Bernard Tegtmeier

The value of bronchoalveolar lavage and bronchial washings in the diagnosis of invasive pulmonary aspergillosis

The objective of this study was to clarify conflicting reports of the sensitivity and specificity of bronchoalveolar lavage or bronchial washings for diagnosing invasive pulmonary aspergillosis. The study was a retrospective review of 300 consecutive patients in a tertiary referral centre subjected to 343 fiberoptic bronchoscopic procedures for the evaluation of pulmonary infiltrates. Classification of paired fungal culture and cytologic examination of bronchoalveolar lavage or bronchial washing fluid according to clinical, radiographic, histological and autopsy evidence of invasive pulmonary aspergillosis. One-hundred and fifteen deaths occurred, with a 58% autopsy rate. A diagnosis of invasive pulmonary aspergillosis was made in 21 immunosuppressed patients with 16 deaths. Bronchoalveolar lavage cytology showed aspergillus in 19 specimens (invasive pulmonary aspergillosis in 16), cultures yielded aspergillus in 41 (invasive pulmonary aspergillosis in ten), with both tests positive in nine. Cytology sensitivity was 64.0%, specificity 99.1%, positive predictive value 84.2%, and negative predictive value 97.2%. Culture sensitivity was 40.0%, specificity 90.3%, positive predictive value 24.4%, and negative predictive value 95.0%. Concordant cytology and culture sensitivity was 32.0%, specificity 99.7%, positive predictive value 88.9%, and negative predictive value 94.9%. In conclusion, when characteristic hyphae are visualized in bronchoalveolar lavage specimens from immunosuppressed patients with compatible clinical data, it is advisable to treat for presumptive invasive pulmonary aspergillosis.

Late Cytomegalovirus Disease in Marrow Transplantation Is Predicted by Virus Load in Plasma

Late occurrence of cytomegalovirus (CMV) disease after day 100 after bone marrow transplantation has become an increasing problem; whether a quantitative measurement of CMV DNA in plasma by polymerase chain reaction (P-PCR) could be predictive of such disease was investigated. In a prospective study, 117 subjects undergoing allogeneic marrow transplantation were followed for 120 days with weekly CMV blood cultures, with day 35 bronchoalveolar lavage CMV cultures, with weekly CMV P-PCR, and with clinical follow-up for an additional 1-2 years. Despite preemptive ganciclovir, CMV disease occurred in 9% of subjects, with a median time of onset of 176 days. Quantitative CMV P-PCR was associated with the late development of CMV disease (P = .01). Of 43 subjects with positive P-PCR results, 23% developed CMV disease, but no disease occurred in the 74 subjects with negative P-PCR (P < .001), despite the fact that 22% had CMV isolated from lung lavage fluid and 32% had CMV isolated from blood.

Voriconazole Serum Concentrations in Obese and Overweight Immunocompromised Patients: A Retrospective Review

To evaluate the relationship between voriconazole dose and corresponding serum concentrations in obese and overweight immunocompromised patients.

Increased Programmed Death-1 Molecule Expression in Cytomegalovirus Disease and Acute Graft-versus-Host Disease after Allogeneic Hematopoietic Cell Transplantation

To study the role of the programmed death-1 molecule (PD-1) in cytomegalovirus (CMV) infection and disease after allogeneic hematopoietic cell transplantation (HCT), 206 subjects were followed prospectively for immune response to CMV and assigned to 3 groups based on CMV outcome. The subjects were analyzed retrospectively for PD-1 expression in cryopreserved CD4+ and CD8+T cells collected at days 40, 90, 120, 150, 180, and 360 posttransplantation. HCT recipients with CMV disease (n=14) were compared with recipients with prolonged CMV infection, but no CMV disease (median duration of infection, 3 months; n=14) and with controls with no CMV infection who received similar transplants (n=22). The CMV disease group had a significantly higher mean fluorescein intensity of PD-1 in CD4+ (P < .05) and CD8+ (P < .05) lymphocytes at all time points studied. PD-1 expression also was significantly elevated in those with severe acute graft-versus-host disease (aGVHD), including the no-viremia group. The data suggest that PD-1 is induced by aGVHD even in the absence of CMV infection. This enhanced PD-1 expression during severe aGVHD and with CMV reactivation could explain the known role of aGVHD as a risk factor for CMV disease.

Brief Report: Nosocomial Infection Rates in a Cancer Treatment Center

This report describes the results of a prospective study of nosocomial infection in 7,714 patients hospitalized during a 24-month period at a cancer treatment center. An overall nosocomial infection rate of 9.3% was observed with site-specific infection rates of 2.6% for urinary tract, 1.9% for surgical wound, 2.2% for bacteremia and 1.9% for respiratory tract infection. Within specific patient groups, the overall nosocomial infection rates observed were: 8.2% in medical patients, 14.9% in surgical patients and 1.5% in pediatric patients. Despite the markedly elevated nosocomial infection rate in surgical patients (P less than 0.001), surgical wound infection rates were not unlike those observed in general hospitals: clean-2.4%, clean contaminated-5.8%, contaminated-13.2%, and dirty-11.8%. These observations provide evidence that institutions which provide medical care predominantly for cancer patients can expect to observe higher nosocomial infection rates than general care hospitals.

Impact of pretransplant serum ferritin level on risk of invasive mold infection after allogeneic hematopoietic stem cell transplantation.

Invasive mold infections (IMI) are life‐threatening complications of allogeneic hematopoietic stem cell transplantation (HSCT) and are mostly caused by Aspergillus species and Mucorales. We examined whether elevated serum ferritin prior to HSCT was associated with increased risk of IMI after allogeneic HSCT. Elevated serum ferritin was defined as values ≥1000 ng/mL. Pretransplant ferritin levels were available for 477 transplants. Nine developed IMI at day 30 and 21 had IMI at day 100 for a cumulative incidence of 1.9% and 4.4%, respectively. Among the high ferritin group, eight of 220 transplant cases (3.6%) developed an IMI within 30 d after HSCT compared with one of 257 (0.4%) in the low ferritin group (P = 0.01). Fourteen of 220 (6.4%) and seven of 257 transplant cases (2.7%) in the high and low ferritin groups, respectively, had developed an IMI by day 100 after HSCT (P = 0.07). Nine of 53 (17%) patients with grades III and IV acute GVHD and iron overload experienced IMI, when compared to three of 37 (8.1%) with high‐grade aGVHD, but no iron overload. Among patients without aGVHD, those with elevated ferritin had a 2.7% incidence of IMI compared with 0.9% for patients without elevated ferritin. There was a marginally significant difference in cumulative incidence function between high and low ferritin groups for IMI (P = 0.06). However, elevated serum ferritin (≥1000 ng/mL) was not a significant risk factor for IMI in a multivariate competing risk regression model after adjusting for aGVHD.

Survival following lung resection in immunocompromised patients with pulmonary invasive fungal infection.

OBJECTIVES Pulmonary invasive fungal infections (IFIs) are associated with high mortality in patients being treated for haematological malignancy. There is limited understanding of the role for surgical lung resection and outcomes in this patient population. METHODS This is a retrospective cohort of 50 immunocompromised patients who underwent lung resection for IFI. Patient charts were reviewed for details on primary malignancy and treatment course, presentation and work-up of IFI, reasons for surgery, type of resection and outcomes including postoperative complications, mortality, disease relapse and survival. Analysis was also performed on two subgroups based on year of surgery from 1990-2000 and 2001-2014. RESULTS The median age was 39 years (range: 5-64 years). Forty-seven patients (94%) had haematological malignancies and 38 (76%) underwent haematopoietic stem cell transplantation (HSCT). Surgical indications included haemoptysis, antifungal therapy failure and need for eradication before HSCT. The most common pathogen was Aspergillus in 34 patients (74%). Wedge resections were performed in 32 patients (64%), lobectomy in 9 (18%), segmentectomy in 2 (4%) and some combination of the 3 in 7 (14%) for locally extensive, multifocal disease. There were 9 (18%) minor and 14 (28%) major postoperative complications. Postoperative mortality at 30 days was 12% (n = 6). Acute respiratory distress syndrome was the most common cause of postoperative death. Overall 5-year survival was 19%. Patients who had surgery in the early period had a median survival of 24 months compared with 5 months for those who had surgery before 2001 (P = 0.046). At the time of death, 15 patients (30%) had probable or proven recurrent IFI. Causes of death were predominantly related to refractory malignancy, fungal lung disease or complications of graft versus host disease (GVHD). Patients who had positive preoperative bronchoscopy cultures had a trend towards worse survival compared with those with negative cultures (hazard ratio: 1.80, P = 0.087). CONCLUSIONS Surgical resection of IFI in immunocompromised patients is associated with high perioperative mortality. Long-term survival is limited by recurrent malignancy, persistent fungal infection and GVHD but has improved in recent years. Selection for surgical resection is difficult in this patient population, but should be carefully considered in those who are symptomatic, or have failed antifungal treatment.

Chronic Leptomeningitis and Spinal Intradural Mass Secondary to Alternaria Infection in a Patient with Ventriculoperitoneal Shunt

Fungal infection following placement of ventriculostomy or ventriculoperitoneal (VP) shunt is uncommon. We report the first case of Alternaria related central nervous system (CNS) shunt infection in a patient with CNS ependymoma manifesting as leptomeningitis and a spinal intradural mass. This case illustrates the diagnostic and management challenges.

Abstract P1-10-19: Skin, and nail, infections associated with the addition of pertuzumab to trastuzumab-based chemotherapy

Objectives: We have maintained a local registry of skin and nail infections in patients receiving pertuzumab and trastuzumab as treatment for HER2 positive breast cancer. Over the past 16 months, we have continued to observe an increase in infectious complications in patients receiving the combination of pertuzumab and trastuzumab with or without chemotherapy. We expand a series of prospectively identified patients who developed infections while on these regimens. Methods: We became concerned about an increased incidence of infections shortly after the FDA approval of pertuzumab, and created an IRB approved registry of these patients. Results: Twenty-eight women were identified to have 32 separate infections (often at more than one site); 9 after cycle 1; 6 after cycle 2, 9 after cycle 3 and 8 after 4 or more cycles. The median age was 51 (Range 25-67); 14 received pertuzumab, trastuzumab, carboplatin, and docetaxel (PTCH), 5 pertuzumab, trastuzumab, and docetaxel, 7 pertuzumab, trastuzumab, and nab-paclitaxel, and 2 pertuzumab and trastuzumab. Folliculitis of the scalp, abdomen, and/or buttocks was observed in 19 patients, abscesses in 8 patients (4 of whom required incision and drainage) and cellulitis in 2. Severe paronychial infections involving one to 16 digits were observed in 4; 2 pt required surgical removal of 2 nails. Quantitative immunoglobulins were found to be low in 8 of 17 women tested; 2 patient had low total protein but did not have an assessment of quantitative immunoglobulins. All patients were initially treated with oral antibiotics, and 6 required hospitalization. Cultures were obtained in 10 patients; Staphylococcus aureus was identified in 4, methicillin resistant Staphylococcus aureus (MRSA) in 5, Enterococcus faecalis in 1. A 57 year old pt receiving neoadjuvant PTCH died on cycle 2 day 7. Autopsy was consistent with sepsis and gram positive cocci were identified. A 62 year old became septic and developed renal failure. Skin biopsies were performed in 3 patients and are consistent with changes associated with EGFR inhibition. Conclusions: We believe these infections are a result of combining pertuzumab with trastuzumab as 2 pts received no concurrent chemotherapy. An awareness of this complication is critical as some infections may be life-threatening. We have initiated patient education to ensure awareness of this potential complication. Citation Format: Mortimer JE, Yuan Y, Jung J, Kruper L, Stewart D, Chung S, Yu WK, Mendelsohn M, D9Apuzzo M, Tegtmeier B, Dadwal S. Skin, and nail, infections associated with the addition of pertuzumab to trastuzumab-based chemotherapy. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-10-19.

Abstract P4-15-21: Skin infections associated with the addition of pertuzumab to trastuzumab-containing chemotherapy

Objectives: The addition of pertuzumab, to trastuzumab-based chemotherapy is currently considered first-line therapy for locally advanced and metastatic disease HER2 positive breast cancer and has also been suggested for use in the adjuvant setting. Over the past 12 months, we have observed an increase in the incidence of severe skin infections in patients receiving chemotherapy with pertuzumab and trastuzumab. We report the natural history of what we believe is a previously unrecognized toxicity of these regimens. Methods: Shortly after the FDA approval of pertuzumab, our clinical team appreciated an increase in invasive skin infections. We discussed this concern and identified new cases at our weekly research meeting, keeping a log of cases as they were identified. Infection control reviewed the individual patient and hospital data during this time period. Results: Eleven women were identified to have severe skin and/or nail infections; 6 after cycle 1; 2 after cycle 2, 1 after cycle 3 and 2 after cycle 6. The median age was 51 (Range 46-64); 9 received pertuzumab, trastuzumab, carboplatin, and docetaxel (PTCH) and 2 pertuzumab, trastuzumab, and docetaxel. Folliculitis of the scalp, abdomen, and/or buttocks were observed in 4 patients. Abscesses were observed in 5 patients, 4 of whom required incision and drainage. Severe paronychial infections involving one to 16 digits were observed in 3 (including one who also had folliculitis). 1 pt required surgical removal of 2 nails. Quantitative immunoglobulins were found to be low in 2 of 8 women tested; 1 patient had a total protein of 4.7 but did not have an assessment of quantitative immunoglobulins. All patients were initially treated with oral antibiotics, but 3 required hospitalization. Cultures were obtained on 6 patients, Staph aureus was identified in 2 and methicillin resistant Staph (MRSA) in 4. All patients resolved their infections and 9 of 10 were able to complete six cycles of chemotherapy. Infection control could identify no increase in Staph infections at our institution. Patients were treated at different locations and received different lot numbers of drug. Conclusions: We believe this is the first report of a substantial incidence of invasive skin and nail infections with the addition of pertuzumab to trastuzumab-based regimens not reported in the product label. Low levels of quantitative immunoglobulin in select patients suggest a possible mechanism. Citation Format: Joanne E Mortimer, Yuan Yuan, Daphne Stewart, Samuel Chung, Laura Kruper, Louise C Wong, Mary Mendelsohn, Carolyn Behrendt, Sanjeet Dadwal, Bernard Tegtmeier. Skin infections associated with the addition of pertuzumab to trastuzumab-containing chemotherapy [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-15-21.