The following cases and commentary, which focus on HIV, are excerpted from ACP's Medical Knowledge Self-Assessment Program (MKSAP 18).
Case 1: Recent HIV diagnosis, cough, and chest pain
A 25-year-old man is evaluated in the emergency department for fever, productive cough, dyspnea, and pleuritic chest pain that began several days ago. He reports no other symptoms. Intravenous ceftriaxone and oral azithromycin are initiated, and he is hospitalized. Medical history is significant for a recent diagnosis of HIV infection, for which he began antiretroviral therapy 1 month ago. Other medications are lamivudine, abacavir, and dolutegravir.
On physical examination, temperature is 39.2 °C (102.6 °F), blood pressure is 136/84 mm Hg, pulse rate is 110/min, and respiration rate is 20/min. Oxygen saturation is 90% breathing ambient air. Cardiac examination is normal, and the lungs are clear bilaterally.
Laboratory studies at the time of HIV diagnosis showed a viral load of 95,420 copies/mL and CD4 cell count of 256/µL. The interferon-γ release assay for tuberculosis was indeterminate because of inadequate response to the positive control. One week ago, HIV viral load was 1077 copies/mL and CD4 cell count was 313/µL.
A chest radiograph shows an infiltrate in the right middle lobe and bilateral hilar enlargement.
Sputum acid-fast bacilli smear shows acid-fast bacilli; culture results are pending.
Which of the following is the most appropriate management?
A. Await culture results
B. Pause antiretroviral therapy
C. Start prednisone
D. Start rifabutin, isoniazid, ethambutol, and pyrazinamide
Case 2: Young patient with rash on his posterior chest
A 22-year-old man is evaluated in the emergency department for a 2-day history of painful rash on the left side of his posterior chest. Medical history is unremarkable, and he takes no medications.
On physical examination, temperature is 37.5 °C (99.5 °F), blood pressure is 115/62 mm Hg, pulse rate is 78/min, and respiration rate is 20/min. A vesicular rash is shown.
Which of the following is the most appropriate test to perform next?
A. CH50 activity
B. Fourth generation HIV-1/2 antigen/antibody combination immunoassay
C. IgA measurement
D. Quantitative immunoglobulin measurement
Case 3: Nurse with a needlestick
A 33-year-old woman is evaluated after sustaining a needlestick puncture in an infusion clinic, where she works as a nurse. The needle was being placed for intravenous therapy and had blood on it; it is from a patient at the clinic who is known to have HIV infection and is taking antiretrovirals, but the recent viral load is unknown. The nurse has already cleaned her wound. Medical history is unremarkable, and she takes no medications.
On physical examination, vital signs are normal, and other examination findings are noncontributory.
Which of the following is the most appropriate immediate management?
A. Begin tenofovir and emtricitabine
B. Begin tenofovir, emtricitabine, and dolutegravir
C. Begin tenofovir, emtricitabine, and ritonavir-boosted darunavir
D. Determine source patient's viral load
Case 4: Sore throat and odynophagia
A 30-year-old man is evaluated for a 1-week history of sore throat and odynophagia. He reports no fever, nausea, vomiting, diarrhea, or other symptoms. He was recently diagnosed with HIV infection and began antiretroviral therapy 2 weeks ago. Medications are tenofovir alafenamide, emtricitabine, dolutegravir, and trimethoprim-sulfamethoxazole.
On physical examination, vital signs are normal. Oral examination findings (shown) include whitish plaques on the posterior pharynx. Lymph nodes are palpable in the anterior and posterior cervical regions bilaterally. The remainder of the examination is normal.
Laboratory studies at the time of HIV diagnosis showed a CD4 cell count of 55/µL and HIV viral load of 138,855 copies/mL.
Which of the following is the most appropriate management?
A. Intravenous caspofungin
B. Oral fluconazole
C. Nystatin swish-and-swallow
D. Upper endoscopy
Case 5: Lymphadenopathy
A 37-year-old man is evaluated in the hospital for rapidly enlarging axillary and supraclavicular lymphadenopathy. He is HIV positive. His only medication is efavirenz-emtricitabine-tenofovir.
On physical examination, vital signs are normal. A left supraclavicular lymph node is enlarged to 5 cm, and a left axillary node is enlarged to 6 cm. The remainder of the physical examination is normal.
Laboratory studies show creatinine 1.7 mg/dL (150.3 mmol/L), hemoglobin 8.6 g/dL (86 g/L), lactate dehydrogenase 2459 U/L, leukocyte count 2600/µL (2.6 × 109/L), platelet count 110,000/µL (110 × 109/L), and urate 13.3 mg/dL (0.78 mmol/L).
Biopsy of the node shows CD20-positive Burkitt lymphoma.
A CT scan of the chest, abdomen, and pelvis without contrast identifies mesenteric and retroperitoneal lymphadenopathy and splenomegaly. There is no hydrone phrosis.
Before starting chemotherapy, which of the following is the most appropriate treatment?
A. Allopurinol and intravenous hydration
B. High-dose glucocorticoid therapy
C. Radiation therapy
D. Rasburicase and intravenous hydration
Answers and commentary
Correct answer: D. Start rifabutin, isoniazid, ethambutol, and pyrazinamide.
The most appropriate management for this patient is to start rifabutin, isoniazid, ethambutol, and pyrazinamide therapy for tuberculosis. He began antiretroviral therapy 1 month ago and has responded well, with a significant decrease in viral load and increased CD4 cell count. The timing of his presentation is consistent with the immune reconstitution inflammatory syndrome (IRIS) (median 48 days), the return of a robust immune response resulting from treatment of the HIV that “unmasks” a pre-existing infection that appears like a new acute infection. This presentation is common with tuberculosis, which may present as a much more acute pulmonary illness resembling bacterial pneumonia. He had an indeterminate result on interferon-γ release assay (IGRA) because of an inadequate response to the positive control, which was the result of immunocompromise at the time of presentation; additionally, the results of IGRA testing are a poor indicator of active tuberculosis infection. He should begin four-drug antituberculous therapy while results of culture and susceptibility testing are pending. Nucleic acid amplification testing of the specimen may give information on the identification of the organisms and even the possibility of rifamycin resistance. Initial empiric treatment for tuberculosis should include a rifamycin as one of the four drugs, but rifabutin is often preferred over rifampin in patients with HIV because of fewer drug-drug interactions between rifabutin and antiretrovirals, including dolutegravir.
If this patient does have active tuberculosis, treatment is needed urgently; culture results may take weeks, so waiting would be inappropriate.
Antiretrovirals should not be stopped when IRIS occurs. Therapy should be continued while providing treatment for the newly diagnosed infection.
Prednisone can be added if IRIS is life threatening or involves the pericardium or central nervous system. None of these is the case in this patient; giving glucocorticoids without a known diagnosis increases the risk of worsening an infection that is not being directly treated.
- Immune reconstitution inflammatory syndrome is the return of a robust immune response resulting from treatment of HIV that may “unmask” a pre-existing infection; when this occurs, the underlying infection should be treated while antiretroviral therapy is continued.
Correct answer: B. Fourth generation HIV-1/2 antigen/antibody combination immunoassay.
The most appropriate test to perform next is a fourth generation HIV-1/2 antigen/antibody combination immunoassay. This test combines an immunoassay for HIV antibody with a test for HIV p24 antigen. This improves the ability of the test to detect early HIV infection because p24 antigen becomes detectable a week before antibody in acute infection. Detection of antigen may help diagnose patients as early as 2 weeks after infection. This patient's painful vesicular rash distributed over a thoracic dermatome is classic for infection with varicella-zoster virus. Older adults and immunocompromised patients, including patients with HIV infection, are at increased risk. Severe or recurrent varicella-zoster virus infections or infection at a young age should prompt an evaluation for HIV infection.
Patients with terminal complement component deficiencies usually present with recurrent, invasive infections with encapsulated bacteria such as Neisseria meningitides, Haemophilus influenzae, and Streptococcus pneumoniae. These patients should be screened for complement deficiency by assaying for CH50 activity. If CH50 activity is normal, alternate pathway function should be assessed with an alternative complement pathway (AH50) assay. If results of either assay are abnormal, specific component concentrations should be determined.
Selective IgA deficiency is one of the most common B-cell immunodeficiencies. Inheritance may be autosomal dominant or recessive; most cases are sporadic. Patients with selective IgA deficiency may be asymptomatic or present with recurrent sinopulmonary infections (otitis media, sinusitis, pneumonia) or gastrointestinal infections (giardiasis). Other common manifestations include inflammatory bowel disease; celiac disease; an increased frequency of autoimmune disorders, including rheumatoid arthritis, systemic lupus erythematosus, and chronic active hepatitis; and allergic disorders, including asthma, allergic rhinitis, and food allergies.
Common variable immunodeficiency involves B- and T-cell abnormalities and results in clinically significant immune dysregulation. The primary manifestation is hypogammaglobulinemia, and recurrent respiratory infections are a common presentation in adults. The gastrointestinal tract is frequently involved and causes malabsorption or chronic diarrhea. Infection with Giardia, Campylobacter, or Yersinia species may occur, as may opportunistic infections. Concurrent autoimmune disorders occur in up to 25% of patients. The risk for malignancy is increased, including gastrointestinal cancers and non-Hodgkin lymphoma. Patients also have a poor or an absent response to protein and polysaccharide vaccines. Serum immunoglobulin levels are usually low, circulating B cells may be normal or low, and T-cell function varies. The diagnosis is made by confirming low levels of total IgG and IgA or IgM, as well as by a poor antibody response to vaccines.
- Infection with varicella-zoster virus in a young patient should prompt testing for HIV infection.
Correct answer: B. Begin tenofovir, emtricitabine, and dolutegravir.
This patient has sustained a possible exposure to HIV and should begin postexposure prophylaxis as soon as possible with a three-drug regimen of tenofovir, emtricitabine, and dolutegravir. Significant risk factors for the exposure include that it was a hollow-bore needle with visible blood. If the source patient was known to have an undetectable viral load in blood, the risk would be reduced but not eliminated; however, the source patient's viral load is unknown at this time. Drug selection may be modified depending on the source patient's history of viral resistance, but the preferred empiric postexposure prophylaxis regimens include tenofovir disoproxil fumarate, emtricitabine, and either dolutegravir or raltegravir, and should be given for 4 weeks. The same recommendations are appropriate whether the exposure was occupational or nonoccupational. The exposed patient should be tested for HIV immediately, 4 to 6 weeks later, and 3 months after the exposure. Exposed persons should also be counseled on transmission, symptoms of acute infection, and toxicity of the medications being prescribed.
A two-drug regimen for postexposure prophylaxis (compared with pre-exposure prophylaxis) is no longer recommended.
Protease inhibitors such as darunavir, whether boosted or not, are not recommended for prophylaxis because of their higher rates of adverse effects.
Because postexposure prophylaxis must begin promptly to be most effective, it would not be appropriate to wait for results of the source patient's viral load before determining therapy. The source patient should also be tested for other blood-borne pathogens, such as hepatitis B and C.
- Preferred HIV postexposure prophylaxis regimens include tenofovir disoproxil fumarate, emtricitabine, and either dolutegravir or raltegravir and are appropriate whether the exposure was occupational or nonoccupational.
Correct answer: B. Oral fluconazole.
Oral fluconazole is the most appropriate management for this patient's likely esophageal candidiasis; he should be treated presumptively and followed for response. The diagnosis of oropharyngeal candidiasis is usually made clinically; although whitish plaques are often prominent, oral candidiasis may also present as diffuse erythema without plaques. The presence of oral candidiasis and painful swallowing symptoms indicates likely esophageal involvement. The preferred treatment is oral fluconazole regardless if the disease is isolated to the oral cavity or extends into the esophagus; however, esophageal involvement warrants a more prolonged course (14-21 days rather than 7-14 days). Clinical response is usually apparent within a few days.
Because this patient is able to swallow pills, oral therapy is appropriate, and intravenous therapy is unnecessary. Additionally, fluconazole has higher rates for complete resolution without relapse of disease than the echinocandins and is preferred therapy unless resistance is documented, which would not be expected in a patient who has not been taking long-term azole therapy.
Topical agents such as nystatin are less effective than systemic fluconazole for oropharyngeal candidiasis and are especially ineffective for esophageal disease.
If presumptive treatment for candida esophagitis is ineffective in improving symptoms, then upper endoscopy is indicated to better define the cause.
Cytomegalovirus esophagitis is seen in immunocompromised patients and rarely occurs in patients with an intact immune system. Although herpes simplex virus (HSV) esophagitis can be seen in immunocompetent and immunocompromised patients, it is much more likely to be found in an immunocompromised person. These viral infections usually manifest as esophageal ulcerative lesions rather than plaques. Biopsies of the ulcer should be performed to confirm cytomegalovirus and HSV. Treatment of cytomegalovirus with valganciclovir (or HSV with acyclovir) would not be appropriate without first seeing evidence for it on endoscopy.
- The preferred treatment for oropharyngeal candidiasis, including esophageal disease, is oral fluconazole, although esophageal involvement warrants a more prolonged treatment course.
Correct answer: D. Rasburicase and intravenous hydration.
The most appropriate treatment is the administration of rasburicase along with intravenous hydration with normal saline and furosemide. Malignancies associated with rapid cell turnover can release large quantities of electrolytes and procoagulants into the circulation, causing the potentially life-threatening complication of tumor lysis syndrome. Spontaneous tumor lysis syndrome occurs commonly in patients with leukemia and Burkitt lymphoma and after treatment of bulky large B-cell lymphoma or advanced chronic lymphocytic leukemia. Rapid cell breakdown results in hyperkalemia, hyperphosphatemia, hyperuricemia, hypocalcemia, and disseminated intravascular coagulation. Hyperuricemia can lead to uric acid nephropathy and acute kidney injury. In this patient, proceeding with rasburicase, intravenous hydration, and furosemide with plans for prompt initiation of systemic therapy is appropriate. Rasburicase can rapidly and effectively lower serum urate levels and reduce the risk of acute uric acid nephropathy seen with tumor lysis syndrome. Because of its rapid onset of action and ability to lower urate levels quickly, which may be renoprotective, rasburicase should be administered before initiation of chemotherapy in patients with underlying kidney disease or those with signs of kidney disease, including an elevated serum creatinine level and a low urine output. Intravenous hydration with diuretics to maintain a high urine output is also key to reducing the risk of kidney failure and managing hyperkalemia and hyperphosphatemia, as well as hyperuricemia.
Large-volume intravenous hydration with normal saline plus administration of allopurinol to limit hyperuricemia is usually effective to prevent tumor lysis syndrome. However, this patient has hyperuricemia and an elevated serum creatinine level, making rasburicase preferred to allopurinol.
Whereas glucocorticoids and radiation therapy may be effective at shrinking this patient's tumors, such therapy will not prevent and will likely exacerbate tumor lysis syndrome.
- Burkitt lymphoma often presents with early signs of tumor lysis, and it is important to institute tumor lysis syndrome prophylaxis before initiation of chemotherapy.