Correct!
5. All of the above

Cultures grew Histoplasma capsulatum from the sputum, blood cultures, BAL and bone marrow biopsy. This patient has two infections (PCP and disseminated histoplasmosis) that are, with rare exceptions, only seen in immunocompromised patients.  When such infections are seen, patients should be evaluated for immunocompromising conditions.  Therefore, HIV serology and other tests of immunocompromise are indicated.

After discharge from the hospital, the patient was seen in the endocrinology clinic and ultimately diagnosed with Cushing’s disease secondary to pituitary adenoma, which likely led to her immunosuppressed state and disseminated histoplasmosis and co-infection with PCP.  The adenoma was surgically removed. She completed a course of trimethoprim/sulfamethoxazole and remains on itraconazole for the disseminated histoplasmosis and replacement doses of oral steroids.

Clinical Pearls (Useful information for care providers)

Provider Pearls (Physicians/PAs/NPs)

Histoplasmosis has been reported throughout the world, but Histoplasma capsulatum (H. capsulatum) is endemic to the Americas and some parts of Europe and Africa. Clinical cases are usually secondary to sporadic exposure, but outbreaks in areas of construction have been documented. H. capsulatum is a dimorphic fungus with a soil-based environmental reservoir and has been noted to thrive in areas with bird and bat excrement.

H. capsulatum causes clinical infection after inhalation. In the alveolar space, it is phagocytized by macrophages and via the macrophages is disseminated throughout the reticuloendothelial system. The immune response is dependent T-cell mediated response and multiple cytokines.

The majority of H. capsulatum infections are self-limiting with symptoms often confused with an acute viral syndrome or community-acquired pneumonia. Multiple clinical entities secondary to infection exist, although not all require antifungal treatment (although may require other supportive treatments). Traditionally, the entities requiring treatment include acute and pulmonary histoplasmosis, progressive disseminated histoplasmosis and mediastinal lymphadenitis.

Patients with reduced cellular immunity (e.g. AIDS, corticosteroids and extremes of age) are at risk for dissemination. Symptoms include, but are not limited to, fever, malaise, anorexia and weight loss. Physical exam may show signs of pancytopenias, cutaneous lesions or ulcerations, lymphadenopathy and hepatosplenomegaly. Laboratory findings may include pancytopenias, elevated alkaline phosphatase, LDH and inflammatory markers. The disease can involve any organ system, and therefore presentations can vary dramatically.

Diagnosis of H. capsulatum infection can be done via antigen detection, PCR assay, antibody tests, skin tests, biopsies and BAL. In acutely ill patients, biopsy and/or BAL (if appropriate) should be done as soon as possible.

Treatment for histoplasmosis varies based on type and severity of infection. Mild and moderate infections may be treated with oral itraconazole. For patients who are acutely ill Amphotericin B is the treatment of choice with transition to itraconazole once clinical improvement has occurred. Duration of treatment also varies, but is normally prolonged (months to years). Immunosuppressed patients with a history of disseminated histoplasmosis should receive secondary prophylaxis after completion of treatment until immune reconstitution.

Cushing’s disease is responsible for about 70% of the cases of noniatrogenic Cushing’s syndrome, but is responsible for less than 10% of related opportunistic infections.  Some of her presenting symptoms, such as the weakness and easy bruising may have also been related to the glucocorticoid excess. The immunosuppression secondary to glucocorticoid excess essentially affect all cell lines involved with immune and inflammatory responses, although depletion of CD4+ cells, cytokine dysregulation and suppression of neutrophil function are of significant concern when discussing the immune response to H. capsulatum.

Nursing Pearls

• Nursing would verify and initiate what kind of isolation is required for patient. Histoplasmosis and Pneumocystis jiroveci pneumonia (PCP) require standard precautions only (Standard Precautions provide the primary strategy for prevention and control of healthcare associated infections. They are to be routinely used in the care of all patients. Appropriate personal protective equipment must be used when exposure to blood and/or body fluids is anticipated.)
• Supportive care and symptom management as needed
• Psychosocial support for patient and family as needed

• Education on tests and procedures as well as patient disease/diagnosis as needed.

Respiratory Therapy Pearls

• Oxygen therapy as needed.
• The need for bronchial hygiene therapy should be assessed.
• Assessment should include:

• Ineffective cough, secretion retention, atelectasis
• Assist cough devices, vibratory PEP devices, or lung expansion therapy can be considered.
• If patient still has need for bronchial hygiene adjuncts upon dismissal, education on the devices needs to be done before dismissal.

Pharmacy Pearls

• Amphotericin liposomal formulations are dosed at 3-5 mg/kg/day and generally the preferred product. If amphotericin deoxycholate is used, recommended dosing is 0.7-1.0 mg/kg/day.
• Oral Itraconazole:
• Administer a loading dose of 200 mg three times daily for three days, then decrease to 200 mg twice or once daily. No dose adjustment is needed for renal dysfunction. 
• Itraconazole capsule absorption is acid dependent, give capsules with food and avoid acid suppressing medications. Itraconazole solution should be given on an empty stomach.
• Itraconazole has a long half life. Levels should be collected at seven days from initiation. Random levels are sufficient, goal serum level >1 mcg/mL by HPLC method or >3 mcg/mL by bioassay level. Combine itraconazole plus hydroxy-itraconazole metabolite for total level.  
• Fluconazole is active against histoplasmosis but is not as effective and has resistant issues.
• Voriconazole has shown promise in treating histoplasmosis, but further clinical data is needed. The echinocandins do not have activity against histoplasmosis.     

References

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2. Hauser PM, Bille J, Lass-Flörl C, Geltner C, Feldmesser M, Levi M, Patel H, Muggia V, Alexander B, Hughes M, Follett SA, Cui X, Leung F, Morgan G, Moody A, Perlin DS, Denning DW. Multicenter, prospective clinical evaluation of respiratory samples from subjects at risk for Pneumocystis jirovecii infection by use of a commercial real-time PCR assay. J Clin Microbiol. 2011;49(5):1872-8. [CrossRef] [PubMed]
3. Kauffman CA., Histoplasmosis: a clinical and laboratory update. Clin Microbiol Rev. 2007;20(1):115-32. [CrossRef] [PubMed]
4. Lionakis, M.S. and D.P. Kontoyiannis, Glucocorticoids and invasive fungal infections. Lancet. 2003;362(9398):1828-38. [CrossRef] [PubMed]
5. Kirk LF Jr, Hash RB, Katner HP, Jones T. Cushing's disease: clinical manifestations and diagnostic evaluation. Am Fam Physician. 2000:62(5):1119-27, 1133-4. [PubMed]
6. Knox, K.S. and C.A. Hage, Histoplasmosis. Proc Am Thorac Soc. 2010:7(3):169-72.
7. [CrossRef] [PubMed]
8. Kosseifi SG, Nassour DN, Shaikh MA, Sarubbi FA, Jordan RM, Peiris AN. Nodular pulmonary histoplasmosis in Cushing's disease: a case report and literature review. Tenn Med. 2007;100(12):44-6.[Pubmed]
9. Kadaria D, Muthiah MP, Sinclair SE. Unusual presentations of disseminated histoplasmosis. Tenn Med. 2012;105(3):39-40. [PubMed]

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