A 38-year-old male is brought to the ED when family noticed that he was confused. Per report, he was well until about 3 weeks ago when he developed generalized malaise and a dry cough followed by daily fevers of 100.6°F to 100.8°F. Over the last week, he had been feeling increasingly short of breath. His past medical history is significant for HIV for which he is receiving highly active antiretroviral therapy (HAART), untreated hepatitis C infection complicated by cirrhosis, and smoking-related chronic obstructive pulmonary disease (COPD) for which he has been receiving prednisone 40 mg daily for the last 2 weeks. His CD4 count 1 month ago was 640 cells/mL with an undetectable HIV viral load. He has no history of opportunistic infections. On physical examination, he has normal heart sounds, coarse crackles on the right lung base, his abdomen is soft and nontender without evidence of ascites, and his neurological examination is unremarkable except that he is not oriented to time, place, or person. In the ED, laboratory data are:
Chest x-ray shows a right lower lobar consolidation. Two sets of blood cultures are drawn, and he is started on vancomycin and piperacillin/tazobactam. Over the next 72 hours, his oxygen requirements increase to requiring 6 L via nasal cannula and he continues to spike fevers. His increasing confusion is attributed to delirium, and he is started on lactulose for possible hepatic encephalopathy. On day 5 of admission, he is transferred to the ICU with worsening hypoxia requiring intubation. He undergoes bronchoscopy for diagnostic bronchoalveolar lavage (BAL). The initial stain shows yeast with thick capsules, and the following day cultures show growth of pigmented colonies.
What is the next best step in management for this patient?
A. Check bacterial multiplex PCR on BAL fluid for identification of the causative organismCorrect Answer: D
This scenario is concerning for disseminated cryptococcosis involving the lungs and meninges. LP should therefore be performed to measure opening pressure and to establish whether CNS involvement is present as this would directly affect management.
Cryptococcus neoformans is one of the most common causes of meningitis in HIV positive individuals and usually occurs when CD4 counts fall below 100 cells/mL. Cryptococcus is being increasingly recognized as causative of lung, CNS, and disseminated disease in other immocompromised populations including organ or stem cell transplantation, receiving other forms of immunosuppression, and in patients with diabetes. Cirrhosis, which leads to impaired humoral as well as cell-mediated immunity, is also considered to be a risk factor for cryptococcosis. Even in the absence of any of these risks, immunocompetent individuals can also occasionally be affected. The primary mode of transmission is inhalation of the fungus with dissemination from the lung through hematogenous spread. Invasive cryptococcal disease classically presents as a meningoencephalitis, but lung involvement in the form of lobar pneumonia, nodules, or even cavitary lesions is common in HIV-negative individuals either alone or concomitant with CNS infection. Skin involvement may occur with a variable presentation ranging from papular rash to cellulitis and even ulceration. cryptococcal meningitis is usually an indolent and subacute process presenting with a few weeks of headache, malaise, fever, and/or altered mental status. It is uncommon to have rapid progression of disease with significant neurological impairment although that can occur. Signs of meningeal irritation may or may not be present.
Whenever a diagnosis of extraneural cryptococcosis is made, including that of isolated Cryptococcemia, an LP is indicated to establish CNS involvement. CNS cryptococcosis is treated with amphotericin ideally in combination with flucytosine, whereas fluconazole alone may otherwise be sufficient for isolated lung, skin, or other organ disease. Additionally, intracranial pressures may be very high in cryptococcal meningitis in which case repeat LPs for therapeutic drainage or drain/shunt placement may be indicated. Other than high opening pressures, the CSF analysis is usually of limited utility with low to normal glucose, mildly elevated protein, and mild, if any, pleocytosis. Culture of CSF remains the gold standard for diagnosis. The identification of cryptococcal antigen in the CSF has very high sensitivity and specificity and is also useful for monitoring the effect of treatment. Serum cryptococcal antigen is also highly sensitive for meningoencephalitis (not for other organs) and if positive, is sufficient to rule in CNS involvement in patients with an absolute contraindication to LP.
Although the patient’s HIV is well controlled, his steroid use and cirrhosis place him at risk for cryptococcosis. The presence of non-Candida yeast in the BAL, which grows with pigmented colonies (due to melanin production) on culture is characteristic of Cryptococcus neoformans. Candida, CMV, typical bacterial pneumonia, or nontuberculous mycobacterial disease would not fit this clinical picture.
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