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Progressive Dyspnea and Hypoxemia With Diffuse Pulmonary Infiltrates in a Previously Healthy Woman

      Case Presentation

      A 50-year-old woman presented with 3 months of cough, dyspnea, and fatigue. She also reported new fevers, night sweats, and a rash on her face and torso. On presentation she was tachycardic and tachypneic, with oxygen saturation of 81% on 2 L/min of oxygen. She was in mild respiratory distress. Results of the physical examination were remarkable for tender left cervical and axillary adenopathy and bibasilar pulmonary crackles. She had an acneiform rash on her face, chest, and back, consisting of multiple nonblanching erythematous or violaceous macules and papules (Fig 1) and had conjunctival edema. Admission laboratory test results were significant for a WBC count of 56,000, of which 79.5% were lymphocytes. Hemoglobin and platelet levels were normal. She was admitted for further management.
      Additional focused history was negative for chest pain, hemoptysis, arthralgias, weakness, dysphagia, orthopnea, or leg swelling. She was a lifetime nonsmoker who worked as a schoolteacher and denied recent travel. She took no medications.
      The patient’s initial chest radiograph showed bibasilar consolidation (Fig 2). A high-resolution CT (HRCT) of the chest obtained shortly after admission (Fig 3) showed dense airspace consolidation, predominantly of the lower lobes, with interlobular septal thickening and air bronchograms. There were also areas of ground-glass opacity. There were no pleural effusions. There were subcentimeter axillary lymph nodes, but no supraclavicular adenopathy. Several small and borderline enlarged mediastinal and hilar lymph nodes were noted.
      Figure thumbnail gr1
      Figure 1Photograph of patient’s face showing dozens of nonblanching telangiectasias and violaceous macules coalescing into patches.
      Figure thumbnail gr2
      Figure 2Portable anteroposterior chest radiograph on presentation. Patchy bibasilar consolidations with small pleural effusions. No pneumothorax.
      Figure thumbnail gr3
      Figure 3High-resolution CT on presentation. Axial plane, 1.25-mm thickness. A-D, progress cranial to caudal, showing dense airspace consolidation predominantly of the lower lobes with interlobular septal thickening and air bronchograms. There are also patches of ground-glass opacity and some areas of sparing.
      An echocardiogram showed normal left ventricular size and function and normal diastolic function. Right atrial pressure and right ventricular size and function were normal, with an estimated right ventricular systolic pressure of 35 mm Hg.
      A bone marrow biopsy specimen was markedly hypercellular for age, with sheets of abnormal T cells positive for CD3, CD8, CD5, and CD2 while negative for CD4, CD56, CD34, and TdT. Cytogenetics indicated an abnormal karyotype, with inversion of chromosome 14. T cell gene rearrangement studies were also positive.
      We performed a bronchoscopy, which disclosed normal-appearing airways and a mild amount of thin secretions. A BAL and transbronchial biopsies were performed of the right lower lobe. Histologic examination of this tissue showed fragments of lung parenchyma with an interstitial infiltrate of small lymphocytes showing irregular nuclei, condensed chromatin, occasional nucleoli, and a small amount of cytoplasm (Fig 4). Immunostains showed the lymphocytes to be the same population as in the bone marrow. A punch biopsy of a macular purpuric lesion of the left upper chest showed an atypical perivascular T-cell infiltrate, also with the same staining pattern.
      Figure thumbnail gr4
      Figure 4Right lower lobe transbronchial biopsy. A, hematoxylin & eosin, original magnification ×10; B, hematoxylin & eosin, original magnification ×40; C, CD3 immunostain, original magnification ×20; D, CD20 immunostain, original magnification ×20. Sheets of small T cells in the interstitium with irregular nuclei, condensed chromatin, occasional nucleoli, and a small amount of cytoplasm.
      What is the diagnosis?
      Diagnosis: T-cell pro-lymphocytic leukemia with pulmonary leukemic infiltrates

      Discussion

       Clinical Discussion

      T-cell pro-lymphocytic leukemia (T-PLL) is a rare and aggressive mature T-cell leukemia. On presentation it frequently involves the liver, peripheral lymph nodes, and skin.
      • Dearden C.E.
      T-cell prolymphocytic leukemia.
      Clues in this patient’s history and physical examination, particularly the fevers and adenopathy, clearly raised concern for a hematologic malignancy before the diagnosis was definitively made by bone marrow biopsy. T-PLL has rarely been associated with symptomatic pulmonary leukemic infiltrates, with only one other case report describing this entity.
      • Blanc K.
      • Lefebvre A.
      • Chapuis N.
      • et al.
      Acute respiratory failure in a patient presenting T-cell prolymphocytic leukemia: specific leukemic lung involvement?.
      In the setting of acute leukemia, the differential diagnosis for acute respiratory insufficiency and pulmonary infiltrates is broad, as described in Table 1. Evaluation starts with a thorough medical history and physical examination and must consider the distribution of infiltrates and their timing relative to chemotherapy treatment. In the pretreatment and early (<2 weeks) treatment periods, localized infiltrates are most likely to be due to bacterial infection and diffuse infiltrates due to pulmonary edema, hemorrhage, or leukemic infiltrates.
      • Nucci M.
      • Nouer S.A.
      • Anaissie E.
      Distinguishing the causes of pulmonary infiltrates in patients with acute leukemia.
      This patient had diffuse infiltrates, but her echocardiogram did not show heart failure, and her normal platelet count and coagulation panel made pulmonary hemorrhage less likely.
      Table 1Differential Diagnosis for Pulmonary Infiltrates in Patient With Newly Diagnosed Hematologic Malignancy
      Clinical DiagnosisConsiderations in This PopulationClues on CT Scan
      InfectionBacterial, viral, and fungal pathogens possible in setting of immunosuppressionVariable, including diffuse or patchy ground glass, small nodules, tree-in-bud pattern, consolidation ± air bronchograms, cavitation
      Diffuse interstitial lung diseaseImmunomodulators and chemotherapyVariable, including diffuse or patchy ground glass, subpleural reticulation, air trapping, nodules, fibrosis
      Cardiogenic pulmonary edemaCardiomyopathy from prior chemotherapy or immunotherapyInterlobular septal thickening, dependent ground glass, effusions
      Pulmonary alveolar proteinosisAssociated with hematologic malignancy itself or treatment-related immunosuppressionSmooth intralobular and interlobular septal thickening, patchy or geographic ground glass (“crazy paving”)
      Acute pulmonary hemorrhageIncreased risk with thrombocytopeniaRange from ground glass to consolidation
      Pulmonary leukostasisRisk highest when WBC count >100,000Findings of pulmonary edema due to vascular obstruction
      Pulmonary leukemic infiltratesOften seen on pathology specimens in absence of clinical or radiographic findingsVariable including ground glass opacities, consolidation, thickening of bronchovascular bundle, centrilobular nodules
      Acute cell lysis pneumopathyUsually occurs 1-3 days after chemotherapy in patients with hyperleukocytosis, concurrent with tumor lysis syndromeFindings of ARDS, including bilateral ground glass infiltrates and consolidation
      Transfusion-related acute lung injuryAppropriate history of recent transfusionFindings of pulmonary edema
      Pulmonary graft-vs-host diseaseMay be acute or chronicAcute: nodules, diffuse fibrosis

      Chronic: patchy ground glass (organizing pneumonia) or bronchial wall thickening, ground glass, air trapping (bronchiolitis obliterans)
      Pulmonary infarctionCT angiogram preferred for diagnosisOn noncontrast CT scan, may find wedge-shaped opacification representing infarct, halo representing hemorrhage, low attenuation, cavitation
      Later in the treatment phase, with increasing immunocompromise, infiltrates are more likely to represent opportunistic infections, which are not usual in the pretreatment period
      • Tenholder M.F.
      • Hooper R.G.
      Pulmonary infiltrates in leukemia.
      and must be identified because they can lead to rapid deterioration. In addition to bacteria, local infiltrates may be attributable to fungi such as mucormycosis, aspergillus, and Fusarium, and may show the halo sign or cavitation on imaging.
      • Nucci M.
      • Nouer S.A.
      • Anaissie E.
      Distinguishing the causes of pulmonary infiltrates in patients with acute leukemia.
      Viruses such as cytometalovirus and metapneumovirus and the fungus Pneumocystis may cause diffuse infiltrates. Pulmonary alveolar proteinosis (PAP), which may cause diffuse infiltrates in patients with hematologic malignancy because of diminished granulocyte-macrophage colony-stimulating factor, is itself associated with opportunistic infections, including Nocardia and mycobacterial pathogens.
      • Punatar A.D.
      • Kusne S.
      • Blair S.J.
      • Seville M.T.
      • Vikram H.R.
      Opportunistic infections in patients with pulmonary alveolar proteinosis.
      Other diagnoses, such as pulmonary graft-vs-host disease, transfusion-related acute lung injury, and pulmonary or cardiac toxicity from immunotherapy or chemotherapy, also must be considered in a patient treated for leukemia, but this did not apply to the patient at the time of her presentation.
      Pulmonary embolism (PE) should always be considered in a patient with malignancy and respiratory distress or hemodynamic instability. We did not rule out a PE with dedicated imaging in this patient because her CT chest findings were not characteristic of PE, and we believed the extensive consolidations would be able to generate a shunt fraction large enough to explain her hypoxemia.
      A patient’s rash should be carefully appraised, because its duration, distribution, and features may suggest a particular underlying condition. The differential diagnosis for this patient’s rash was initially very broad, as many causes of lung disease, including infectious, autoimmune, and malignant pathologic conditions, also cause characteristic rashes,
      • Franquet T.
      • Gimenez A.
      • Caceres J.
      • Sabate J.M.
      • Nadal C.
      Imaging of pulmonary-cutaneous disorders: matching radiologic and dermatologic findings.
      as documented in Table 2. After the patient’s diagnosis of T-PLL, the differential diagnosis for the rash was narrowed to cutaneous small vessel vasculitis, leukemia cutis, and hypergammaglobulinemic purpura of Waldenstrom, a benign skin finding of tender purpura associated with hypergammaglobulinemia. Cutaneous involvement occurs in one third of T-PLL cases, with presentations including facial plethora, total body erythroderma, conjunctival involvement, and periorbital petechial.
      • Ventre M.O.
      • Bacelieri R.E.
      • Lazarchick J.
      • Pollack R.B.
      • Metcalf J.S.
      Cutaneous presentation of T-cell prolymphocytic leukemia.
      The diagnosis of leukemia cutis in this patient was made by biopsy as described previously.
      Table 2Differential Diagnosis for Presentation With Skin Rash and Pulmonary Infiltrates
      Clinical SyndromeSkin FindingsCharacteristics of Infiltrates
      Bacterial sepsis complications, including DIC, TTP, and septic emboli from IEViolaceous nonblanching patches or plaques (purpura), which may be in branching pattern (retiform) or widespread (fulminans)Findings of pneumonia (can include ground glass, consolidations, effusions, adenopathy); septic emboli are usually peripheral nodular opacities with cavitation; lung or extrapulmonary infection can lead to ARDS with diffuse bilateral ground glass opacities; alveolar hemorrhage may be central predominant consolidation
      Systemic bacterial infectionsVarious classic findings include red macule progressing to ulcer with central necrosis (ecthyma gangrenosum) in Pseudomonas bacteremia, target lesions (erythema multiforme) in Mycoplasma pneumoniae; cellulitis, nodules, or abscess in Nocardia species; and othersFindings of bacterial pneumonia include patchy, nodular, or diffuse ground glass that may cavitate, possibly effusions; atypical pneumonia is most commonly unilateral or bilateral patchy opacities
      Mycobacteria tuberculosis (TB)A variety of findings from direct or hematogenous spreadHilar adenopathy, infiltrates including nodules that can cavitate, effusions; disseminated/military TB demonstrates diffuse small nodules
      Viral infectionsVesiculopustular lesions or nonspecific rashViral pneumonitis, usually diffuse/patchy ground glass
      HIVVariety of skin lesions may be found, depending on degree of immunocompromise and disease complicationsVariety of pulmonary findings are based on patient’s level of immunocompromise, including signs of bacterial or fungal infection, interstitial lung disease, or malignancy
      Fungal infectionsVariety of lesions, including papules, plaques, nodules, abscessesVariety of infiltrates, often cavitary or necrotic nodules, aspergillus has characteristic “halo” surrounding nodules, histoplasmosis includes large possibly necrotic lymph nodes
      Autoimmune
      Connective tissue diseaseClassic findings include hard, thick skin in systemic sclerosis (SSc), “butterfly rash” in systemic lupus erythematosus (SLE), xerosis and pruritis in Sjogren’s syndrome, firm painless subcutaneous nodules in rheumatoid arthritis (RA), scaly Gottron’s papules on dorsal hands or rash on chest or back in dermatomyositis (DM), and thick/cracked mechanic’s hands in DM or polymyositis (PM)Findings of idiopathic interstitial pneumonias including diffuse, patchy, or reticular ground glass or fibrotic changes in a variety of patterns, including UIP, NSIP, OP, AIP, and others; Sjogren’s syndrome is particularly associated with LIP and possibly cysts; RA may show rheumatoid nodules, which are usually subpleural and may be solid or cavitary
      Pauci-immune vasculitisGranulomatosis with polyangitis (GPA) and microscopic polyangitis (MPA) may cause purpura accompanied by ulceration and necrosis; eosinophilic granulomatosis with polyangitis (EGPA) can cause tender subcutaneous nodules on extensor surfaces or maculopapular rashIn GPA and MPA, diffuse or patchy opacities, possibly in UIP or NSIP pattern, often nodules that may be cavitary, and hilar adenopathy as well as upper airway destructive abnormalities; EGPA may have nonspecific pulmonary infiltrates, nodules, or effusions but more commonly airway disease
      Malignant
      Cutaneous metastasesPapules, plaques, nodules, or ulcers from hematogenous, lymphatic, or direct spreadFindings of primary lung cancer or metastases to the lung, which may include nodules, effusions, or adenopathy
      ParaneoplasticVariety, including hyperkeratosis, bullae, findings of vasculitisFindings of primary lung cancer or metastases to the lung, which may include nodules, effusions, or adenopathy
      Leukemia cutisViolaceous papules, nodules, or plaquesVariety may include ground glass or consolidation from leukemic infiltrates or findings of associated pathologic conditions
      Other
      SarcoidosisPapular or nodular lesions often involving the face or trunk; lupus pernio is violaceous plaques predominantly on the face; erythema nodosum is painful nodules on the shins, may be pigmentedFindings may include hilar adenopathy, reticular opacities, peribronchial nodules, or fibrotic changes
      ThrombocytopeniaPetechia, purpura, ecchymosesAlveolar hemorrhage appears as predominantly central or dependent airspace consolidation
      AIP = acute interstitial pneumonia; DIC = diffuse intravascular coagulation; IE = infective endocarditis; LIP = lymphocytic interstitial pneumonia; NSIP = nonspecific interstitial pneumonia; OP = organizing pneumonia; TTP = thrombotic thrombocytopenic purpura; UIP = usual interstitial pneumonia
      The finding of leukemic cells infiltrating the interstitium on transbronchial biopsy suggested that the abnormal cells themselves were the source of the impaired oxygen diffusion. Leukemic infiltrates signify organ involvement, but it must be noted that the migration of circulating leukemic cells into the pulmonary interstitium is relatively common and is not always clinically significant.
      • Bodey G.P.
      • Powell R.D.
      • Hersh E.M.
      • Yeterian A.
      • Freireich E.J.
      Pulmonary complications of acute leukemia.
      The diagnosis of pulmonary leukemic infiltrates as the cause of this patient’s respiratory symptoms and hypoxemia, however, was strongly supported by a rapid decrease in her oxygen requirement after the initiation of dexamethasone at 40 mg, which correlated with a dramatic decrease in WBC count.
      Concurrent with 3 days of high-dose dexamethasone, she began chemotherapy in the hospital with cyclophosphamide, fludarabine, and mitoxantrone. Her rash and conjunctival edema improved in response. She was discharged on oxygen at 4 L/min. After 4 months of treatment, her dyspnea and hypoxemia resolved, and follow-up imaging showed near complete resolution of infiltrates (Fig 5). She was treated with further chemotherapy as an outpatient and subsequently underwent a successful allogeneic stem cell transplant.
      Figure thumbnail gr5
      Figure 5CT scan 4 months after hospital discharge, showing near complete resolution of pulmonary infiltrates.

       Radiologic Discussion

      As shown in Table 1, characteristics of infiltrates on chest imaging can help revise the differential diagnosis and plan further diagnostics. This patient’s infiltrates were bilateral and diffuse and included areas of ground glass as well as consolidation. These findings can be seen with viral or bacterial infections and are less likely with fungal infections, which are usually patchier in appearance.
      • Demirkazik F.B.
      • Akin A.
      • Uzun O.
      • Akpinar M.G.
      • Ariyurek M.O.
      CT findings in immunocompromised patients with pulmonary infections.
      Other possible causes based on this pattern include inflammation, such as from drug toxicity or an idiopathic interstitial pneumonia, and alveolar filling, such as by blood, fluid, or protein. The HRCT did not show pulmonary vascular congestion or effusion, making cardiogenic pulmonary edema less likely. Absent were tree-in-bud opacities, which could indicate small airways disease, and mosaic attenuation, which suggests air trapping as seen in hypersensitivity pneumonitis.
      In a retrospective review of imaging in adults with T-cell leukemia or lymphoma, the CT scans showed predominantly ground-glass opacities (62%), centrilobular nodules (42%), thickening of the bronchovascular bundles (37%), and consolidation (22%).
      • Okada F.
      • Ando Y.
      • Kondo Y.
      • Matsumoto S.
      • Maeda T.
      • Mori H.
      Thoracic CT findings of adult T-cell leukemia or lymphoma.
      Thus, the patient’s HRCT findings were in keeping with those previously seen but too nonspecific to narrow the differential.
      Attempts have been made to characterize the radiographic findings associated with pulmonary leukemic infiltrates. One study compared HRCT findings in patients with pulmonary leukemic infiltrates with those in control subjects. Compared with control subjects, patients with leukemic infiltrates had significantly more frequently observed peribronchovascular thickening and prominence of peripheral pulmonary arteries, which correlated on biopsy with the presence of leukemic cells in these structures.
      • Tanaka N.
      • Matsumoto T.
      • Miura G.
      • et al.
      CT findings of leukemic pulmonary infiltration with pathologic correlation.
      This patient’s HRCT did not show thickening of the bronchovascular bundle, but instead showed airspace consolidation that extended to the periphery with normal vasculature. The particular structures that show changes radiographically may depend on the extent and duration of the patient’s leukocytosis and pulmonary infiltration.

       Pathologic Discussion

      As noted, the differential diagnosis for the pulmonary infiltrates comprised infection, including unusual and opportunistic pathogens, an inflammatory process such as organizing pneumonia, alveolar hemorrhage, PAP, and leukemic involvement. A bronchoscopy was indicated for further evaluation because a BAL sample could be sent for culture, particularly for organisms that can be difficult to culture from noninvasive samples, such as Nocardia species, and stained, for example, for Pneumocystis carinii. Serial BAL aliquots with hematocrit measurement can rule out alveolar hemorrhage. We performed transbronchial biopsies in addition to BAL, because transbronchial biopsy has been demonstrated to be an effective way of establishing a diagnosis in an immunocompromised patient with lung infiltrates,
      • Jain P.
      • Sandur S.
      • Meli Y.
      • Arroliga A.C.
      • Stoller J.K.
      • Mehta A.C.
      Role of flexible bronchoscopy in immunocompromised patients with lung infiltrates.
      and it is superior to BAL in diagnosing neoplastic infiltrates.
      • Mulabecirovic A.
      • Gaulhofer P.
      • Auner H.W.
      • et al.
      Pulmonary infiltrates in patients with haematologic malignancies: transbronchial lung biopsy increases the diagnostic yield with respect to neoplastic infiltrates and toxic pneumonitis.
      Biopsy specimens enabled tissue culture and evaluation for invasive fungal elements, inflammatory patterns, periodic acid-Schiff-positive material indicating PAP, and malignant cells.
      Detection of a pulmonary infection would have impacted the initiation of steroids or chemotherapy. Conversely, if PAP had been diagnosed, it likely would not have changed management, because PAP secondary to a hematologic malignancy is usually managed by treating the malignancy, although the customary whole-lung lavage may be considered.
      • Chaulagain C.P.
      • Pilichowska M.
      • Brinckerhoff L.
      • Tabba M.
      • Erban J.K.
      Secondary pulmonary alveolar proteinosis in hematologic malignancies.
      The treatment plan for the leukemia itself was not modified by the presence of pulmonary leukemic infiltrates, because the patient already met the criteria for “active” T-PLL based on other systemic findings such as B symptoms and skin involvement.
      Although sometimes their detection is incidental, symptomatic leukemic infiltrates may be diagnosed as the cause of a patient’s respiratory failure when aggregates of leukemic cells are seen in septal, perivascular, or peribronchial distributions in the presence of specific clinical and hematologic criteria.
      • Kovalski R.
      • Hansen-Flaschen J.
      • Lodato R.
      • Pietra G.
      Localized leukemic pulmonary infiltrates: diagnosis by bronchoscopy and resolution with therapy.
      This patient’s interstitium was densely infiltrated with sheets of abnormal lymphocytes, consistent with this distribution. The presence of leukemic cells predominantly in the pulmonary vasculature would have suggested the diagnosis of leukostasis instead,
      • Porcu P.
      • Cripe L.D.
      • Ng E.W.
      • et al.
      Hyperleukocytic leukemias and leukostasis: a review of pathophysiology, clinical presentation and management.
      although it can be difficult to differentiate between cells simply traversing the blood vessels and cells causing vascular obstruction, particularly in transbronchial biopsy samples, which contain only small vessels. Leukostasis was thought to be unlikely because it is not common in mature leukemias, and the patient’s WBC count was not sufficiently elevated.
      Not surprisingly, the same population of abnormal lymphocytes was present in this patient’s bone marrow, circulating blood, subcutaneous chest wall tissue, and alveoli, as detected by BAL cytology. As described, although any of these findings may have helped make the diagnosis of T-PLL, the pulmonary diagnosis of leukemic infiltrates required a broad differential and further diagnostics.

      Conclusions

      Pulmonary leukemic infiltrates associated with T-PLL or other hematologic malignancy may cause a clinical syndrome of dyspnea and hypoxemia. Chest imaging is unlikely to show findings specific to the diagnosis of pulmonary leukemic infiltrates but may enable the exclusion of other pathologic conditions. The differential diagnosis for a rash accompanying pulmonary infiltrates is broad, but characteristics of the rash and radiologic findings may help identify the cause. The presence of interstitial or alveolar leukemic cells on biopsy specimens may be incidental but may be the culprit if other pathologic conditions have been effectively excluded. Treatment of symptomatic pulmonary leukemic infiltrates is focused on addressing the underlying malignancy.

      Acknowledgments

      Financial/nonfinancial disclosures: None declared.
      Other contributions: CHEST worked with the authors to ensure that the Journal policies on patient consent to report information were met.

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