma or IL-12 deficiencies, interferon gamma therapy may be useful as adjunctive therapy.[118,119]

Treatment should be continued for 12 months and until antigen levels have declined. Experience in solid-organ transplant patients suggest that antifungal therapy can be successfully discontinued even in the case of persistently positive antigen levels if clinical and radiologic responses are achieved after a prolonged course.[105] In patients with HIV/AIDS, antifungal therapy should be continued until antigen levels in urine and serum are at least <2 ng/mL (preferably undetectable) and until CD4 T cell count is ≥150 cells/mm3, the HIV viral load is less than 50 copies/mL (preferably undetectable) and patients are fully adherent to antiviral and antifungal therapy.[44] In HIV/AIDS patients with Histoplasma meningitis, suppressive antifungal therapy should be continued indefinitely.

Clinical worsening while on appropriate therapy is suggestive of treatment failure, immune reconstitution inflammatory syndrome (IRIS),[44–46] or an unrelated infectious or noninfectious process. IRIS is more likely when clinical decompensation occurs despite treatment adherence, therapeutic itraconazole levels, declining antigen levels, treatment intensification, and when repeat tissue sampling yields negative cultures (though demonstration of nonviable yeast on pathology is possible). Rapid improvement with a trial of corticosteroids is suggestive of IRIS.

After discontinuation of therapy, patients should be carefully monitored for relapse clinically and with antigen testing every 3 months for 1 to 2 years. Relapse has been reported over a decade after the initial presentation.[120]

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