Disseminated Histoplasmosis Complicated By Adrenal Insufficiency

A 78-year-old man presented to his primary care physician with a 4-month history

of worsening fatigue, generalized weakness, and anorexia, and reported an unintentional

weight loss of about 25 lb (11.4 kg). He reported subjective fevers, chills,

drenching night sweats, dry mouth, a nonproductive cough, dyspnea with minimal

exertion, and nausea with occasional emesis. He became light-headed on standing

and had become largely bedridden in the preceding month. He reported no headache,

changes in vision, dysphagia, chest pain, palpitations, flushing, abdominal discomfort,

changes in bowel habits, melena, or rash.

Striking features of this patient’s history include his weight loss and symptoms of

postural hypotension. Constitutional symptoms such as fever, drenching night sweats,

or clinically significant weight loss can be caused by chronic infections, rheumatologic

illness, or cancer. His postural light-headedness suggests orthostasis, which may

arise from hypovolemia, adrenal insufficiency, autonomic or peripheral neuropathy,

or cardiac dysfunction. These conditions may contribute to generalized weakness,

as would anemia or a myopathic disorder. He also has focal respiratory and gastrointestinal

symptoms that may point to a localized process.

The patient’s medical history was notable for myasthenia gravis, which had been diagnosed

5 years earlier and was now well controlled with mycophenolate. He had

undergone corneal transplantation in both eyes for Fuchs’s endothelial dystrophy

15 years earlier and had been treated for vitiligo with methoxsalen and ultraviolet

radiation

40 years earlier. His current medications included mycophenolate, pyridostigmine,

and timolol–dorzolamide and fluorometholone ophthalmic drops. He was

a retired neuroscientist who was born and raised in India and immigrated to the

United States 45 years ago. He lived with his wife and two adult children, all of whom

were healthy. The patient had a remote history of cigarette use and reported no use of

alcohol or recreational drugs. His last travel outside the United States was to India

8 years earlier.

Some notable potential contributors to the patient’s current condition have emerged.

He has a history of autoimmune diseases requiring treatment with immunosuppressive

agents and is from India, where tuberculosis is endemic. Given his long-term

use of mycophenolate, it is possible that the cause of his symptoms is an opportunistic

infection, such as tuberculosis, cytomegalovirus (CMV), or invasive fungal disease,

or a noninfectious condition, such as cancer. Subacute bacterial endocarditis is

possible, as is autoimmune polyendocrine syndrome type 2, which is characterized by vitiligo, adrenal insufficiency, type 1 diabetes

mellitus, and thyroiditis. Pure red-cell aplasia

and thymoma are associated with myasthenia but

would be unlikely to explain several of this patient’s

presenting symptoms.

The patient reported the development of escalating

pain, erythema, and blurred vision in his right

eye, without antecedent trauma, 18 months earlier;

1 month before the onset of these symptoms, he

had traveled to the Great Smoky Mountains, after

which he sustained a brief febrile illness. Ophthal

mologic evaluation showed vitritis in one eye.

The results of blood and urine cultures were negative.

Induration at the site of a tuberculin skin test

measured 12 mm in diameter; he had never been

vaccinated with bacille Calmette–Guérin.

Serum antibody testing for Lyme disease, toxoplasma,

and Bartonella henselae was negative, as

were tests for CMV antigen, rapid plasma reagin,

and urinary histoplasma antigen. Antinuclear antibodies,

antineutrophil cytoplasmic antibodies, cyclic

citrullinated peptide antibodies, and rheumatoid

factor were not detected. Genotyping for HLA-B27

was negative, and an enzyme-linked immunosorbent

assay was negative for the human immunodeficiency

virus (HIV). Vitreous fluid showed a

polymorphous cellular infiltrate, and a smear

and culture for acid-fast bacilli were negative.

Polymerase-chain-reaction studies of the vitreous

for lymphoma, CMV, varicella–zoster virus, herpes

simplex virus, Mycobacterium tuberculosis, and toxoplasma were also negative. Chest radiography,

performed because of concern about tuberculosis,

showed patchy bibasilar lung opacities.

Computed tomography (CT) of the chest revealed

mild basilar lung atelectasis and nodules measuring

1.6 cm in diameter on both adrenal glands,

with a density of 35 to 45 Hounsfield units (a density

of 10 units or less is considered to be consistent

with benign adrenal nodules) (Fig. 1).

The patient was treated with isoniazid, which

was discontinued after 1 month, owing to unacceptable

side effects. Despite empirical treatment

with acyclovir, ophthalmic prednisolone, and oral

prednisone, a progressive erythema developed,

and the patient lost vision in the right eye. Corneal

dehiscence with globe rupture occurred 10 months

before the current presentation, and the patient

underwent emergency enucleation of the right

eye. Pathological examination of the eye showed

nonspecific granulomatous inflammation in the

anterior ciliary body, posterior chamber, and subretinal

space.Uveitis, or inflammation of the middle anatomical

structures of the eye, can be caused by infection

(e.g., herpesvirus infection, syphilis, toxoplasmosis,

tuberculosis, and B. henselae infection), by

inflammatory conditions (e.g., seronegative spondylo

arthropathies, sarcoidosis, Behçet’s syndrome,

systemic lupus erythematosus, and granulomatous

polyangiitis [formerly known as Wegener’s

granulomatosis]), and by cancers such as lymphoma.

In this patient, the negative serologic, microbiologic,

and vitreous testing renders most of these

causes unlikely, with the exception of tuberculous

ophthalmitis, since extrapulmonary tuberculosis

can be difficult to detect. The Vogt–Koyanagi–

Harada syndrome, which is characterized by uveitis,

vitiligo, and neurologic abnormalities, can affect

persons of South Asian descent, although most

such patients are women, and the

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