Miliary Patterns on Computerized Tomography Imaging of Chest in Immunocompromised Patient: Unveiling Disseminated Histoplasmosis

Introduction

One granulomatous disease that relentlessly progresses and mimics many other granulomatous diseases, including tuberculosis, especially in immunocompromised patients, is disseminated histoplasmosis. Histoplasmosis is caused by Histoplasma capsulatum, a dimorphic fungus noted to be endemic to the Midwest region in the United States. It can range from asymptomatic to disseminated infection, based on the patient’s immunity. Since the incorporation of tumor necrosis factor (TNF) alpha inhibitors into clinical practice and their widespread use for various inflammatory autoimmune conditions, there has been an increase in hospitalizations with histoplasmosis in endemic regions among these patients [1]. Diagnosing disseminated histoplasmosis can be challenging due to its diverse clinical manifestations and other diseases mimicking the presentation. As disseminated histoplasmosis has a nonspecific presentation, differentiation from other infections is challenging, especially tuberculosis, given the possibility of the coexistence in immunocompromised patients [2]. The sensitivity of cultures for detection of fungi, which is the criterion standard test, is variable, as it is based on the patient’s immunity and requires around 6 weeks for optimal growth. The detection of antibodies can also give false negative results, based on the patient’s immunity, but has a higher sensitivity to antigen detection in this patient population [3]. Molecular testing with polymerase chain reaction is a promising test and has 100% sensitivity, but availability is limited [4]. All these limitations cause a delay in the diagnosis and treatment of patients with disseminated histoplasmosis, more so in immunocompromised patients. Given the myriad conditions causing miliary patterns on chest imaging, this case highlights the importance of early diagnosis, treatment, and high suspicion for uncommon and rare causes, especially in immunocompromised patients [5,6]. We present a patient with disseminated histoplasmosis who came in with shortness of breath, was on active treatment with TNF α inhibitor for rheumatoid arthritis, and was initially treated for pneumonia, with no improvement. Later, a diagnosis of disseminated histoplasmosis was made. Disseminated histoplasmosis is not uncommon and the patient in this case presented with atypical symptoms and classic miliary pattern on computed tomography (CT) images. Due to atypical clinical presentation, overlapping imaging findings, time-intensive sample collection, and culture methods, there was a diagnostic dilemma and delay in diagnosis.

Case Report

An 81-year-old woman with a past medical history of rheumatoid arthritis presented to the hospital for shortness of breath for about 2 to 3 weeks and an associated non-productive cough. She also had associated low-grade fever, decreased appetite, and weight loss. The patient had been following up with the rheumatology clinic for her rheumatoid arthritis, and her active treatment for rheumatoid arthritis included denosumab, ibuprofen, methotrexate, folic acid, and intravenous (i.v.) golimumab. Before this, she was on i.v. infliximab and abatacept, which did not help her much. She was afebrile, saturating well on room air, and hemodynamically stable on admission. On physical examination, she had new-onset mild crackles in both lung fields, but the examination was otherwise unremarkable. Initial laboratory work-up showed a white blood cell count of 6.07×103/mcL, hemoglobin of 14 g/dL, elevated liver enzymes with aspartate transaminase level of 40 U/L, alkaline phosphatase level of 152 U/L, mild hyponatremia with sodium level of 128 mmol/L, and elevated lactate dehydrogenase level of 417 U/L. The initial chest radiograph showed chronic-appearing coarse lung opacities bilaterally, with no other acute cardiopulmonary abnormality. She was started on empiric treatment for community-acquired pneumonia, given her symptoms. Despite this, her shortness of breath did not improve, and given her immunocompromised state, a CT of the chest without contrast was ordered on day 3 of admission, which showed multiple bilateral pulmonary nodules and miliary disease throughout the lungs, as shown in Figure 1, with yellow arrows depicting the miliary nodules. Differential diagnoses included tuberculosis, fungal infections, metastases, sarcoidosis, pneumoconiosis, hypersensitivity pneumonitis, and Langerhans cell histiocytosis. Miliary tuberculosis was first in the differential, given the classic distribution of the nodules in a miliary pattern. She was placed under droplet isolation, and 3 sputum acid-fast bacilli cultures were collected and sent. The Pulmonology Department was consulted because the chest CT findings were concerning for miliary tuberculosis. The case was discussed with the Infectious Disease Department, which recommended to order a fungal antibody panel and fungitell and urine histoplasma antigen, given the symptoms, immunosuppression, and miliary pattern on imaging findings. The patient had a positive histoplasma urine antigen of 0.9 ng/mL, and the reportable range for this assay is 0.2 to 25 ng/mL. She underwent bronchoscopy, which showed mucosal pallor throughout, with no endobronchial lesions and minimal, thin, and white secretions present in the trachea, main carina, left lung, and right lung, as shown in Figure 2A–2C, marked with red arrows. Secretions were easily removed by therapeutic aspiration, and the airway was cleared. Bronchoalveolar lavage was performed 1 time in the right middle lobe, with 120 mL of saline instilled and a total return of 60 mL. The fluid appeared clear, as shown in Figure 2D, marked with a red arrow. Bronchoalveolar lavage samples were sent for acid-fast bacilli and fungal cultures. All initial cultures were negative, and later, bronchial alveolar lavage fluid tested positive for the histoplasma antigen, further confirming miliary histoplasmosis. A GeneXpert test was non-detectable for Mycobacterium tuberculosis, and a histopathological examination was not performed. Bronchoalveolar lavage fluid was negative for aspergillus and Pneumocystis jirovecii pneumonia. Serum histoplasma antibodies and a complement fixation assay were negative, an expected finding in an immunocompromised hosts who cannot launch an immune response [7]. The patient had a CT of the abdomen/pelvis with contrast, which showed a 3×1-cm right adrenal nodule and 9-mm left adrenal nodule, as depicted in Figure 3, marked with red arrows, along with hypoattenuating lesions in the spleen. These lesions were considered to be probably secondary to disseminated histoplasmosis. The patient was started on i.v. amphotericin at 3 mg/kg every 24 h for a total of 14 days and later de-escalated to oral itraconazole. The patient’s urine histoplasma antigen was positive despite 1 week of amphotericin; therefore, a total of 2 weeks of treatment with i.v. amphotericin was given. She was discharged home and was tapered to itraconazole 200 mg orally 3 times daily for 3 days and later to 200 mg 2 times daily for 1 year. The patient was recommended for CT of the chest, abdomen, and pelvis after completion of at least 1 year of treatment as a follow-up. Most of the previously seen diffuse pulmonary nodules had resolved on 3-month follow-up imaging with CT of the chest, abdomen, and pelvis, with contrast. Also, the adrenal lesions had decreased in size, showing a response to the treatment, as shown in Figures 4 and 5, marked with yellow and red arrows.

Discussion

Miliary pattern is the presence of diffuse lung nodules on chest imaging that resemble millet seeds and occur due to lymphohematogenous dissemination and ineffective response of cellular defense mechanisms or an underlying infiltrative process that spreads through the lung interstitium [5]. It is an uncommon presentation but is increasingly seen in clinical practice, given the rise of the immunocompromised and immunosuppressed patient population. The miliary pattern is a characteristic radiological manifestation of micronodular lung disease, and the common entities causing this pattern are infectious, immune or inflammatory, pneumoconiosis, and malignancy. This pattern, when seen, is characteristically interpreted as miliary tuberculosis [8]. However, given the increase in the population of immunocompromised patients, other causes, such as disseminated fungal infections, need to be evaluated to increase diagnostic accuracy and early treatment. Histoplasmosis has become the most common fungal infection among patients treated with TNF antagonists for rheumatoid arthritis, inflammatory bowel disease, and dermatological disease [9]. Immunocompromised hosts are more likely to have severe disease than are immunocompetent hosts, and disseminated infection is a more common clinical picture among immunocompromised hosts [10]. Radiological investigations in disseminated histoplasmosis show characteristic signs of fibrosing mediastinitis compressing major vessels, and other organ involvement typically seen is acromegaly, hepatosplenomegaly, and mediastinal and abdominal lymphadenopathy [11]. CT findings of pulmonary histoplasmosis are varied and nonspecific, with acute cases showing diffuse bilateral opacities, subacute cases presenting focal opacities that may calcify, and severe cases, especially in immunosuppressed patients, leading to extrapulmonary dissemination with pericarditis, hepatosplenomegaly, skin changes, and rheumatologic disorders. Pulmonary histoplasmosis commonly presents as solitary or multiple nodules, often mimicking malignancy, while CT findings in acute cases can show irregular consolidation resembling bacterial pneumonia, organizing pneumonia, or neoplasia. Chronic cavitary histoplasmosis, which is rare and typically seen in patients with chronic obstructive pulmonary disease, presents as upper lobe consolidation with progressive cavitation, volume loss, and pleural thickening, resembling tuberculosis. Disseminated histoplasmosis, primarily in immunocompromised patients, manifests as diffuse pulmonary micronodules or airspace opacities, often mimicking miliary tuberculosis or metastatic disease [12].

Miliary histoplasmosis is seen in immunocompromised patients and is caused by Histoplasma capsulatum, which is a dimorphic fungus endemic to regions of Ohio and Mississippi river valleys, including the south-central United States [13]. Histoplasma infection is acquired by inhalation of microconidia, which is followed by the generation of mycelia and yeast forms. These are engulfed by immune cells, resulting in either containment or dissemination of infection, depending on the host’s immune response. Immunocompromised patients are likely to have disseminated infection, which could be particularly severe and prolonged [14]. Clinical presentation depends on the involvement of histoplasmosis, and pulmonary involvement of histoplasmosis very closely mimics tuberculosis and has a resemblance in upper lobe cavitation, nodular shadows, miliary nodules, and mediastinal lymphadenopathy [15]. Our patient was immunocompromised from TNF inhibitor use, making her prone to disseminated infection. High-resolution CT cannot better specify the pattern of miliary nodules for a differential diagnosis. They are usually divided into 3 groups, with centrilobular, random, and perilymphatic distribution. In diffuse panbronchiolitis, a centrilobular pattern is noted, with a lighter version and ill-defined borders, and scarring is noted posteriorly in hypersensitivity pneumonitis. A random distribution of these miliary nodules is usually seen in tuberculosis, which was seen in our patient. A perilymphatic distribution with increased nodules along the septum and fissures with small nodules along the pleural surfaces can be seen in some pneumoconiosis and lymphangitic carcinomatosis [16]. An extrapulmonary involvement needs to be looked for in any patient with suspected miliary nodules and a concern for tuberculosis, especially in immunosuppressed and immunocompromised patients. A miliary pattern on CT or chest X-ray can be seen in a diverse range of cases, including febrile and afebrile causes. Some febrile causes include infections such as tuberculosis, fungal, viral pneumonitis, nocardiosis, salmonella, and sometimes hypersensitivity pneumonitis. Some of the common afebrile causes include miliary metastasis in the setting of thyroid, breast, or renal carcinomas. Pancreatic neoplasms, osteosarcoma, and malignant melanoma can also present with metastases to the lungs in advanced stages. A few other conditions to consider on observing a miliary pattern are pulmonary alveolar proteinosis, Langerhans cell histiocytosis, pulmonary hemosiderosis, and pneumoconiosis, among others [17].

Histopathology and culture are criterion standards for the diagnosis of histoplasmosis. Given the sensitivity of histopathology and cultures, diagnosis is delayed, as there is a need for invasive procedures for sample collection and a delay in the growth of organisms [18]. Diagnosis is made by visualizing yeast on histopathology, isolating organisms from sputum culture, or detecting histoplasma antigens. Detection of yeast in cultures and DNA probes can take around 4 weeks, delaying the diagnosis. Also, there is a high chance of cross-reactivity of the histoplasma antigen with other fungal antigens, leading to misdiagnosis, as seen in a case report in which fungal antigen was positive for coccidioidomycosis antigen in an HIV-positive patient, but ultimately, the culture was positive for histoplasmosis [19]. Histoplasmosis is generally treated with antifungal medications, such as azoles. Itraconazole was the preferred choice, but with central nervous system involvement, as per IDSA guidelines, voriconazole, posaconazole, isavuconazole, and fluconazole can be given as the treatment of choice [20]. Some studies show that fungal burden clearance in disseminated histoplasmosis was better with amphotericin B, and this drug is also widely used in the treatment of disseminated histoplasmosis [21].

Radiographic improvement in histoplasmosis varies with disease severity and patient immune status. In acute pulmonary histoplasmosis, chest radiographs often show patchy pneumonia in one or more lobes, with enlarged hilar and mediastinal lymph nodes. Improvement is prompt in most cases, with treatment showing disappearance or decrease in the miliary nodules; however, in some patients, clinically, fatigue can linger for several months [22]. In chronic pulmonary histoplasmosis, chest radiographs often reveal emphysematous lungs, with apical bullae surrounded by segmental airspace disease. Progressive thickening of cavity walls and retraction of adjacent lung tissue occurs over time [23]. Overall, radiographic improvement depends on the histoplasmosis form, disease severity, and patient’s immune status. Monitoring radiographic changes is essential for assessing treatment response and disease progression, and our patient showed a clear radiographic improvement on the 3-month follow-up after initiation of treatment.

Conclusions

This case highlights the challenges faced in diagnosing and treating miliary histoplasmosis in immunocompromised patients. Miliary nodules in the lung can be seen in a host of other infectious conditions other than miliary tuberculosis and need to be considered in patients with miliary pulmonary nodules. As clinical presentation is similar in all these infectious conditions, careful history regarding exposure and immunocompromised states should be considered. Despite the inability to detect antibodies in immunocompromised patients, definitive diagnostic tests need to be considered before the exclusion of other infectious causes, through culture and histopathology, which are the criterion standard tests. There should be a low suspicion for histoplasmosis in patients treated with TNF inhibitors, as mortality is reportedly high in such cases and early diagnosis and appropriate antifungal therapy initiation will have a good response.