June 24, 2015 Grand Rounds

Case 1. This is a management dilemma case. 

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.

June 17, 2014 Grand Rounds

Case 1: 73 year old man with neutropenia secondary to chemotherapy for a recent diagnosis of AML who presents with acute onset appearance of diffuse skin nodules and fever secondary to Fusarium sp.

1. Always think of disseminated Candida and Fusarium infection in a neutropenic patient who presents with sudden onset skin nodules and fever.

2. We usually treat serious Fusarium infection with amphotericin plus voriconazole. This is because different species of Fusarium may display different susceptibility patterns. For example. Fusarium solani and Fusarium verticilliodes are azole-resistant while Fusarium oxysporum and Fusarium moniliforme are usually susceptible to either voriconazole or posaconazole.A good review of Fusarium infection in immunocompromised patients can be found here.

3. The greatest risk factor for mortality secondary to Fusarium infection is persistent neutropenia.

Case 2: 7 month old infant who presented with fever, morbiliform rash, acute mental status change, and seizure secondary to vanishing white matter disease.

1. The discussion centered on why measles was unlikely in this case (i.e. vaccination was up to date, measles Ig M was negative, rash preceding onset of fever).

2. The discussion also talked about measles encephalitis. It commonly develops during the viral exanthem or within 8 days of illness onset. Around 51% of patients with measles may have EEG abnormalities in the absence of actual encephalitis. Patients with measles may also have a CSF with <10 cells (15%).

3. Vanishing white matter disease, caused by specific genetic abnormalities, is characterized by gradual disappearance of the white matter after an initial normal development.

Case 3: 49 year old man with diffuse lymphadenopathy, hepatosplenomegaly, fever, constitutional symptoms, and necrotizing granulmatous lesions on bone marrow biopsy

1. Differential diagnoses are broad: tuberculosis, fungal infection, Q fever, bartonellosis, syphilis, lymphoma, et al. A good review is found here.

2. In this patient, multiple cultures failed to isolate an infective agent. Biopsy smears were also negative. In this situation, further tissue biopsy should be done as lymphoma can sometimes be difficult to diagnose.

3. Necrotizing granulamotous disease in a sick patient may warrant empiric anti-tuberculosis treatment while waiting for culture results.

June 10, 2014 Grand Rounds

Case 1: Malaria in a 24-year old returned traveler from Africa and Saudi Arabia

1. Important differential diagnoses in a returned traveler who presents with fever include: malaria, dengue, typhoid fever, rickettsial infection, leptospirosis, and N. meningitidis.

2. Since the patient here presented with fever and prominent headache, African trypanosomiasis (African sleeping sickness) was also included in the differential diagnoses. It was pointed, however, that this diagnosis is very rare. In a cohort of more than 17,000 patients from the GeoSentinel data, only one had African trypanosomiasis. This article can be found here.

3. Coartem (artemether/lumefantrine) is the oral agent of choice for uncomplicated malaria. Malarone (atovaquone/proguanil) is an alternative oral agent. In this patient, Malarone, which was the initial drug administered, did not clear the parasetemia even after 4-5 days of treatment. Parasetemia eventually cleared after switching the medication to Coartem.

4. How soon should we expect clearance of parasetemia with the use of Malarone? In a single study, the use of Malarone led to complete clearance of the parasetemia in all patients on day 3 of treatment. 

5. Atovaquone resistance is easily inducible in vitro. We don't see it a lot in clinical practice because mutations that lead to atovaquone resistance render the parasite less fit.


Case 2: Mycoplasma infection associated with multiple deep vein thromboses and pulmonary embolism in a 14-year old immunocompetent person

1. Remember that Mycoplasma infection can induce a procoagulant state (elevated cardiolipin), much like infection with parvovirus B19, tuberculosis, EBV, CMV, etc.). More 23 case reports have been published in the literature.


Case 3: Extensive cutaneous Alternaria infection in a patient with multiple episodes of bloodstream infections

1. Repeated episodes of bloodstream infection, in the absence of endocarditis, gastrointestinal pathology, central lines, or prosthetic devices should behoove clinicians to do a thorough dermatologic examination. This patient presented with extensive cutaneous Alternaria infection that caused him to develop burn-like lesions enough to compromise cutaneous barrier against infection.

2. The treatment of choice for Alternaria is amphotericin. Posaconazole and voriconazole also display good activity. Surprisingly, some Alternaria sp. have low MIC's to the echinochandins.

June 3, 2014 Grand Rounds

Case 1: Invasive Aspergillus sphenoid sinusitis associated with cavernous sinus thrombosis in a patient with lymphoma receiving chemotherapy

1. The discussion centered on the use of combination antifungal therapy for invasive mold infection. The bottom-line is that, although there is no good data to support the routine use of combination antifungal therapy, no antagonism in vivo and in vitro is seen between different antifungal combinations, especially with that of amphotericin plus an echinocandin. A good review is found here.


Case 2: Acute generalized exanthematous pustulosis (AGEP) secondary to a brown recluse spider bite in a 5-year old immunocompetent child

1. Always keep brown recluse spider bite in your differential diagnosis for somebody who presents with a localized cellulitis that is associated with fever and Coombs-positive hemolytic anemia. The bite of the brown recluse spider does not always have to be obvious. It may sometimes appear as a localized swelling without an eschar. Severe cases can also lead to multi-organ failure and DIC (systemic loxoscelism). A good review is found here.


2. AGEP should always be entertained in the differential diagnosis of diffuse pustular rash associated with fever. The most common cause is exposure to certain medications. Rarely, it can be caused by spider bites. Certain viral infections have also been shown to cause AGEP, including adenovirus, parvovirus B19, enterovirus, hepatitis B, hepatitis C, EBV, and CMV. AGEP can mimic other serious dermatologic conditions including pustular psoriasis of von Zumbusch, Behcet's disease, DRESS, and SJS/TEN. A good review is found here.


Case 3: Scedosporium pulmonary infection in a neutropenic patient

1. All Scedosporium sp. are universally resistant to amphotericin. The drug of choice is voriconazole.

2. Scedosporium prolificans is a nasty fungus. It is known to be resistant to almost all antifungals. Treatment success has been reported with the use of voriconazole plus terbinafine.

3. A "buzzword" for Scedosporium infection among immunocompetent hosts is "near-drowing" since several infections with this fungus have been documented among patients with near-drowning experience.