Case 1: Cutaneous tuberculosis
By Michael J. Hoffman, MD
A 41-year-old man who had emigrated from China three years earlier presented with fever. He had previously been diagnosed with dermatomyositis and was treated with high-dose prednisone, mycophenolate mofetil, hydroxychloroquine, methotrexate, and intermittent IV immunoglobulin for approximately one year. He was not screened for latent tuberculosis infection prior to initiation of immunosuppressants. He had been admitted for proximal extremity weakness two months prior, at which time he was noted to have isolated fever. Infectious evaluation was negative, and the fever spontaneously resolved.
On the current admission, he was febrile with a temperature of 102.7 °F, tachycardic, tachypneic, and hypotensive. Large areas of swelling and erythema, tender and warm to the touch, were noted on the right thigh and left forearm. Labs showed a white blood cell count of 11.5 K/µL (normal range, 4.4 to 10.6 K/µL) with 94% neutrophils on differential, as well as a hemoglobin level of 9.2 g/dL (normal range, 12.9 to 16.8 g/dL) and lactic acid level of 3.2 mmol/L (normal range, 0.9 to 2.47 mmol/L). A chest X-ray was unremarkable.
A CT of the abdomen, pelvis, and right lower extremity revealed a peripherally enhancing fluid collection in the right thigh from the greater trochanter to the mid-shaft of the right femur (Figure 1). Operative incision and drainage revealed purulent fluid and necrotic muscle. Empiric antibacterial therapy was initiated, but the patient remained febrile and bacterial cultures were negative. A fluid smear was found to be positive for acid-fast bacillus (AFB), and sputum AFB and interferon gamma release assay (IGRA) were also positive. Polymerase chain reaction (PCR) testing of both the operative fluid and sputum was positive for Mycobacterium tuberculosis (Mtb) complex. The patient's Mtb isolate showed no resistance, and he received standard combination therapy. He responded well with eventual resolution of cutaneous lesions. His therapy was completed at seven months.
This patient was diagnosed with cutaneous tuberculosis (CTB), a rare extrapulmonary form of Mtb infection. Cutaneous infection is an uncommon presentation, typically manifesting in only 1% to 2% of Mtb cases worldwide. However, incidence of CTB is rising in regions where HIV and multidrug-resistant Mtb are prevalent. There is a spectrum of cutaneous disease depending on the mechanism of infection. Tuberculosis verrucosa cutis (primary inoculation tuberculosis) arises from direct inoculation from an exogenous source and yields isolated and localized cutaneous Mtb infection. Most cases arise from contiguous spread of a deeper infection (scrofuloderma, tuberculosis cutis orificialis, or lupus vulgaris), or from hematogenous spread leading to multifocal, metastatic tuberculous abscess or acute miliary tuberculosis. The bacterial load also contributes to the clinical presentation, with metastatic tuberculous abscess resulting from multibacillary infection. Risk factors for CTB include emigration from a place with endemic Mtb (particularly multidrug-resistant Mtb), as well as host immunosuppression. In the case of metastatic tuberculous abscess, decreased cell-mediated immunity, as can occur with prolonged use of corticosteroids or tumor necrosis factor-alpha inhibitors, is a significant risk factor.
The gold standard for any Mtb diagnosis is mycobacterial culture, which can then also be used to determine sensitivity to antituberculous drugs. As time to culture positivity can be lengthy, more rapid diagnostic testing includes AFB smear and Mtb PCR testing on source samples. Sensitivity of these tests is higher in exudative, purulent, and multibacillary forms of cutaneous Mtb. Tuberculin skin testing may be positive in cutaneous forms of Mtb; however, a positive test does not necessarily confirm active Mtb infection as it identifies those who have been previously sensitized to Mtb. Also, the sensitivity of skin testing is diminished in those with decreased cellular immunity. IGRA testing can be useful in suspected cutaneous Mtb cases, with one study suggesting a sensitivity of 92% and a specificity of 76%. Treatment of CTB is the same as for other nonmeningoencephalitis extrapulmonary Mtb infections, consisting of combination therapy. Generally, treatment is continued for two months beyond the resolution of CTB lesions. Adjunctive surgical therapy may be necessary depending on the size and location of cutaneous infection.
- CTB is an uncommon (1% to 2% of cases) manifestation of extrapulmonary tuberculosis infection.
- The gold standard for diagnosis of tuberculous abscesses remains mycobacterial culture, while more rapid diagnostic testing includes AFB smear and Mtb PCR of source samples; adjunctive IGRA testing may be helpful if clinical suspicion is high.
Case 2: Spontaneous tumor lysis syndrome
By Udit Joshi, MD, ACP Resident/Fellow Member, and Shweta Gupta, MD, FACP
A 56-year-old man with diabetes presented with a two-month history of left upper quadrant abdominal and left flank pain. The pain radiated to the left groin and testicle, was worse when he was lying on his back, and was associated with nausea and occasional nonbloody, nonbilious emesis. Vital signs were normal, and systemic examination was significant for an ill-defined left upper abdominal mass. A CT scan of the abdomen showed a left renal mass (Figure 2), which was deemed nonresectable by urological surgeons. A biopsy of the mass revealed poorly differentiated high-grade sarcoma of the kidney. He was discharged with outpatient oncology follow-up.
The patient presented again three weeks later with generalized weakness, fatigue, and persistent vomiting for one week. Vital signs were significant for a regular tachycardia of 125 beats/min. The remainder of his physical examination was unchanged. Laboratory analysis showed a potassium level of 4.5 mg/dL (normal range, 3.5 to 5.0 mg/dL), a calcium level of 8.5 mg/dL (normal range, 8.5 to 10.5 mg/dL), a creatinine level of 4.4 mg/dL (normal range, 0.6 to 1.4 mg/dL), a phosphate level of 9.2 mg/dL (normal range, 2.5 to 4.5 mg/dL), and a uric acid level of 16.0 mg/dL (normal range, 3.0 to 7.0 mg/dL). A repeat CT scan showed new ascites, as well as growth of the left renal mass. The patient received fluid hydration and rasburicase, but his renal function worsened and ultimately required hemodialysis. His overall condition, including renal failure, worsened despite treatment, and he died on the eighth day of admission.
This patient's diagnosis was spontaneous laboratory and clinical tumor lysis syndrome (TLS) resulting from renal sarcoma. TLS occurs when tumor cells break down in large numbers, releasing intracellular contents into the bloodstream and causing hyperuricemia (uric acid level >8 mg/dL or >25% above baseline), hyperphosphatemia (phosphate level >4.5 mg/dL or 25% above baseline), hyperkalemia (potassium level >6 mEq/L or >25% above baseline), and hypocalcemia (calcium level <7 mg/dL or >25% below baseline) in adults. Presence of two of the four metabolic derangements defines laboratory TLS, while organ dysfunction (acute kidney injury, arrhythmias, seizures, or sudden death) defines clinical TLS. Although hematological malignancies such as acute leukemias and non-Hodgkin's lymphomas are the most common causes, there are increasing reports of solid malignancies causing TLS, including germ-cell tumors, lung and breast tumors, and sarcomas. Most TLS occurs between three days before and seven days after initiation of antitumor therapy. However, spontaneous TLS, which is extremely rare with solid tumors, can occur unrelated to therapy. Tumor characteristics associated with increased risk of TLS include tumors that are rapidly proliferative, that are bulky, that involve multiple organs, or that are highly sensitive to anticancer therapy. Conditions that predispose a patient to TLS include pre-existing renal dysfunction, volume depletion, or exposure to nephrotoxins.
Management of spontaneous TLS, as with treatment-induced TLS, includes hydration, medication to reduce uric acid concentration, and correction of electrolyte abnormalities. Hemodialysis is necessary if renal function worsens despite treatment.
- TLS, especially when spontaneous, is a rare complication of solid tumors.
- Risk factors for the development of TLS include rapidly proliferating tumors, bulky tumors, multiorgan involvement, and high sensitivity to anticancer therapy. Patients with pre-existing renal dysfunction or dehydration are at high risk for TLS.
Case 3: Superior vena cava syndrome
By Vijaya Mukthinuthalapati, MD; Omid Behnamfar, MD, ACP Resident/Fellow Member; and Poushali Bhattacharjee, MD, MS, ACP Member
A 69-year-old woman with a 25-pack-year smoking history presented with bilateral neck, facial, and left upper extremity swelling of three weeks' duration, associated with significant weight loss and anorexia. Physical examination was significant for bilateral supraclavicular lymphadenopathy, dilated anterior chest veins, and pitting edema of the left upper extremity. Apart from a hemoglobin level of 9.9 g/dL (normal range, 11.7 to 14.9 g/dL), her labs were unremarkable. A chest CT angiogram (Figure 3) revealed extensive soft tissue infiltration throughout her superior mediastinum, with pronounced compression of the superior vena cava. It also confirmed mediastinal and bilateral supraclavicular lymphadenopathy. A bone scan and imaging of brain, abdomen, and pelvis did not reveal any distant metastases. Biopsy of the mediastinal mass revealed small-cell lung cancer (SCLC), and the tumor was staged as T4, N3, M0 (stage IIIB).
The patient received cisplatin-etoposide chemotherapy with concurrent radiotherapy to the right lung, mediastinum, and bilateral supraclavicular regions. Afterward, the chest collateral veins partially regressed, and repeat CT imaging showed a significant decrease in the size of the mediastinal mass.
The patient was diagnosed with superior vena cava (SVC) syndrome and further classified as having mild symptoms. SVC syndrome is a constellation of symptoms and signs that occur due to extrinsic compression or direct invasion of the SVC by a tumor and resultant interstitial edema within draining tissues. Stratification based on severity of symptoms is crucial to determine management. Mild symptoms do not cause functional impairment and include edema, plethora, cyanosis, and vascular distention with visible collateral vessels. Symptoms causing functional impairment, such as dysphagia or impaired movement of jaw, head, or eyelids, as well as visual disturbances, are termed moderate and constitute 50% of all cases. Symptoms due to edema in critical structures, such as dizziness and headache from cerebral edema, stridor and tachypnea from laryngeal edema, and syncope, are considered severe. Other severe symptoms that are considered life-threatening include confusion, respiratory distress, and hypotension. SVC syndrome is caused by malignancy in 60% to 85% of cases, with lung cancer (75%) and non-Hodgkin's lymphoma (10%) accounting for the majority.
When symptoms are mild to moderate, cross-sectional chest imaging (CT or MRI) is typically used to define the extent of venous obstruction, view collaterals, and aid in diagnosis. Venography is preferred for severe or life-threatening symptoms. For patients with mild to moderate symptoms, it is imperative to first make a histopathologic diagnosis, followed by targeted chemotherapy and radiation, which will typically reduce tumor bulk, thereby improving symptoms. Invasive approaches such as endovascular stenting, thrombectomy, and urgent surgery are reserved for those with severe to life-threatening symptoms and are pursued urgently, even before biopsy for diagnosis. Once the patient has stabilized, the malignancy can be managed with chemotherapy and radiation.
- The most common cause of SVC syndrome is malignancy, with lung cancer and lymphoma accounting for most cases.
- In patients presenting with severe symptoms suggestive of cerebral edema or airway narrowing, emergent endovascular stenting is recommended, followed by radiotherapy.
Case 4: Acute HIV infection
By Anthonia Ijeli, MD, and Poushali Bhattacharjee, MD, MS, ACP Member
A 22-year-old man presented with three weeks of nausea, vomiting, and abdominal pain. He also reported subjective fever, hematochezia, hematemesis, oral ulcers, gingival bleeding, dark-colored urine, and unintentional weight loss over the past month. The patient reported having male and female sexual partners. The physical exam was significant for right lower quadrant abdominal tenderness, and a rectal exam revealed red-colored stool without visible hemorrhoids. Laboratory tests revealed a serum creatinine level of 1.9 mg/dL (normal range, 0.6 to 1.4 mg/dL), a blood urea nitrogen level of 44 mg/dL (normal range, 8 to 20 mg/dL), and mild transaminitis. Complete blood count was initially normal, but hemoglobin levels subsequently declined. Anemia workup was significant for a lactate dehydrogenase level of 2,100 µ/L (normal range, 85 to 210 µ/L), a reticulocyte count of 0.5% (normal range, 0.3% to 2.7%), and a ferritin level greater than 7,500 ng/mL (normal range, 23 to 336 ng/mL). Erythrocyte sedimentation rate and C-reactive protein levels were elevated. HIV-1 and HIV-2 combination antibody testing was positive, yet follow-up testing with the HIV-1 and HIV-2 differentiation assay was negative.
On day seven of admission, high-grade fevers were noted. Bacterial and fungal cultures were obtained, and the patient was started on broad-spectrum antibiotics. HIV RNA polymerase chain reaction (PCR) returned with greater than 2 million copies/µL on day nine of admission. Blood cultures remained negative. He was started on highly active antiretroviral therapy (HAART) with emtricitabine, tenofovir alafenamide, and dolutegravir. Over the next five days his symptoms of fever, anemia, and acute kidney injury improved, and he was discharged home.
This patient presented with acute HIV infection. Acute HIV refers to the first few weeks of infection, when there are high levels of HIV RNA in the blood before HIV antibodies are formed. Of note, not all patients will be symptomatic during this time, although the exact prevalence of symptomatic acute HIV is unclear. Patients who present during the acute phase of infection typically report nonspecific symptoms including fever, sore throat, myalgias, lymphadenopathy, diarrhea, weight loss, painful mucocutaneous ulcers, and a maculopapular rash. Due to this wide array of findings, the clinical presentation is often confused with other infections such as influenza, infectious mononucleosis, acute hepatitis, acute pharyngitis, and disseminated gonorrhea. Ethnic minorities, specifically African-American and Hispanic patients, carry a disproportionate burden of new HIV cases (approximately 50% and 20%, respectively). Among women, unprotected heterosexual intercourse is the greatest risk factor; in men, the risk is highest in those who have sex with other men. Injection drug use continues to be a risk factor regardless of gender, not only due to nonsterile needles but also from associated at-risk sexual practices. The risk of contracting HIV is compounded when multiple risk factors are present.
For patients in whom there is a high index of suspicion for acute HIV, it is recommended to obtain an HIV-1 and HIV-2 combination antibody test concurrently with HIV RNA PCR. The combination antibody test has a sensitivity of 80% in acute HIV, but a negative combination assay with a viral load greater than 1,000 copies/mL suggests acute infection. With HIV RNA PCR, false-positive results occur less than 5% of the time, and typically with lower viral loads. A viral load less than 1,000 to 2,000 copies/mL could suggest a false-positive result, and repeat testing should be performed. Acute HIV is still a possibility when both the combination assay is positive and the HIV RNA viral load is elevated, but this should prompt testing with the HIV-1 and HIV-2 differentiation assay. A negative differentiation assay supports a diagnosis of acute HIV. This differs from the diagnosis of chronic HIV, in which the time of disease acquisition is less clear, the patient may be asymptomatic, and HIV antibodies have already formed. For patients with suspected chronic HIV, a positive combination antibody result should be followed by an HIV-1 and HIV-2 differentiation assay, both of which have a sensitivity and specificity of nearly 100% in chronic HIV.
Patients with acute HIV are highly infectious due to their high viral burden. Early diagnosis can help mitigate risky behaviors through appropriate counseling. Furthermore, rapid initiation of HAART in those with acute HIV decreases viral evolution and progression before the virus adapts to host immune responses and protects the immune system from the harmful effects of sustained HIV viremia. Early therapy has also been associated with improvement in presenting symptoms, higher chances of immune reconstitution with near-normal CD4 levels, and decreased viral reservoirs.
- Acute HIV presents with nonspecific symptoms and typically in patients with risk factors, including people with African-American or Hispanic ethnicity, men who have sex with men, those who use IV drugs, and those who have unprotected sex.
- HIV RNA PCR testing concurrent with an HIV antibody assay increases accuracy of diagnosis and can prevent delays in treatment.