A 38-year-old female with no significant past medical history was brought to the emergency department with confusion and lethargy. Her family noted that the patient had been complaining of worsening headaches for the last several days. On admission, she was afebrile and hemodynamically stable. Initial laboratory workup showed leukopenia (white blood cell [WBC] count of 3 000 cells/mL) with absolute lymphopenia. Human immunodeficiency virus (HIV) testing was positive with a ribonucleic acid (RNA) viral load of 68 000 copies/mL and CD4 count of 25 cells/µL. Magnetic resonance imaging (MRI) of the brain revealed multiple ring-enhancing lesions of different sizes with surrounding edema and mass effect.
What is the NEXT BEST step to diagnose her disease process?
Correct Answer: B
This patient with newly diagnosed HIV/AIDS, and a CD4 count <100 cells/µL has central nervous system manifestation of toxoplasmosis. Clues to the diagnosis are compatible clinical features and multiple ringenhancing lesions with mass effect on MRI.
Toxoplasmosis, caused by the protozoan parasite Toxoplasma gondii, is the most common CNS opportunistic infection associated with HIV and is an AIDS-defining illness per the Centers for Disease Control and Prevention (CDC). Incidence of toxoplasmosis varies from 24% to 47% in T. gondii seropositive patients with a CD4 count <100 cells/µL. In immunosuppressed patients, disease is caused by the reactivation of latent infection and the CNS is the most common site of reactivation.
Toxoplasma encephalitis presents with fever, headache, mental status changes, focal neurologic deficits, or seizures. Mental status changes can result from global encephalitis and/or increased intracranial pressure.
In the appropriate clinical setting, a presumptive diagnosis can be made if the patient has a positive serology consistent with prior infection—a positive T. gondii immunoglobulin G (IgG)—and brain imaging (MRI) with multiple ring-enhancing lesions, often with surrounding edema. A presumptive diagnosis is sufficient to start anti-toxoplasma treatment. Identification of the organism on a tissue biopsy sample can confirm a suspected diagnosis but is not required especially given the morbidity and mortality associated with an invasive brain biopsy. Sulfadiazinepyrimethamine is the drug of choice. Clinical improvement is expected within 10 to 14 days of treatment initiation; if no improvement is observed by this time period, alternative diagnoses should be considered.
The differential diagnosis for ring-enhancing lesions in the brain in a patient with known HIV includes primary CNS lymphoma, mycobacterial infections, cryptococcosis, and bacterial or fungal abscesses.
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A 29-year-old male is admitted from the emergency department with fevers. He complained of night sweats and painful cervical lymphadenitis for the last 7 days. He was diagnosed with HIV/AIDS 1 month ago when he was admitted with an episode of communityacquired pneumonia. His CD4 count was 80 cells/µL and HIV RNA viral load was 1 million copies/mL at the time of diagnosis. He was started on anti-retroviral therapy (ART) with tenofovir-emtricitabine and raltegravir. On examination, his blood pressure is 90/45 mm Hg and pulse rate is 106 beats per minute. Blood cultures are in process. He is appropriately fluid resuscitated and started on vancomycin and piperacillin-tazobactam to cover potentially hospital-acquired pathogens. Immune reconstitution inflammatory syndrome (IRIS) secondary to disseminated mycobacterium avium complex (MAC) infection is suspected.
What is the NEXT BEST step regarding his ART during this admission?
Correct Answer: C
This patient’s clinical presentation is suggestive of IRIS, an inflammatory disorder manifesting with the emergence or worsening of a preexisting, underlying infection. IRIS usually develops within weeks to months after the initiation of ART during immune recovery. Symptoms and signs relate to the exposed infection.
The diagnosis of IRIS requires the presence of AIDS with a pretreatment CD4 count less than 100 cells/µL, a positive virologic and immunological response to ART, and a temporal association between ART initiation and the onset of clinical features of illness. Common opportunistic infections associated with IRIS are mycobacterial and cryptococcal infections although any infection can present with IRIS.
In this case, the clinical presentation is consistent with MAC infection. Symptoms of MAC are generally nonspecific but often include fevers and diffusely painful lymphadenitis. Laboratory abnormalities include anemia, elevated alkaline phosphatase, and elevated lactate dehydrogenase. The diagnosis is typically confirmed by the isolation of MAC on cultures, although the microorganism burden may be low in IRIS. MAC usually grows on culture within 7 to 10 days.
Management of ART is crucial in IRIS associated with AIDS. Mild manifestations of IRIS usually resolve spontaneously in few days to weeks. Patients with severe symptoms may need adjunctive corticosteroids. Patients on ART who develop IRIS should continue ART alongside appropriate treatment of the exposed opportunistic infection. If the patient presents with MAC at the time of AIDS diagnosis, however, ART should be held until antimicrobial therapy for MAC has been initiated for 2 weeks.
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A 65-year-old male is admitted to the hospital with malaise and fatigue for the past week. His WBC count on admission was 27 000 cells/mL. The patient was ultimately diagnosed with high-grade acute promyelocytic leukemia. A tunneled central venous catheter was placed and the patient was started on all-trans-retinoic acid, daunorubicin, and cytarabine. Four days after initiation of chemotherapy, he developed a fever of 39.1°C (102.3°F) and altered mental status. His blood pressure was 90/54 mm Hg, heart rate 108 beats per minute, respiratory rate 24 breaths per minute, and oxygen saturation 94% on 5 L of supplemental oxygen. Laboratory evaluation was significant for neutropenia (absolute neutrophil count 300 cells/µL). His chest x-ray showed a focal consolidation in the right middle lobe. He was admitted to the intensive care unit and blood cultures were obtained.
What is the BEST empiric intravenous antibiotic regimen for this patient?
Correct Answer: D
Neutropenia can be seen in varying degrees. Mild neutropenia is defined as an absolute neutrophil count (ANC) <1 500 cells/µL, while moderate neutropenia requires an ANC <1 000 cells/µL and severe neutropenia requires an ANC <500 cells/µL or an ANC that is expected to decrease to <500 cells/µL over the next 48 hours. Profound neutropenia is defined by an ANC <100 cells/µL. Fever in neutropenic patients is defined as a single oral temperature of 38.3°C (101°F) or a temperature of 38.0°C (100.4°F) sustained over 1 hour. Patients with prolonged (>7 days) and profound neutropenia are at high risk for complications such as hypotension and inhospital mortality.
Infections in neutropenic patients are presumed to arise from patient’s existent bacterial flora. Although common sites of infection include the skin, lungs, and intestinal tract, the majority of febrile neutropenia episodes do not have an identifiable source of infection.
Empiric antibiotics should be initiated within 120 minutes of patient presentation. Blood cultures should be drawn preferably before antibiotics are initiated. Empiric antimicrobial therapy should include an antipseudomonal beta-lactam agent (cefepime, piperacillin-tazobactam, or a carbapenem). Aminoglycosides and fluoroquinolones may be added as an additional anti-pseudomonal agent. Vancomycin should be added if pneumonia, skin and soft tissue infection, or central venous catheter infection is clinically suspected. Hemodynamic instability is another indication for the addition of vancomycin to a neutropenic patient’s initial regimen. Empiric antifungal therapy is only considered in those patients who are persistently febrile and neutropenic on empiric antibacterial therapy for at least 4 days. Candida species–related infections are commonly seen after the first week and mold infections such as aspergillosis are seen after 2 weeks of persistent neutropenia. In our patient, pneumonia and central venous catheter infection are diagnostic considerations meriting vancomycin in addition to piperacillintazobactam for empiric antimicrobial therapy.
A 60-year-old female was admitted to the ICU with acute hypoxic respiratory failure. She endorsed malaise, fevers, and neck swelling for 2 weeks prior to presentation. She received a bilateral lung transplant [cytomegalovirus (CMV) donor negative/recipient negative, Epstein-Barr virus (EBV) donor negative/recipient positive] 4 months ago for idiopathic pulmonary fibrosis and is currently on immunosuppression with azathioprine 200 mg daily and tacrolimus 2 g twice daily. Her antimicrobial prophylaxis includes trimethoprim-sulfamethoxazole one double-strength tablet thrice weekly and itraconazole 200 mg daily. On admission, she was alert and oriented, afebrile, and hemodynamically stable. Cervical lymphadenopathy was present. Her:
Her chest x-ray showed bilateral diffuse infiltrates. Blood cultures showed no growth on culture at 24 hours of collection. Serum EBV quantitative deoxyribonucleic acid (DNA) PCR was 100 000 copies/mL (undetectable on prior measurement 1 month ago). Posttransplant lymphoproliferative disease is suspected.
What is the NEXT BEST step in the management of this patient?
The EBV status and viral load in this solid organ transplant patient point toward a diagnosis of PTLD. Reduction of immunosuppression is a critical step in the management of this condition
PTLD is the most common malignancy complicating solid organ transplantation. Nine out of ten patients with PTLD have evidence of EBV infection by serologic studies or EBV viral load. PTLD occurs as a consequence of the proliferation of infected B cells in the setting of posttransplant immunosuppression. EBV serostatus and the degree of Tcell immunosuppression are the principal risk factors for the development of disease.
In general, the clinical presentation of PTLD is variable. Initially, the disease may present with a mononucleosis-like syndrome, associated with nonspecific constitutional symptoms such as fever, weight loss, and fatigue as well as peripheral lymphadenophathy. It can also present with tissue infiltrative disease or localized lymphomas. Diagnosis is confirmed by histological examination.
The treatment of PTLD must balance the goals of eradicating disease and maintaining a functional graft. Management strategies are based on the category of disease. Early lesions are managed with careful reduction of immunosuppression alone. Other therapies like rituximab are recommended in addition to the reduction of immunosuppression in patients with polymorphic PTLD (CD20+ PTLD). Rituximab alone or in combination with chemotherapy is used in patients with monomorphic PTLD, and chemotherapy with or without radiation is used in patients with classic Hodgkin lymphoma–like PTLD, which is the least common form.
A 62-year-old male who underwent bilateral lung transplantation (CMV donor positive/recipient negative, EBV donor positive/recipient negative) for end-stage lung disease due to chronic obstructive pulmonary disease is admitted to the ICU with left lower quadrant abdominal pain, diarrhea, and hypotension. His symptoms started 5 days ago and have been progressively worsening. Diarrhea is mainly watery and frequency ranges from four to five times per day. On examination, the patient was afebrile with blood pressure 84/60 mm Hg, heart rate of 100 beats per minute, and dry oral mucosa. His abdomen was diffusely tender to palpation. An x-ray of the abdomen demonstrated colonic ileus with no evidence of gas under the diaphragm. Stool Clostridium difficile PCR, stool ova and parasites testing, and stool cultures are negative. CMV is undetectable by PCR in the plasma.
What is the next BEST step in managing this patient?
This patient with a discordant CMV serology status (donor positive, recipient negative) presenting with diarrhea is most likely to have CMV tissue-invasive disease and colitis despite a negative plasma CMV PCR. Tissue biopsies from multiple sites in the colon showing characteristic histopathology are needed to confirm the diagnosis.
CMV is a member of Herpesviridae genus that causes life-threatening infection in both solid organ transplant and hematopoietic stem cell transplant recipients. The virus can cause primary infection that occurs in seronegative patients or secondary infection, usually attributed to reactivation of latent infection. Primary infections are usually more severe than secondary infections.
Plasma CMV PCR can be negative in 15% of tissue-invasive CMV colitis. In patients with compartmentalized CMV disease like colitis, viremia may be very low or transient. Thus, biopsy is needed to confirm the diagnosis. CMV replicates within the nuclei of infected cells which is represented by the large eosinophilic intranuclear inclusion bodies on hematoxylin and eosin staining of tissue samples. There may be associated tissue necrosis and endothelial damage.
However, repeat colonoscopy with biopsy is not required to document clearance after appropriate antimicrobial treatment is completed. A computed tomography (CT) scan of the abdomen is not diagnostic in CMV colitis. Empiric therapy is not indicated in suspected colitis without viremia as ganciclovir treatment is associated with significant marrow toxicity.
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