A 34-Year-Old Man With HIV/AIDS and a Cavitary Pulmonary Lesion

Abstract

A 34-year-old man presented to a community hospital with fever and fatigue for 3 days and was found to be febrile and tachycardic with a cavitary pulmonary lesion and paratracheal adenopathy on CT imaging. One month before, he had presented to his primary care provider with a palmar rash; he had been diagnosed and treated for syphilis and was also diagnosed with HIV. He had a CD4 count of 106 cells/μL and an HIV viral load of 1,290,000 copies/mL. Pneumocystis prophylaxis with trimethoprim-sulfamethoxazole and antiretroviral treatment with only tenofovir and emtricitabine therapy were started 2 weeks before presentation.

The patient’s medical history was notable for syphilis presenting as a rash the year before that was treated with IM penicillin and right inguinal hernia repair 20 years earlier. He had no pertinent family history. His social history was notable for ten pack years of smoking, social alcohol use, no illicit drug use, and unprotected sex with women. He immigrated from South America a year earlier and reported having a friend who had been diagnosed with tuberculosis a year and half before his current presentation and having contact with a coworker with a flu-like illness the week before his current illness.

He was begun empirically on antituberculosis therapy, and sputum was collected for acid fast bacilli smears and culture. Tenofovir and emtricitabine therapy was stopped, and piperacillin-tazobactam was started empirically. Sputum acid fast bacilli smears were negative twice. Two days later, he experienced the development of a diffuse erythematous rash over his chest, back, abdomen, and thighs. A drug reaction was suspected, and trimethoprim-sulfamethoxazole therapy was stopped, and atovaquone therapy was started for pneumocystis prophylaxis. He remained febrile with tachycardia throughout his course and experienced hypotension responsive to fluids. Immune reconstitution inflammatory syndrome (IRIS) was suspected; on day 5 of his admission, he was transferred to National Institutes of Health (NIH), consented, and enrolled onto a NIH institutional review board approved protocol (NCT#0214705), which was conducted in accordance with the amended Declaration of Helsinki.

On arrival at the NIH, he was found to be febrile and experienced hypotension that required a transfer to the ICU. He was resuscitated with fluids and continued on broad spectrum antibiotics with meropenem. His antituberculosis therapy was stopped. Sputum induction was unsuccessful, and he underwent bronchoscopy with brushings of the cavity and transbronchial aspiration of paratracheal lymph node.

Physical Examination Findings

His vital signs on arrival were a temperature of 39.1°C, heart rate of 132 beats/min, respiratory rate of 30, blood pressure of 114/74 (which dropped to 91/52 hours after admission), and oxygenation saturation of 87% on room air that improved to 98% on 2L of oxygen. He was alert and oriented to person, place, and time with articulate speech; his cranial nerves were grossly intact. His strength and sensation were intact. He had a generalized blanching erythematous rash over his arms, trunk (chest involvement greater than back), and thighs without blisters and no mucosal involvement. His oropharynx was without oral lesions. His pulmonary and cardiac examinations were notable for minimal work of breathing and tachycardia, but otherwise unremarkable. He had diffuse abdominal tenderness without peritoneal signs and palpable cervical and inguinal lymphadenopathy.

Diagnostic Studies

Laboratory tests on admission included a hemoglobin of 10 g/dL and platelet count of 73,000/ mm³. WBC count was 4,130/mm³ with a neutrophil predominance of 85.9%. Acute care panel revealed a sodium level of 131 mmol/L and bicarbonate level of 19 mmol/L, with a lactate of 2.9 mmol/L. Triglycerides were 262 mg/dL; erythrocyte sedimentation rate was 100 mm/hr, and C-reactive protein was 226.1 mg/L. Serum cryptococcus antigen, urine histoplasmosis antigen, and QuantiFERON were negative. human herpesvirus-8 DNA quantitative polymerase chain reaction detected >10,000,000 copies/mL.

CT imaging showed no filling defects in the pulmonary arterial system, small bilateral pleural effusions and moderate mediastinal/hilar adenopathy with bilateral multifocal patchy, consolidative, and nodular opacities, and a cavitary lesion in the right upper lobe (Fig 1A).

Figure 1.

A, Coronal cut of CT scan shows cavitary lesion in the right upper lobe. B, Grocott-Gomori’s methenamine silver stain of the cytopathologic specimen from bronchoscopy shows yeast forms.

Bronchoscopy demonstrated normal bronchial mucosa and anatomy with no endobronchial lesions and with copious thin, watery secretions. Growth of narrow-based budding encapsulated yeast cells from bronchoscopy fungal culture was observed on day 4 of culture (Fig 1B).

What is the diagnosis?

Answer: Cryptococcus neoformans

Discussion

The differential of a cavitary lesion in a patient with HIV/AIDS is extensive and includes TB, nontuberculous mycobacteria, bacterial pneumonia, or abscess, fungal pneumonias that include cryptococcus and endemic mycoses, nocardiosis, Rhodococcus equi, and noninfectious causes including Kaposi sarcoma, squamous cell cancer, and lymphoma. In patients with CD4 counts >200 cells/μL pulmonary TB should be a leading diagnosis in the right epidemiologic setting; however, as the CD4 count declines, other opportunistic organisms, which includes invasive fungal infections like Cryptooccus neoformans should be considered. Noninvasive sputum sampling should be the first diagnostic approach of a cavitary lesion; however, often invasive procedures such as bronchoscopy or image-guided biopsy are required to obtain a diagnosis. Empiric therapy based on demographics and presentation should be discouraged, given reports of cavitary lesions in cryptococcosis misdiagnosed as TB with lethal outcomes. Additionally, cryptococcosis has been reported to coinfect (or coexist) with other pathogens, which further reinforces the consideration for a diagnostic procedure.

The lung is the entry site for C neoformans that may then disseminate to other areas that include the CNS. Most patients with HIV/AIDS with pulmonary cryptococcus will have a CD4 count of <100 cells/μL. Pulmonary cryptococcus can have a variety of manifestations from well-defined lung nodules, infiltrates, hilar and mediastinal lymphadenopathy, pleural effusions, and cavitation. Often the most common finding for pulmonary cryptococcosis in HIV/AIDS are interstitial infiltrates and lymphadenopathy, and the majority of patients present with symptoms of fever, cough, and dyspnea. Diagnosis can be made from serum cryptococcal antigen (CRAG) detection of the capsular polysaccharide antigen, microscopic examination and culture of sputum, BAL, pleural fluid samples, needle aspiration, or lung biopsy. Serum CRAG is a reliable indicator of disseminated cryptococcal disease in HIV-infected patients with high sensitivity and specificity; however, it may not always be positive in isolated pulmonary cryptococcal involvement. Encapsulated yeast forms may not be seen with microscopy, and culture is often positive in respiratory specimens from patients with HIV/AIDS, typically with growth within 3 to 7 days of culture.

The optimal therapy for pulmonary cryptococcus is not clear because there are no trials that are investigating outcomes of cryptococcal pneumonia treatment and recommendations are extrapolated from data of CNS disease. Clinical presentation, dissemination, and immune status are guiding factors in the determination of the therapeutic regimen. Typically, milder clinical presentations (mild-to-moderate symptoms, no diffuse pulmonary infiltrates, absence of dissemination, absence of severe immunosuppression) are treated with fluconazole; more severe presentations (severe symptoms, diffuse pulmonary infiltrates, disseminated disease, severe immunosuppression) may require induction with amphotericin B with transition to fluconazole. Treatment duration is often recommended for 12 months, pending immune reconstitution.

In this test-and-treat era of HIV, early initiation of antiretroviral therapy (ART) may lead to unmasking IRIS of opportunistic infections in patients with severe lymphopenia. Diagnosis of this phenomenon is reliant on the history of recent ART initiation and pursuit of a diagnosis of the underlying opportunistic infection. Unmasking IRIS typically can be addressed with treatment of the underlying opportunistic infection; however, severe presentations may require immunosuppressive therapy with corticosteroids.

Evidence has shown the benefit of starting patients on ART at diagnosis, even those with high CD4 cell counts. Studies have demonstrated a potential risk of patients being placed on an incorrect regimen, particularly in the hospital setting, which may lead to viral resistance or adverse effects. To assure appropriate care, newly diagnosed people with HIV benefit from oversight by an expert provider who is practiced in the use of ART. First-line therapy generally consists of two nucleoside reverse transcriptase inhibitors in combination with a third active antiretroviral drug from another class.

Clinical Course

C neoformans grew from culture of the bronchoscopy specimens with nondiagnostic lymph node aspiration. The serum cryptococcal antigen remained negative. The timing and severity of symptoms in the patient were consistent with unmasking IRIS. He was treated with liposomal amphotericin for 1 week and transitioned to oral fluconazole. He actually started to improve before the antifungal therapy with resuscitation and holding tenofovir and emtricitabine therapy and had further improvement of clinical and laboratory indexes after the initiation of antifungal therapy. A genotype was obtained that showed resistance mutations with M184 I/V and V106I, and he was initiated on ART with bictegravir, tenofovir, and emtricitabine. Repeat CT imaging after 2 months of antifungal treatment demonstrated decreased size of the cavity and resolving adenopathy. After 12 weeks on ART, the CD4 count increased to 120 cells/μL, and the viral load was suppressed to <40 copies/mL. Even though the positive human herpesvirus-8 testing was not related to his initial presentation, his course was later complicated by unmasking cutaneous Kaposi sarcoma that was treated symptomatically and subsequently improved on ART.

Clinical Pearls

• 1.Cryptooccus neoformans should be in the differential diagnosis of a cavitary lesion in a HIV-infected patient, even if serum cryptococcal antigen is negative
• 2. Noninvasive sputum sampling should be the first step for diagnosis of a cavitary lesion in a patient with HIV/AIDS; however, if nothing is revealed, then sampling with bronchoscopy or image-guided biopsy should be considered because the differential is broad and empiric therapy may lead to adverse outcomes.
• 3. Unmasking IRIS is likely to be seen more frequently in the test and treat era in late presenters (CD4 count, <100 cells/μL), and providers should monitor these patients carefully after ART initiation for signs/symptoms that are consistent with IRIS.
• 4. ART regimens should be started ideally at the time of diagnosis after consultation with available local HIV treatment guidelines and/or an HIV health-care provider.