A 45/M with h/o cryptococcal meningitis and recurrent admissions for headache relieved by lumbar puncture despite negative fungal cultures. The patient had more than 2 reinduction therapies with Ambisome followed by fluconazole consolidation/maintenance therapies. Despite this, the patient kept getting admitted for recurrent headache, CSF pleocytosis, mild to moderate CSF protein elevation, but negative fungal cultures.
1. Fluconazole-resistant Cryptococcus is rare. However in Africa, it is an emerging problem given that fluconazole prophylaxis and use of fluconazole monotherapy for cryptococcal meningitis is widespread. In a study done in South Africa (read here), two thirds of patients with symptomatic relapse had positive culture. Of these positive cultures, 76% had reduced fluconazole susceptibility.
2. Repeating cryptococcal antigen in the serum or CSF of this patient was suggested. The guideline (read here) explicitly mentioned that changing antigen titer (or positive India ink, or changes in CSF chemistries and cellular reactions) is insufficient in making a diagnosis of relapse. Let's go over some of the definitions:
A. Relapse: Cryptococcus culture positive + recurrence of signs and symptoms; suggests prior
clearance of cultures and resolution of signs symptoms;
B. Persistence: persistence of positive Cryptococcus culture after 4 weeks of effective therapy at
effective doses.
In this particular patient, measuring CSF cryptococcal antigen may be informative. Dr. Powderly and colleagues published in 1994 a study (read here) that showed that during therapy for acute meningitis, an unchanged (defined as 0-1 dilution change) or increased titer (defined as a rise of at least 2 dilutions) CSF antigen was correlated with clinical and microbiological failure especially among patients with baseline antigen titer of > or = 1:8.
3. It was suggested that in the absence of good evidence of relapsed infection in this patient, chronic management of elevated intracranial pressure (e.g. VP shunt placement) may suffice without reinstituting induction therapy.
Case 2. 12 year old boy with common variable immunodeficiency (CVID) presenting with 3 months of fever, night sweats, and weight loss as well as multiple enhancing mediastinal and inguinal lymph nodes. Patient eventually found to have non-caseating granulomas associated with AFB+ organism on lymph node biopsy.
1. Tuberculosis and non-tuberculous Mycobateria infection are rare in patients with CVID. There is a short list of case reports, however.
2. Fifty percent of CVID patients develop complications: 20% of complicated cases have non-caseating granulomas, 50% have lymphoproliferative diseases, 20% have autoimmune diseases, and 4% have lymphoma.
3. Most common sites of granuloma formation are the lungs, spleen and liver. They tend to respond better with corticosteroid therapy compared to granulomas located elsewhere.
4. This patient was maintained on antibiotics that target both tuberculosis and non-tuberculous Mycobacteria since all his cultures were negative.
Case 3.This is another management dilemma case.
A 28/F with recurrent mitral valve lesion over 3 years. Patient had 3 different courses of infective endocarditis treatment and two major valve surgeries. Work-up for infection, autoimmune disease, and hypercoagulable state have been unrevelaing.
1. Let's review common causes of culture-negative endocarditis. In a case series of 348 patients with blood culture-negative endocarditis (read here), the following organisms were isolated by different testing methods: Coxiella (48% ), Bartonella (28%), Streptococci (4 cases), Tropheryma (2 cases), Abiotrophia (1 case), Mycoplasma (1 case), and Legionella (1 case).
2. The value of utilizing next generation sequencing in this patient was brought up, in reference to the case recently published in the New England Journal of Medicine (read here) and the New York Times (read here). The article tells the story of a 4-year old boy with recurrent meningitis and unrevealing tests. With the help of next generation sequencing, the boy was diagnosed with neuroleptospirosis.
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