Cases from Oregon Health & Science University

Red-cell aplasia, septic thromboembolus, and more.


Case 1: Parvovirus-induced red-cell aplasia

By Johnny Cai, DO, ACP Resident/Fellow Member; Emilio Sulpizio, MD, ACP Resident/Fellow Member; Emily Fay, MD, ACP Resident/Fellow Member; and Michael Heinrich, MD, FACP

The patient

A 30-year-old woman with a congenital noncompaction cardiomyopathy had undergone orthotopic heart transplant two months prior and was on immunosuppression. She was assessed by our hematology team for acute-on-chronic anemia after having presented for routine right-heart catheterization following her transplantation. Her history was negative for obvious sources of bleeding. Aside from fatigue, a complete review of systems was negative. On presentation, her vital signs were normal and physical examination was unremarkable. Labs showed a normal white count, a hemoglobin level of 6.7 g/dL (reference range, 12 to 15 g/dL for women), a hematocrit of 20.7% (reference range, 36% to 47%), a mean corpuscular volume of 79.9 fL (reference range, 80 to 100 fL), a red-cell distribution width of 47.1% (reference range, 11.5% to 14.5%), a reticulocyte count of 0.2% (reference range, 0.5% to 1.5%) with a reticulocyte index of 0.05 (reference range, >2), and normal platelet count. Ferritin and iron saturation were within normal limits. Nutritional studies revealed normal homocysteine and methylmalonic acid levels. Erythropoietin was appropriately elevated, with lactate dehydrogenase and haptoglobin within normal limits. Inflammatory markers were unremarkable, and Coombs and direct antiglobulin testing were negative.

The patient's hemoglobin level decreased further to 4.4 g/dL the day following her procedure. Tests for Epstein-Barr virus and cytomegalovirus were negative, but a parvovirus B19 polymerase chain reaction (PCR) test was positive, with a value greater than 100,000,000 IU/mL. Treatment with IV immunoglobulin (IVIG) therapy was successful, with immediate uptrend of hemoglobin noted. On outpatient follow-up, the patient had durably stable hemoglobin levels between 10 to 11 g/dL.

The diagnosis

The diagnosis in this patient is parvovirus-induced red-cell aplasia. Parvovirus B19 is a single-stranded DNA virus that replicates in erythroid progenitor cells. Parvovirus is a common infection worldwide. By age 15, approximately 50% of children have detectable parvovirus-specific IgG, or evidence of previous infection, while more than 80% of adults are seropositive. Patients can present with manifestations ranging from fever and erythema in children (i.e. Fifth disease) to fever, rash, and symmetric arthropathy in adults. Fetal complications are also possible. Parvovirus B19-induced red-cell aplasia is classically reported in patients with sickle-cell disease but is also one of the more serious complications in patients following solid organ transplant. Although parvovirus B19 disease is uncommon, studies report an incidence of approximately 2% after transplantation. In more recent publications, it has been suggested that up to 30% of organ transplant recipients develop parvovirus B19 viremia after transplantation and may present with clinical or subclinical infection.

The clinical presentation of parvovirus-induced red-cell aplasia can be varied. Possible syndromes include erythropoietin-resistant anemia or anemia with inappropriate reticulocytosis. Organ-invasive disease such as hepatitis, myocarditis, pneumonitis, neurological disease, or vasculitis is also seen. Common symptoms of parvovirus infection include fever, arthralgia, or rash. The anemia is progressive due to impaired production; typically, the gradual decline in hemoglobin level allows for compensation and symptoms may be less than would be expected for the degree of anemia at the time of diagnosis. Diagnosis of parvovirus infection can be more challenging in immunocompromised individuals, as negative serologies do not rule out the diagnosis. In the case of a negative PCR and serology with a clinical picture suggestive of parvovirus B19 infection, bone marrow examination along with in situ hybridization or immunohistochemical staining may establish the diagnosis.

Traditional treatment of parvovirus-induced anemia is IVIG, but alternative regimens include red-cell transfusion, recombinant erythropoietin, rituximab, or immunosuppressive medications. Changing immunosuppressive regimens in solid organ recipients has been anecdotally successful, but no data support widespread implementation. IVIG treatment is highly effective, though relapses are common, and immunosuppressed patients can remain dependent on maintenance infusions. The prognosis is generally favorable.

Pearls

  • Parvovirus B19 is a single-stranded DNA virus classically reported in patients with sickle-cell disease, but it can also cause red-cell aplasia in solid organ transplant recipients.
  • IVIG is the mainstay of treatment for parvovirus-induced red-cell aplasia, but alternative regimens include red-cell transfusion, recombinant erythropoietin, rituximab, or immunosuppressive drugs; for transplant patients already taking immunosuppressive drugs, treatment should be individualized.

Case 2: Septic right-heart thromboembolus

By Joel R. Burnett, MD, ACP Resident/Fellow Member; Kelsi L. Manley, MD, ACP Resident/Fellow Member; and Kevin Piro, MD, ACP Member

The patient

A 57-year-old woman with systemic scleroderma and esophageal dysmotility requiring total parenteral nutrition via central venous catheter (CVC) presented with fever and chills. On examination, she was febrile, tachycardic, normotensive, and tachypneic. She had normal lung sounds, normal heart sounds with no murmur, a normal skin exam including absence of erythema or fluctuance at the CVC insertion site, and no lymphadenopathy. She was found to have catheter-related bloodstream infection due to coagulase-negative Staphylococcus and was treated with IV antibiotics. Her CVC was removed with a plan for catheter replacement and hospital discharge after completion of IV antibiotics.

On the fifth hospital day, she agreed to point-of-care ultrasound (POCUS) for educational purposes. On POCUS examination of the heart, she was noted to have a large, mobile, hyperechoic mass in the right ventricle and atrium concerning for thrombus or vegetation. She underwent formal transthoracic echocardiogram (TTE), which showed a 6.3- × 1.4-cm mobile mass. Cardiac MRI confirmed a non-enhancing mobile mass extending from the mid-superior vena cava through the right atrium and tricuspid valve into the right ventricle, consistent with thromboembolus. A new CVC was placed, and her IV antibiotic course was extended to 28 days due to presumed septic thrombosis. Cardiothoracic surgery was not pursued due to high operative risk, and she was discharged on oral anticoagulation. Three months later, she remained asymptomatic and repeated TTE demonstrated thrombus resolution.

The diagnosis

The patient's diagnosis is septic right-heart thromboembolus in the setting of catheter-related bloodstream infection. The management of catheter-related infections, including septic thrombosis, is discussed extensively in clinical practice guidelines. The diagnosis and management of right-heart thrombosis, in contrast, currently lack guideline-based recommendations. Intracardiac thrombi may arise de novo, in association with intracardiac devices, or in transit from the systemic vasculature. Previous retrospective analyses of symptomatic right-heart thrombosis in patients without intracardiac instrumentation have demonstrated concomitant deep venous thrombosis of the lower extremities in approximately 90% of patients, suggesting that most thrombi have embolized from a distal source. The overall incidence of right-heart thrombosis is unknown. Studies show that the condition may be found in up to 18% of cases of acute pulmonary embolism (PE) and nearly all cases of right-heart thrombosis are diagnosed in the setting of PE, which likely represents selection bias. Estimates of CVC-related right-heart thrombosis vary, and prospective studies suggest up to 12.5% of patients with CVC may develop right-heart thrombosis visible on TTE.

Diagnosis of right-heart thrombosis is most often made by TTE or transesophageal echocardiogram. However, case reports of diagnosis by POCUS are emerging. Therapeutic options for right-heart thrombosis include anticoagulation, systemic thrombolysis, and surgical embolectomy. In the absence of randomized trials, optimal management remains unclear. Current expert opinion recommends an individualized approach to therapy.

Pearls

  • Right-heart thrombosis may have several causes; most cases are due to deep venous thromboemboli.
  • Therapeutic options for right-heart thrombosis include anticoagulation, systemic thrombolysis, and surgical embolectomy; optimal management remains unclear and should be individualized.

Case 3: Pulmonary aspergillosis

By Whitney Elg-Salsman, DO, ACP Resident/Fellow Member, and Anna K. Brady, MD

The patient

A 53-year-old woman with well-controlled asthma and no history of tobacco use presented with three days of dyspnea. She reported recent travel and exposure to wild sheep and dogs in South America and Eastern Europe, as well as dust exposure from her neighbor's foundation renovation. On initial evaluation she was afebrile, with a pulse of 100 beats/min, a respiratory rate of 12 breaths/min, and an oxygen saturation of 99% on ambient air. Physical examination revealed a middle-aged woman, breathing comfortably, with crackles and diminished breath sounds at the left lung base. Initial chest radiograph revealed a left-sided hydropneumothorax with a ruptured left lower lobe (LLL) cavitary lesion.

A chest tube was placed, and pleural fluid analysis revealed an empyema with significant eosinophilia at 84% (reference range, 0%). Peripheral eosinophilia of 42% (reference range, 1% to 3%) and a total IgE level of 8,000 IU/mL (increased from her prior level of 2,000 IU/mL; reference range, <214 IU/mL) were also noted. CT scan of the chest demonstrated enlargement of the left lower lobe cavitary lesion, new left lower lobe ground-glass opacities and consolidation, and a small pleural effusion. Additional laboratory testing revealed persistent peripheral eosinophilia (36%) and positive Aspergillus fumigatus IgE antibody. Bronchoscopy was performed, with bronchoalveolar lavage fluid notable for 80% eosinophilia (reference range, <1%) but negative fungal cultures, negative aspergillus galactomannan, and negative stain for acid-fast bacilli. The patient ultimately underwent lobectomy of the left lower lobe, and tissue culture revealed Aspergillus fumigatus along with positive 16S PCR testing. This patient initially began taking corticosteroids after empiric treatment for parasitic infections, followed by antifungal therapy when pathology and culture results were available. Her symptoms resolved and eosinophilia improved after four weeks of therapy.

The diagnosis

This patient's diagnosis is pulmonary aspergillosis, with features of allergic bronchopulmonary aspergillosis (ABPA) and chronic cavitary aspergillosis. ABPA can be a risk factor for chronic cavitary aspergillosis; if ABPA is left untreated, recurrent mucus plugging can lead to airway and underlying parenchymal damage and locally invasive disease. Aspergillus is a ubiquitous organism acquired via inhalation and can have diverse clinical presentations, including ABPA, aspergilloma, semi-invasive chronic cavitary aspergillosis, and invasive disease. Although cavitary ABPA has been described in case reports, it is an unusual presentation of this condition. Chronic cavitary pulmonary aspergillosis is a locally invasive disease characterized by cavitary lesions and elevated IgG titers to Aspergillus; this condition is more often found in patients with underlying destructive parenchymal lung disease such as sarcoidosis. It is unusual in patients with asthma. ABPA is an allergic rather than an infectious process that leads to airway inflammation and mucus production; the diagnosis is supported by imaging findings including central bronchiectasis, mucus plugging, and fleeting parenchymal opacities. Aspergillus-specific IgE and IgG antibodies are seen, with total IgE level usually above 1,000 IU/mL. The prevalence of ABPA in patients with persistent asthma is estimated at 1% to 2%.

The treatment of choice for chronic cavitary pulmonary aspergillosis is antifungal therapy with itraconazole or voriconazole for a minimum of six months pending clinical improvement. The first-line therapy for ABPA is corticosteroids, with addition of antifungal therapy for refractory cases. Surgery is considered as for patients with simple aspergillomas but is utilized less commonly in chronic pulmonary aspergillus and/or pleural-based lesions because of increased complication risk, including residual pleural infection predisposing to bronchopleural fistula and/or empyema.

Pearls

  • Aspergillus can cause a range of disease in the lung, including ABPA, aspergilloma, and chronic cavitary and invasive disease; initial therapy for ABPA is steroids, while therapy for chronic cavitary and invasive aspergillosis is antifungal therapy.
  • Chronic cavitary pulmonary aspergillosis is a locally invasive disease characterized by cavitary lesion(s) and elevated IgG titers to Aspergillus; ABPA is an allergic rather than an infectious process that leads to airway inflammation and mucus production.

Case 4: T-cell large granulocytic leukemia

By S. Miles Grovenburg, MD, ACP Resident/Fellow Member; James Clements, MD, ACP Member; and Joseph Shatzel, MD

The patient

An 89-year-old woman with a history of rheumatoid arthritis seropositivity presented for evaluation of febrile neutropenia. For several months, she reported recurrent skin and soft-tissue infections (SSTIs) requiring antibiotics, constitutional symptoms, and unintentional weight loss. Initial evaluation demonstrated a febrile (103 °F) elderly woman with vulvar cellulitis and severe neutropenia (absolute neutrophil count, 100 cells/µL; reference range, 1,800 to 7,700 cells/µL). Chart review revealed a progressive, isolated neutropenia first demonstrated five months prior. A detailed history failed to identify a causal nutritional deficiency or to establish a temporal relationship between medication exposures with the onset of neutropenia.

CT imaging of the patient's abdomen and pelvis showed hepatomegaly. She had a rheumatoid factor level of 341 IU/mL (reference range, <14 IU/mL) and an anti-cyclic citrullinated peptide level of 191 U/mL (reference range, 0 to 19 U/mL) despite the absence of systemic rheumatologic manifestations. Additional evaluation for micronutrient (copper, zinc) and vitamin deficiencies (folate, B12) was negative. Additional testing for potential fungal and viral exposures was unrevealing. The patient's febrile neutropenia was empirically treated with broad-spectrum antibiotics, and her hospital course was complicated by progressive neutropenia managed with granulocyte macrophage colony-stimulating factor (GM-CSF) to avoid agranulocytosis. Peripheral blood smear and peripheral flow cytometry established the presence of an abnormal population of T cells, and she was subsequently found to have anti-neutrophil antibody positivity. Systemic immunosuppression with methotrexate was initiated, followed by rituximab. In subsequent follow-up, her neutrophil counts remained low, but she was managed expectantly with as-needed GM-CSF as she did not experience recurrence of severe infection.

The diagnosis

The patient's diagnosis is T-cell large granulocytic leukemia (LGL), a clinical entity that shares a similar laboratory and clinical phenotype with Felty's syndrome. A common pathogenetic mechanism resulting in an aberrant T-cell repertoire is believed to underlie the shared clinical manifestations of neutropenia, rheumatoid arthritis, and hepatosplenomegaly. Peripheral flow cytometry helps to distinguish these diseases: dominant clonal T-cell expansion is associated with T-cell LGL, whereas oligoclonal T-cell expansions are seen in Felty's syndrome. Chronic neutropenia is the presenting feature in 84% of cases of T-cell LGL, the pathogenesis of which has been attributed to all three pathophysiologic mechanisms of neutropenia: decreased production (low GM-CSF), redistribution (reticuloendothelial sequestration), and destruction (increased apoptosis and anti-neutrophil antibody-mediated autoimmunity). As the most common circulating phagocyte, inadequate neutrophil reserves can greatly increase susceptibility to invasive infection. Recurrent infections attributed to neutropenia constitute the most common indication for treatment of T-cell LGL, which can otherwise be managed expectantly. T-cell LGL is an indolent disease with a median survival time of over 10 years. While there is no agreed-upon standard treatment for T-cell LGL, systemic immunosuppression with low-dose methotrexate can be used for treatment of both T-cell LGL and Felty's syndrome. Other first-line treatments for T-cell LGL include cyclophosphamide and cyclosporine, and there is some evidence for the use of rituximab for both first-line and refractory disease.

Pearls

  • T-cell LGL is a clinical entity sharing a common pathogenetic mechanism and clinical phenotype with Felty's syndrome, including neutropenia, rheumatoid arthritis, and hepatosplenomegaly.
  • Recurrent, invasive infections secondary to neutropenia constitute the most common indication for treatment of T-cell LGL, an indolent disease that can otherwise be managed expectantly.

Case 5: Ocular syphilis

By Justin Lewis, MD, ACP Resident/Fellow Member, and Christina Flaxel, MD

The patient

A 47-year-old man presented with six months of progressively decreasing vision in his right eye. At the time of an earlier presentation, ophthalmologic exam revealed cystoid macular edema that was treated with ocular steroids. Symptoms persisted, and he ultimately developed a right retinal detachment. After retinal surgery, his vision did not improve and he had worsening inflammation. An outpatient serological evaluation was negative for HIV, but rapid plasma reagin was 1:128 and a fluorescent treponemal antibody (FTA) test was positive, prompting hospital admission to expedite management.

At the time of hospital presentation, he reported no previously diagnosed sexually transmitted infections but did report past penile lesions and a history of high-risk sexual behaviors. Physical examination showed diffuse, pruritic, maculopapular lesions scattered throughout his body, which he noted had been present for approximately three months. Visual acuity was 20/400 in the right eye and 20/30 in the left eye, with bilateral uveitis on slit-lamp evaluation. Neurological exam was without focal deficits. Lumbar puncture showed a white blood cell count of 101,000 cells/mm3 (reference range, 0 to 5,000 cells/mm3) and 86% lymphocytes, with a cerebrospinal fluid venereal disease research laboratory (VDRL) test titer of 1:8 (reference range, nonreactive). The patient was started on IV penicillin G and continued on anti-inflammatory eye drops. During treatment, a paradoxical worsening of inflammation and macular edema was noted on optical coherence tomography (OCT) secondary to lysis of organisms and release of endotoxin-like lipoproteins (i.e., the Jarisch-Herxheimer reaction). Although OCT showed worsening of macular edema during this stage, clinical symptoms improved. The patient completed a 14-day course of IV penicillin G, with progressive improvement in his visual and dermatologic symptoms, as well as resolved cerebrospinal fluid and serum studies. Repeat OCT testing at 28 days was much improved.

The diagnosis

This patient's diagnosis is ocular syphilis. Syphilis is a systemic infection that is characterized by four clinical different stages: primary, secondary, latent, and tertiary. Ocular syphilis can develop during any stage of infection and can be difficult to diagnose given its varied presentation. While posterior uveitis and panuveitis are the most common ocular findings, ocular syphilis can involve any structure of the eye. Although ocular syphilis can present with almost any visual symptom, blurry vision and loss of vision are the two most common, followed by eye pain and redness. Ocular syphilis can be seen in patients who use recreational drugs or engage in high-risk sexual behaviors, men who have sex with men, and patients with HIV. Prompt referral to ophthalmology is recommended.

Between 2% and 5% of ocular inflammation cases at tertiary centers are due to ocular syphilis, and early recognition is key to good outcomes. The literature suggests that visual acuity improves significantly in roughly 90% of patients treated; the main factor associated with poor prognosis is a delay of 28 days or more between ocular symptoms and diagnosis. Moreover, while assessing for neurological symptoms can be helpful, the literature suggests that only one-fifth of patients with ocular syphilis have accompanying neurological symptoms. Thus, a benign neurologic exam does not exclude ocular syphilis.

Although ocular syphilis can develop during any stage of syphilis, it requires unique treatment. Whereas early syphilis is treated with one dose of intramuscular penicillin G, and late syphilis is treated with intramuscular penicillin G once a week for three weeks, ocular syphilis is most commonly treated with IV aqueous penicillin G or ceftriaxone for 10 to 14 days.

Pearls

  • Ocular syphilis can complicate any stage of syphilis infection, involve almost any eye structure, and present with a wide array of visual symptoms; prompt referral to ophthalmology is important, as favorable prognosis centers upon diagnosis less than 28 days after symptom onset.
  • Regardless of the stage of syphilis at the time of diagnosis, ocular syphilis is most commonly treated with IV aqueous penicillin G for 10 to 14 days.

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