The patient had a past history of diffuse proliferative lupus nephritis (WHO Class IV) which was resistant to treatment with high dose corticosteroids, cyclophosphamide and mycophenolate mofetil. She was enrolled in an approved study of autologous HSCT for patients with refractory systemic lupus erythematosus (http://clinicalstudies.info.nih.gov/cgi/wais/bold032001.pl?B_04-C-0095.html
). After receiving a conditioning regimen consisting of fludarabine, cyclophosphamide, and rituximab, she received a T-cell depleted autologous HSCT.
The patient was admitted to the Clinical Center at the National Institutes of Health 11 weeks after transplant with dyspnea and cough (see for a summary of her clinical course). A CT scan showed no pulmonary disease and she was discharged 6 days later after improvement on bronchodilators.
Figure 1 Hospital course. Critical events during the patient’s hospitalizations are indicated, including use of antiviral and cytotoxic drugs. Cultures obtained at lung biopsy, BAL, and NP (nasopharyngeal) wash are denoted by circles. Closed circles represent (more ...)
The patient was readmitted to the National Institutes of Health Clinical Center 13 weeks after transplant with dry cough and dyspnea on exertion, nasal congestion, rhinorrhea, and postnasal drip. Her 9 year-old daughter and 5 year-old son had had “a cold” one after another in the previous week, and cases of influenza were reported at their school. Physical examination showed a mildly cushingoid young woman with tachypnea and a constant cough. Her temperature was 36°C, blood pressure 105/55, respiratory rate 24/min, pulse 82/min. Pulmonary examination showed disseminated wheezing and rhonchi and the remainder of the examination was unremarkable. The white blood cell count was 6,950/ml with 75% neutrophils and 19% lymphocytes, the hemoglobin was 11.1 gm/dL, and the platelet count was 107,000/ml. Creatinine was 1.4 mg/dl, total protein was 4.9 gm/dL, and albumin was 3.1 gm/dL. The arterial blood gas on 35% oxygen showed hypoxemia, with a pO2 of 62 mm Hg, a pCO2 of 26 mm Hg, and a pH of 7.35. A CT scan of the lungs performed at the time of this admission showed bilateral pleural effusions and patchy areas of nodular infiltration of the lungs, involving all of the lobes.
A nasopharyngeal wash grew influenza A H3N2 (later shown to be oseltamivir-sensitive), and was negative for influenza B, respiratory syncytial virus, parainfluenza viruses 1–3, and adenovirus. Induced sputum showed a few neutrophils and gram positive cocci in pairs and clusters and gram negative rods. Fungal and mycobacterial cultures were negative. Because the differential diagnosis included influenza infection and lupus pneumonitis, she was begun on oseltamivir 75 mg twice daily and her prednisone was increased to 20 mg daily. A repeat CT scan after 8 days of treatment showed no improvement. Bronchoalveolar lavage (BAL) fluid grew influenza A virus, and was negative for bacteria, fungi, mycobacteria, pneumocystis, mycoplasma, chlamydia, legionella, cytomegalovirus and herpes simplex virus. A thoracentesis showed an exudate with 395 white blood cells/mm3 with 26% neutrophils, 4% lymphocytes, 140 red blood cells/mm3, and 70% other cells. The albumin was 1.9 gm/dL (serum albumin 2.5 g/dL), LDH was 136 U/L (serum LDH 242 U/L), and glucose was 73 mg/dL. No organisms were identified by microscopy or by culture. Due to worsening pulmonary infiltrates, open lung biopsies were performed on day 15 of the hospitalization. The right lung showed diffuse alveolar damage with hyaline membranes (). Stains for fungus, acid fast bacilli, pneumocystis, and cytomegalovirus were negative. Cultures for viruses, including influenza were negative. Immunohistochemistry of the lung tissue was negative for influenza and adenovirus.
Lung biopsy. Hematoxylin and eosin staining of right lung biopsy obtained at week 15 post-transplant.
Due to continued concerns about potential lupus pneumonitis based on the nonspecific results of the lung biopsy, the dose of steroids was increased to methylprednisolone 60 mg daily. Oseltamivir was discontinued after 21 days (16 weeks after transplant). Initially, her oxygenation improved and the dose of methylprednisolone was decreased; however, her hypoxemia subsequently worsened. Since repeat nasopharyngeal washes and BAL fluid continued to grow influenza, oseltamivir was reinstituted at 150 mg twice daily on the 29th
hospital day (17 weeks after transplant). Intravenous immune globulin (IVIG) was administered and steroids were continued; because an antiviral sensitivity test subsequently showed high level (IC50
=770 nM, 14,000-fold increase) oseltamivir resistance, oseltamivir was discontinued and inhaled zanamivir was begun. A CD4 count obtained 20 weeks after transplant was 135 (normal range 385–1259). The patient was discharged from the hospital on zanamivir and a tapering dose of steroids at week 21 after transplant. The steroids were reinstituted when her infiltrates worsened and her pulmonary effusions returned. After improvement of her pulmonary status, steroids were again tapered. Sequencing of the oseltamivir-resistant H3N2 influenza virus isolate A/Bethesda/956/2006 showed an arginine to lysine mutation in the neuraminidase at amino acid 292, a mutation previously shown to be associated with oseltamivir resistance (2
) and with diminished viral fitness in animal experiments and instability in vitro
The patient was readmitted three weeks later (24 weeks after transplant) with worsening pulmonary infiltrates. Zanamivir was continued because nasopharyngeal washes continued to grow influenza virus, although BAL fluid culture was negative for respiratory pathogens including influenza virus. Ribavirin was added in view of her increasing pulmonary infiltrates and persistent shedding of influenza virus from her nasopharynx (which was suggestive of reduced sensitivity of the influenza virus to zanamivir). Cyclophosphamide was added in the final week of life, because of persistent concerns about lupus pneumonitis and worsening of her pulmonary status on tapering doses of corticosteroids. Empiric antibacterials and antifungals were added. The patient died 27 weeks after transplant of hypotension and cardiac arrest.
At autopsy, the lungs showed bronchopneumonia, organizing pneumonitis, and diffuse alveolar damage. BAL fluid and lung tissue both obtained at autopsy were negative by culture for influenza, parainfluenza viruses 1–3, adenovirus, respiratory syncytial virus, bacteria, fungi, mycobacteria and nocardia. Immunohistochemistry of lung tissue was negative for influenza and adenovirus.