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Gorgas Case 2018-05

Epidemiology: Born in Cusco, but has resided the past 45 years in Tambopata, Madre de Dios, in the jungle as a farmer. Wife died 10 years ago of pulmonary tuberculosis and his son was successfully treated for gastrointestinal tuberculosis at the same time. The patient did not receive isoniazid preventive treatment.

PMH: Treated 20 years earlier with an incomplete course of antimony for a chest ulcer which showed leishmania on a scraping. No recurrent skin ulcers.

Physical Examination: BP: 85/60 mmHg, HR: 98x’; RR: 37x’; T°:36°C, Sat02: 85% at FiO2 21%. On examination, the patient appears chronically ill with wasting and respiratory distress. Oral Exam: friable ulcer with well-defined edges on the hard palate. Chest: Respiratory sounds audible with crackles and rhonchi bilaterally. Skin: Pallor of skin and mucous membranes. Abdomen: no visceromegaly. Neurologic examination: normal.

Discussion: India Ink staining was positive from sputum and oral ulcer specimens, but negative from urine and CSF samples. Cryptococcus neoformans was isolated in culture from a tissue sample obtained from the oral ulcer; the India ink stain of the culture shows spherical structures with a thick capsule and single peripheral budding (Image C). AFB staining and TB cultures of sputum, stool and urine samples were negative. HIV 1-2 ELISA: Negative. RPR: negative. HTLV 1-2 ELISA: Positive. Cerebrospinal fluid: Opening pressure 16 cmH2O with 1 white cells, glucose 44 mg/dl (normal), normal protein, Gram stain negative, India ink negative and bacterial culture negative. Culture and smear for leishmania from the oral ulcer negative.

The differential diagnosis of the pulmonary presentation in this case includes paracoccidioidomycosis, histoplasmosis, tuberculosis, leishmaniasis, Kaposi´s sarcoma, and Wegener´s granulomatosis. Paracoccidioidomycosis (PCM) will be the main differential diagnosis in this case. In the chronic multifocal form of PCM oral ulcers are located mostly on the hard palate and have a characteristic fine granular pattern with multiple small hemorrhagic dots, ulcers are very painful and are almost always accompanied by pulmonary involvement, a nodular pattern as in this case, is less common.

Fungi of the Cryptococcus neoformans/Cryptococcus gattii complex are encapsulated, cosmopolitan yeasts 2–10 mm in diameter. C. neoformans var neoformans (serotypes A and D, genotypes VNI–IV) and C. neoformans var gattii (serotypes B and C, genotypes VGI–IV) make up the complex. About 95% of cases are caused by var neoformans, and serotype A (var grubii) is responsible for 95% of those which has a ubiquitous distribution worldwide.

Cryptococcosis can be seen in both apparently immunocompetent and obviously immunosuppressed hosts. Patients with weak cellular immunity are predisposed to present with disseminated disease, most commonly those with HIV. Pulmonary involvement in cryptococcosis is characterized by a wide range of manifestations depending on the degree of immunosuppression, from asymptomatic patients to rapidly progressive disease [Current Opinion Infect Dis 2009;15:254-260]. Pulmonary nodules, reticulonodular infiltrates, segmental or lobar consolidations, mediastinal and hilar adenopathies and less frequently pleural involvement are reported. Our patient presents with a mixed nodular, alveolar and interstitial pattern.

HTLV-1 is endemic in certain areas of the globe including Latin America (Lancet Infect Dis. 2007 Apr;7(4):266-81). A study conducted in Quillabamba, Cuzco, near the place this patient and his parent were born showed an overall prevalence of HTLV-1 infection of 5.1% among 370 individuals evaluated [Am J Trop Med Hyg 1997;56:561]. No information on the status of HTLV-1 infection on his parents was available. He likely got the infection by breastfeeding. A number of clinical conditions are associated with HTLV-1 infection; [see Lancet Infect Dis. 2007 Apr;7(4):266-81 for a detailed discussion]. Included are those caused by autoimmune mechanisms such as tropical spastic paraparesis (TSP), also called HAM (HTLV-1 associated myelopathy) [see Gorgas Case 2002 #8], uveitis, Sjögrens, arthropathy, thyroiditis and polymyositis; cellular immunosuppression such as strongyloides hyperinfection [see also Gorgas Case 2007 #4]; infective dermatitis [see Gorgas Case 2004 #7], crusted scabies (see also Gorgas Case 2013 # 10), tinea corporis, tuberculosis; and oncogenic mechanisms including ATLL (see Gorgas Case 2016 #05) . More recently, a probable association with endemic fungal infections including paracoccidioidomycosis and histoplasmosis has been proposed (Clin Infect Dis 2010;51:250-251 and J Infect Dev Ctries 2011;5:484-488). HTLV-1 infection may alter the immune response to endemic infections including endemic mycoses leading to severe clinical presentations, but this has not been studied yet. Few published reports of cryptococcal disease in patients with HTLV-1 are available. Skin and pulmonary involvement in an HIV-negative patient from Dominica was reported, no mucosal involvement was mentioned [JEADY 2003;17:723-724]. Localized lymphadenitis was reported from Japan in one patient [J Clinical Experimental Histopathol 2017;57:26-30].

The current Infectious Disease Society of America treatment guidelines for patients with pulmonary cryptococcosis recommend to first rule-out meningeal involvement [Clin Infect Dis 2010; 50:291-322]. Non-HIV-infected, non-transplant patients with evidence of disseminated disease outside of the lungs, as in this case, should be treated as per patients with CNS disease with amphotericin B deoxycholate plus flucytosine for 4-week induction therapy, followed by fluconazole for 6-12 months. In settings where flucytosine is not available, extending duration of amphotericin B is recommended. There are no specific recommendations for treating HTLV-1 infected patients. This patient was treated only with a 2-week course of intravenous amphotericin-B deoxycholate plus fluconazole as he requested discharge against medical advice, and was switched to oral fluconazole to complete a one-year course of treatment. The clinical evolution of our patient has been favorable, with disappearance of fever and improvement of respiratory distress. He is being follow by our colleagues in Cuzco.