A 34-year-old woman presents to the ED with several days of worsening abdominal pain, anorexia, nausea, and copious diarrhea. Three months ago, she had underwent matched unrelated-donor allogeneic stem cell transplant for acute lymphocytic leukemia (ALL). Examination reveals an:
She is given 30 mL/kg IVF and SBP remains in the 80s, prompting ICU admission. Laboratory test results are notable for:
Which of the following statements about the most likely diagnosis is true?
Correct Answer: B
The most likely diagnosis here is acute graft-versus-host disease (GVHD), a multisystem inflammatory attack on the host’s tissues by the grafted immune system. Risk factors include the degree of HLA mismatch and the prophylactic regimen employed posttransplant. The pathogenesis involves T lymphocytes primarily, though neutrophils and activated macrophages contribute to a lesser extent. The most common sites of acute GVHD are the GI tract, skin, and liver, and presentation typically occurs within the first few months of transplant. A grading system exists based on the extent of skin involvement, severity of diarrhea, and bilirubin elevations, with higher grades associated with reduced survival. Diagnosis may be made on clinical grounds along with the classic rash of GVHD (maculopapular, involving palms/soles), though biopsy of skin or the distal GI tract (typically not liver) may be performed in cases where infection is higher in the differential diagnosis. Although topical steroids may be effective in GVHD limited to the skin, for any signs of systemic involvement systemic glucocorticoids are indicated as first line treatment. Notably, intense immunosuppression over a prolonged period exposes the host to many risks, including a reduction in the graft-versus-malignancy effect that helps allogeneic stem cell recipients maintain long-term remissions.
References:
A 23-year-old man with pre-B ALL who had an allogeneic stem cell transplant 1 week ago is transferred to the ICU for close monitoring with neutropenic fever and mild septic shock. He improves on antibiotics, has count recovery, and discussions begin about transferring back to the floor 5 days after ICU transfer. However, the oncologists are concerned about rising direct bilirubin (up to 8 mg/dL) associated with epigastric/RUQ pain and weight gain. RUQ ultrasound reveals hepatomegaly and ascites but does not show evidence of biliary obstruction.
Which of the following is the most likely diagnosis?
Correct Answer: E
Hepatic sinusoidal obstruction syndrome (SOS, also known as venoocclusive disease) is an unusual complication of hematopoietic stem cell transplantation and involves injury to the liver venous endothelium likely from the conditioning chemotherapeutic regimen. Fibrin and factor 8 have been found in the vein walls and sinusoids, suggesting the existence of a pro-coagulant state. Risk factors include preexisting liver disease and certain chemotherapeutic agents. Most patients develop the syndrome within 3 weeks of transplant, and the clinical diagnosis is made by a combination of elevated direct bilirubin, hepatomegaly, and sudden weight gain. Important differentials to consider include Budd-Chiari, acute GVHD, viral hepatitis, and cholestatic drug reactions. Some evidence supports the use of prophylaxis with ursodiol or heparin. Management for severe disease includes the use of defibrotide, which increases plasmin activity and decreases vWF expression, though we await completion of the first phase 3 randomized controlled trial for this indication.
A 35-year-old woman who had an allogeneic BMT 10 years ago for pre-B ALL complicated by GVHD of the skin (controlled with topical steroids) presents to the ED with several months of worsening dyspnea. PFTs done a month ago revealed FEV1 of 24% predicted, FVC of 70% predicted, and FEV1/FVC of 0.35. She is afebrile, normotensive, and not hypoxemic but becomes severely dyspneic with mild activity. Chest X-ray is clear. High-resolution chest CT reveals mosaic perfusion and evidence of extensive air-trapping on expiratory views.
Which of the following statements is correct?
Correct Answer: C
This patient suffers from postallogeneic stem cell transplant bronchiolitis obliterans syndrome (BOS) resulting from the destruction of small airways by scarring inflammation, a form of chronic GVHD in the lung. A similar disease occurs in lung transplant patients (mismatch between lung and immune system). Patients may present with symptoms of moderate to severe airflow obstruction, though many patients postallogeneic SCT have mild obstructive lung disease without symptoms. BOS is diagnosed based on new airflow obstruction (FEV1/FVC <0.7 with FEV1 <75% predicted) in the absence of acute infection, with the most specific feature on high-resolution CT of extensive air trapping. Lung biopsy is typically not pursued if imaging does not suggest an alternative diagnosis, especially if the patient has other evidence of GVHD. Although no high-quality RCT evidence exists, most clinicians prescribe inhaled glucocorticoids and beta-agonists. Unfortunately, BOS is often irreversible and lung transplantation is sometimes pursued. Extrapolating from the experience in lung transplant, some physicians used to administer azithromycin post-BMT for prophylaxis. However, a recent RCT showed harm, although there may still be a role for azithromycin in the treatment of newly diagnosed BOS.
A 58-year-old man with a new diagnosis of AML receives induction chemotherapy with cytarabine and doxorubicin on the Oncology ward. About 10 days later he develops neutropenic fever in association with worsening hypoxemic respiratory failure. A chest CT is performed (see figure below) and Infectious Disease and Pulmonary are consulted, with bronchoscopy performed the following day notable for friable-appearing airways but with minimal mucous. Gram stain of BAL is unrevealing. Postbronchoscopy the patient has worsening hypoxemic respiratory failure and is transferred to the ICU and intubated. Despite the administration of vancomycin, cefepime, and voriconazole, fevers persist and hypoxemia continues to worsen, requiring high levels of ventilator support. Serial plain films of the chest show progressive whiteout on the right side. Three days postintubation the patient develops massive hemoptysis and cannot be ventilated, resulting in cardiac arrest and subsequent transition to comfort measures after discussion with family.
The BAL cultures are most likely to show:
Correct Answer: D
The chest CT reveals a cavitary nodule, which in neutropenic patients (severely immunocompromised as in this patient who recently received cytotoxic chemotherapy) is highly concerning for a fungal infection. Although lung cavitation may be seen with bacterial infection (especially Staph, Klebsiella, Nocardia, and occasionally Pseudomonas), with such a high burden of disease Gram stain is likely to be positive and the patient would likely be producing more airway secretions than described (though notably with systemic neutropenia secretions are less purulent than in an immunocompetent host.) A. fumigatus is a ubiquitous mold that causes a spectrum of disease ranging from allergic airway disease to IPA as in this case. KOH stains of respiratory secretions may reveal fungal elements; however, identification of the species requires sporulation and typically takes several days. Galactomannan is a component of Aspergillus (and other mold) cell walls and may be tested in blood and BAL. While awaiting the definitive diagnosis of species and susceptibility, some experts recommend broadening from voriconazole to liposomal amphotericin; though with the introduction of the newer antifungal azoles posaconazole and isavuconazole, this decision should involve expert consultation. Regardless of the mold drug sensitivities, drug penetration into areas of lung destruction by angioinvasive molds is poor and mortality is very high. Notably, lung resection in cases of invasive mold disease in bone marrow transplant patients has been described.
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A 63-year-old man develops acute respiratory failure after autologous stem cell transplant for lymphoma. His initial posttransplant course was notable for mucositis. Approximately 2.5 weeks posttransplant, following count recovery, he develops a dry cough and worsening arterial hypoxemia. Chest CT reveals diffuse ground glass opacities, and he is transferred to the ICU, given diuretics, and placed on high flow nasal cannula oxygen and broad-spectrum antibiotics. On ICU day 2 he is intubated for worsening work of breathing and fatigue. Bronchosopy is unremarkable, and microbiologic studies of BAL including respiratory viral PCR are unrevealing. His ventilatory settings escalate despite low-tidal volume ventilation, and after another week of mechanical ventilation, his course is complicated by multiorgan failure. Care is transitioned to comfort measures only.
Idiopathic pneumonia syndrome is a dreaded complication of hematopoietic stem cell transplantation, defined as diffuse alveolar injury in the absence of evidence of respiratory tract infection. Although the pathogenesis remains unclear, it is thought most likely to be an inflammatory reaction to the pre-transplant conditioning regimen, which may involve high-dose chemotherapy and radiotherapy. Differential considerations include viral pneumonia and diffuse alveolar hemorrhage. Many clinicians administer high-dose steroids; etanercept (TNF-alpha inhibitor) has also been studied, though no high quality evidence exists to support either treatment and the prognosis remains very poor. This patient had an autologous stem cell transplant and so cannot have developed GVHD. Infectious causes are possible despite the negative workup (eg, a viral pathogen not tested for with multiplex PCR), but fungal and bacterial infections are unlikely given the imaging and unrevealing BAL.
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