Bilateral adrenal histoplasmosis presenting as adrenal insufficiency in an immunocompetent host in the Philippines

Abstract

Disseminated histoplasmosis, with the adrenal glands as being the only site of demonstrable disease in an immunocompetent adult, is a rare infection leading to adrenal insufficiency. This disease carries high mortality when unrecognised. We describe the first reported case of adrenal histoplasmosis in the Philippines in a 72-year-old immunocompetent, Filipino man who presented with a 3-month history of intermittent flank pain, weight loss and generalised weakness. His imaging demonstrated bilateral adrenal masses on ultrasonography and contrast-enhanced CT scan. The initial impression was adrenal cancer, however, fine-needle aspiration cytology revealed the presence of yeast cells and blood culture grew Histoplasma capsulatum. The diagnosis of the case represents a diagnostic challenge in immunocompetent individuals because they manifest with non-specific symptoms. A heightened suspicion is therefore needed to prevent significant morbidity and mortality.

Background

Histoplasmosis is an opportunistic fungal infection that commonly affects immunocompromised individuals. Adrenal histoplasmosis as a cause of adrenal insufficiency is a clinically significant entity yet often a missed diagnosis. It represents a diagnostic challenge in non-endemic areas and immunocompetent individuals because it usually presents with non-specific symptoms. A heightened suspicion is therefore needed to prevent significant morbidity and mortality

Case presentation

A 72-year-old Filipino man presented with a 3-month history of intermittent flank pain accompanied by undocumented fever, generalised weakness and weight loss of 6 kg. He also reported dizziness when standing up. He denied cough, difficulty of breathing, bowel movement changes and dysuria.

He has no comorbidities and was not on any medication. He was previously treated with pulmonary tuberculosis 10 years prior to admission. He was a 50 pack-year smoker and has no other vices.

He worked as a welder but also managed chicken poultry in Batangas, Philippines. He had a history of working in Saudi Arabia as a welder for 3 years 3 decades ago. He has not left the Philippines since his return.

On physical examination, he was looking weak, had a supine blood pressure of 90/60 mm Hg, heart rate of 90 bpm, temperature of 37.8°C and a body mass index of 20.34 kg/m². He had anicteric sclerae, pink conjunctivae, no cervical lymphadenopathies nor anterior neck mass. He had clear breath sounds, heart rate was normal with a regular rhythm. There was no abdominal tenderness nor masses. He had no lymphadenopathies, rashes nor hyperpigmentation in all extremities. The neurological examination was normal as well.

Investigations

Due to the persistence of flank pain, an abdominal ultrasound was requested and revealed a well-delineated solid mass in both the suprarenal regions. A triphasic CT scan confirmed a well-circumscribed, bilateral, symmetrical, hypoattenuating adrenal glands with rim enhancement measuring 4.5×2.5 cm and 4.7×3.8 cm on the right and left glands, respectively (figure 1).

Figure 1.

Triphasic CT scan showing bilateral, well-delineated, symmetrical, hypoattenuating adrenal glands.

The initial impression at this time was adrenal cancer versus metastasis from an unknown primary due to the constitutional signs of weight loss, intermittent undocumented fever and generalised weakness. He was seen by a urologist for possible adrenalectomy.

Further examination revealed suspicious fibrosis in the left apex on chest X-ray possibly from the previous pulmonary tuberculosis infection. Other pertinent laboratory findings included anaemia (9.6 g/dL; reference range, 13.5–17.5), hyponatraemia (135 mmol/L; reference range, 137–145) and hypercalcaemia (2.71 mmol/L; reference range, 2.10–2.55) with a low intact parathyroid hormone (PTH) test (0 pg/mL; reference range, 10–65). Skeletal scintigraphy was also negative for bone metastasis.

In patients presenting with bilateral adrenal mass, it is imperative that we do adrenal function tests. His 24-hour urine metanephrine was normal at 0.68 mg (reference range, 0–1 mg/24 hours). A low 8:00 cortisol (83.86 nmol/L) was suggestive of adrenal hypofunction. Adrenal insufficiency was confirmed by performing an adrenocorticotropic hormone (ACTH) stimulation test (cortisol baseline was 127 nmol/L, 60 mins cortisol 85 nmol/L).

Differential diagnosis

The differentials at this time included adrenal metastasis, a primary adrenal malignancy, lymphoma, and infection. The management of each differential is very different from the other, hence, establishing the correct diagnosis is vital.

An ultrasound-guided fine-needle aspiration biopsy was performed on both adrenal glands and showed acellular amorphous eosinophilic debris consistent with necrotic material on H&E stain. There were no observed native adrenal cortical nor medullary cells as well as malignant cells. This prompted further workup with the periodic acid-Schiff (PAS) stain to rule out other possible infectious etiologies.

PAS staining on both biopsy specimens highlighted small yeast-like structures. These were interspersed among necrotic debris and in tight clusters, probably representing intracellular accumulation within histiocytes. Most of these yeast-like elements were noted with narrow-based budding structures (figure 2). The differential was now narrowed to an adrenal fungal infection. Narrow-based budding yeasts may either represent Histoplasma spp or Cryptococcus spp; however, clustering of such structures intracellularly within histiocytes favours the former. Other differential diagnoses included the small variant of Blastomyces dermatitidis and endospores of Coccidioides spp.¹

Figure 2.

Periodic acid-Schiff stain of the adrenal gland aspiration biopsy in oil-immersion view (1000×) showing small yeasts arranged individually and in clusters, with note of narrow-based budding (arrows point to narrow based budding).

Other tests performed included the cryptococcal antigen latex agglutination test and HIV screen which both turned out negative. The fungal blood culture eventually grew Histoplasma capsulatum after 12 days of incubation (figure 3). With this finding, a review of his possible exposure could be his chicken poultry in Batangas. The only risk factor identified for this patient is his age.

Figure 3.

Actual fungal culture of blood collected from the patient. (A) Mould phase of Histoplasma capsulatum. (B) On magnification, characteristic tuberculate macroconidia are seen. (C) Gross appearance of mould phase of H. capsulatum.

Treatment

He was treated with itraconazole 200 mg/tablet two times per day for the histoplasmosis and prednisone 5 mg/tablet once a day for his adrenal insufficiency. On his second week of treatment, he reported no recurrence of fever and improved general well-being.

Outcome and follow-up

After 6 months of treatment, he gained a total of 4 kg and is back to his activities of daily living. All other laboratory parameters including creatinine, sodium, complete blood count were back in the normal range.

Discussion

Infections comprise 10% of primary adrenal insufficiency in the developed world but limited data exist on its prevalence in developing countries. The differentials include tuberculosis, HIV/AIDS, opportunistic infections like cytomegalovirus and rarely, fungal infections such as histoplasmosis, cryptococcosis, coccidioidomycosis, and paracoccidioidomycosis.² These entities most often exist in immunocompromised hosts such as AIDS, transplant patients, haematological malignancies and patients on corticosteroids.³ Only case reports exist among immunocompetent patients.

Histoplasmosis is the most common among the fungal infections affecting the adrenal glands. It is a granulomatous infectious disease caused by a thermal dimorphic fungus, H. capsulatum. It is endemic in North America and Central America and thrives well in soil rich in nitrogen. The excreta of certain birds and bats make it conducive for the fungus to grow. Certain activities such as spelunking, excavation and cleaning of chicken coops that disrupt the soil are associated with a high level of exposure.⁴

Histoplasmosis, although increasingly reported in South East Asian countries, is rarely reported in the Philippines. A study revealed a histoplasmin skin hypersensitivity of 26% in the country, but, to date, there are only 11 reported cases of histoplasmosis in the Philippines, most of which are the progressive disseminated form and with immunocompromising comorbidities.^5–11 None has been reported in the country involving the adrenal glands in an immunocompetent host.

Infection happens when a person inhales the microconidia of the mould phase of the fungus. Once inside the body, it transforms into a yeast form which is then taken up by the alveolar macrophages. Dissemination happens via the reticuloendothelial system. In 2–3 weeks, the cellular response should mediate the clearance of Histoplasma in the body and failure to do so would lead to the clinical manifestations of the disease.¹²

The development of disease associated with the initial dissemination of H. capsulatum is host-dependent. The majority of the cases happen among immunocompromised hosts, whereas slowly progressive and generally fatal infection due to H. capsulatum mostly occurs in older adults who are not overtly immunosuppressed such as this case.^{13 14}

The clinical manifestations of histoplasmosis can range from self-limiting influenza-like symptoms in 95% of the cases to life-threatening disseminated infection. Other organ systems such as gastrointestinal, central nervous system, bone marrow and adrenals can be involved in disseminated cases.¹⁵

Adrenal histoplasmosis can lead to primary adrenal insufficiency by progressive destruction of adrenal glands. Primary adrenal insufficiency in itself is a rare endocrine disease most commonly caused by autoimmune diseases or by a tuberculous infection. Adrenal histoplasmosis is an unusual cause. It is associated with significant morbidity and mortality rates when unrecognised. Moreover, it is often difficult to diagnose because of its non-specific symptoms such as generalised weakness, tiredness, anorexia, fever and orthostatic hypotension. Physical examination is also non-specific but can include hepatosplenomegaly and lymphadenopathies. Hyponatraemia, hyperkalaemia and hypercalcaemia from extrarenal activation of 1-alpha hydroxylase may be present as seen in our patient. Nevertheless, once the diagnosis is made, it can easily be treated.^{6 16}

On CT imaging, adrenals are typically bilaterally symmetrically enlarged, with central hypodensity and a characteristic peripheral rim enhancement. Calcifications can be seen during the healing phase. Its features are indistinguishable from metastasis, adrenal cancer and other forms of adrenal infection such as tuberculosis, hence, a fine-needle biopsy is warranted to arrive at a diagnosis and subsequently proper treatment. The characteristic fine-needle aspiration cytology reveals Histoplasma with narrow-based budding within the cytoplasm of macrophages on a necrotic background but it can also be seen extracellularly.^{17 18}

The gold standard for diagnosis is still culture. Specimens from blood, adrenal, bronchoalveolar lavage and bone marrow can be sent to confirm the diagnosis. Yeasts show the characteristic microconidia and macroconidia, 2–4 µm in size. Other laboratory examinations may include serological identification of antibodies, immunodiffusion, complement fixation, latex agglutination, Western blot, ELISA and Histoplasma antigen detection.¹⁹

The recommended treatment for critically ill patient is still amphotericin but for mild-moderate disease, itraconazole is used for a treatment duration of at least 12 months.²⁰ In addition, the institution of corticosteroid replacement for patients with adrenal insufficiency is warranted to reverse the symptoms of adrenal insufficiency. Reversal of adrenal dysfunction can be seen in some patients after prolonged antifungal therapy.¹³

Patients are at risk for decompensation not only secondary to adrenal insufficiency but also from further dissemination of infection. Adrenal histoplasmosis must be considered even in immunocompetent adults who acquire adrenal masses since early diagnosis and treatment can prevent catastrophic events.

Learning points.

• Adrenal histoplasmosis as a cause of adrenal insufficiency is a clinically significant entity yet often a missed diagnosis.

• Adrenal histoplasmosis must be considered even in immunocompetent adults who acquire adrenal masses since early diagnosis and treatment can prevent catastrophic events.