Pneumocystis Carinii Pneumonitis Research Articles

Pilot trial of yttrium-90 ibritumomab tiuxetan consolidation following rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone chemotherapy in patients with limited-stage, bulky diffuse large B-cell lymphoma

The clinical efficacy and safety of yttrium-90 (90Y)-ibritumomab tiuxetan consolidation treatment following rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) chemotherapy was investigated in patients with limited-stage and bulky diffuse large B-cell lymphoma (DLBCL). This prospective, multi-center, pilot trial included 21 patients who were newly diagnosed with stage I/II, bulky DLBCL and achieved a complete or partial response after six cycles of R-CHOP. The median size of bulky disease was 10.0 × 7.0 cm. After a median follow-up of 28.8 months, the overall response rate after 90Y-ibritumomab tiuxetan consolidation treatment was 80.9%, including 4.8% partial response. However, six patients (28.6%) experienced a progression or relapse. The 3-year overall and progression-free survival rates were 85.0 ± 8.0% and 75.0 ± 9.7%, respectively. Grade 3–4 adverse events were mainly hematologic toxicities, such as thrombocytopenia (35%) and neutropenia (60%). One patient experienced grade 3 Pneumocystis carinii pneumonitis. Thus, 90Y-ibritumomab tiuxetan consolidation following six cycles of R-CHOP resulted in an acceptable response with tolerable toxicity in patients with limited-stage and bulky DLBCL.

Dose-intensity temozolomide after concurrent chemoradiotherapy in operated high-grade gliomas

We performed a new phase II trial enrolling patients with newly diagnosed high-grade glioma (HGG) to test the efficacy of a weekly alternating temozolomide (TMZ) schedule after surgery and concomitant chemoradiotherapy. From January 2005 to January 2007, 34 patients (21 men, 13 women; age range 30-70, mean age 53) were enrolled. There were 32 glioblastoma multiforme and two anaplastic astrocytoma. Each patient after surgery received standard concurrent chemoradiotherapy. After a 4-week break, patients were then to receive 12 cycles of 1-week-on/1-week-off TMZ, with 75 mg/m(2) for the first cycle, 100 mg/m(2) for the second, 125 mg/m(2) for the third, and 150 mg/m(2) from the fourth to the 12th. Hematological toxicity was monitored every week during concomitant chemoradiotherapy and then every 4 weeks. After 12 months from the end of radiotherapy, the overall survival (OS) rate was 59% (20/38), distributed as follows: 60% (18/30) for recursive partitioning analysis (RPA) class 4 patients and 33% (1/3) for RPA class 6 patients; the only RPA class 1 patient was alive and disease free at the time of writing. Median OS was 13 months [95% confidence interval (CI) 11.02-14.98 months]. Hematological toxicity was seen in six patients (18%): grade 1 neutropenia in four, grade 2 thrombocytopenia in one, and grade 4 thrombocytopenia plus grade 1 neutropenia in one. There was one case of opportunistic infection (Pneumocystis carinii pneumonitis). The toxicity of the TMZ dose-dense regimen was very low. Results seem to be encouraging for RPA lower classes (patients with good prognostic factors).

Fludarabine, Idarubicin and High Dose Cytarabine (FLAG-IDA) Followed by Allogeneic Transplantation: A Successful Strategy for Remission Re-Induction in High Risk Pediatric Patients with Relapsed, Refractory and Secondary Acute Leukemias.

Despite significant advances in the treatment of childhood acute lymphoblastic (ALL) and acute myeloid (AML) leukemias, the prognosis of those with primary refractory, secondary and early relapsed disease remains extremely poor with survival reported in most studies at less than 20%. Salvage rates are particularly poor in children with ALL who relapse on therapy and in children with AML who relapse post autologous bone marrow transplant. Encouraging results using the re-induction combination regimen of Fludarabine, high dose Cytarabine and Idarubicin (FLAG-IDA) have been reported, however the majority of data is in adult patients. Here we report the largest series of pediatric patients with high risk acute leukemias receiving this regimen in combination with allogeneic hematopoietic cell transplantation as salvage therapy.Between 1999–2005 a toal of 32 patients at 2 Australian Pediatric Cancer Centers were given Fludarabine (30mg/m2 IV over 1 hour for 5 days); Idarubicin (8mg/m2 IV over 1 hour for 3 days); Cytarabine (2000mg/m2 IV over 4 hours for 5 days) and GCSF (5mcg/kg/day). There were 21 males and 11 females, with a median age of 10.4 years (range 1.7 to 15.5 years). All patients had high risk leukemias; relapsed ALL (n=13), primary refractory ALL (n=3), relapsed AML (n=13), primary refractory AML (n=1) and secondary AML (n=2). For the overall cohort median duration of first complete remission (CR1) was 16 months (range 2–34 months). Relapsed ALL patients were all considered extremely high risk with a CR1 duration of <36 months.Overall, 23 of 32 patients (71.9%) achieved a complete remission (defined as <5% blasts with evidence of marrow regeneration) following a single course of FLAG-IDA. For those with relapsed ALL, 10 of 13 patients (76.9%) achieved a remission. 2 out of the 3 patients with primary refractory ALL achieved a remission (both Philadelphia chromosome positive), 1 following a second course of FLAG-IDA. In the relapsed AML group, 9/13 (69.2%) achieved a remission, including 7 out of 10 patients who had relapsed post autologous BMT. 1 of the 2 patients with secondary AML achieved a remission. All of the 9 patients who did not achieve a remission died of progressive disease. The median time to neutrophil recovery following therapy was 26.5days (range 16–73). One patient remained aplastic and an attempt was made to transplant during this phase.22 of the 23 patients (10 AML and 12 ALL) who achieved remission proceeded to an allogeneic bone marrow transplant, following a further 2–3 courses of FLAG (without IDA) for consolidation. 70% of patients received an unrelated donor transplant. Stem cell source was MUD BM (n=9), unrelated UCB (n=6) and HLA-ID sibling donor (n=7). Overall 17 of the 22 (77.3%) remain alive and leukaemia free (9 AML and 8 ALL patients) with a median duration of 36.5 months (9–84 months). Cause of death in the transplanted patients was progressive disease (n=4) and Pneumocystis Carinii pneumonitis (n=1). In summary, for this group of high risk, early relapsed and heavily pretreated pediatiric patients, re-induction chemotherapy with FLAG-IDA followed by allogeneic transplantation has provided an excellent strategy in the achievement of long term cure.

Acute interstitial pneumonitis during chemotherapy for haematological malignancy

Fourteen adult patients with haematological malignancies (eight non-Hodgkin's lymphoma, one multiple myeloma, one chronic lymphocytic leukaemia, two acute lymphoblastic leukaemia and two acute myeloid leukaemia) developed acute interstitial pneumonitis (IP) during the course of chemotherapy. All patients manifested high fever over 38 degrees C, bilateral diffuse pulmonary interstitial infiltrates in the chest radiograph and severe hypoxia without hypercapnia in the arterial blood gas analysis. Pathogenic microorganisms were not detected in repeated examinations in any patient. Chemotherapy given included various anti-neoplastic drugs. Five patients had received granulocyte colony-stimulating factor (G-CSF) for chemotherapy-induced leucopenia. The onset was associated with an increase of leucocytes in 10 patients. All patients were treated with high dose steroid hormone and broad spectrum antibiotics with or without anti-fungal agents, and three required mechanical ventilation. Eleven patients quickly recovered from these situations, whereas three died. Autopsies were done in two patients and disclosed pneumocystis carinii (PC) pneumonitis in one and non-specific pulmonary congestive oedema and fibrosis in the other. In conclusion, IP of unknown cause could develop in patients with various haematological malignancies especially at the recovery phase of chemotherapy-induced leucopenia irrespective of the previous G-CSF administration. High dose steroid hormone should be used as therapy for such patients as soon as possible after exclusion of an infective aetiology.

Adult T Cell Leukemia/Lymphoma (ATLL) Is a Malignant Counterpart of Regulatory T Cells (Treg).

Adult T cell leukemia/lymphoma (ATLL) is a lymphoproliferative disorder caused by a retrovirus, human T-lymphotropic virus type 1 (HTLV-1). ATLL is subclassified into four subtypes, smoldering, chronic, acute, and lymphoma. The acute type progresses rapidly and is usually resistant to conventional chemotherapy. In contrast, the chronic type shows an indolent clinical course and the patients survive for several years, even without chemotherapy. Irrespective of the subtypes, however, ATLL patients are in a severely immune-suppressed condition and can easily acquire opportunistic infections such as Pneumocystis Carinii pneumonitis. Suppression of cell-mediated immunity has also been reported in HTLV-1 carriers. Although ATLL cells show the activated helper/inducer T-cell phenotypes, CD4+ and CD25+, they exhibit strong immune-suppressive activity in vitro. The recent notion of CD4+ CD25+ regulatory T cells (Treg) prompted us to investigate the origin of ATLL cells from the standpoint of Treg. Forkhead/winged helix transcription factor (Foxp3) is a functional marker of Treg, which plays a central role in their generation. There are other marker molecules for Treg, including glucocorticoid-induced TNFR family-related protein (GITR) and the chemokine receptors CCR4 and CCR8.In the present study, we examined primary ATLL cells from 48 patients: 36 patients with acute type and 12 patients with chronic type. We also examined ATLL cell lines, HTLV-1-infected T-cell lines and peripheral blood mononuclear cells (PBMC) from healthy adults as control cells. We used RT-PCR for detection of Foxp3, GITR, CCR4, and CCR8 mRNA expression. Foxp3 and/or GITR mRNA were detected in over 90% of the patients, and 50% of the patients expressed both. There was no difference between subtypes. In contrast, Foxp3 and GITR mRNA were scarcely detected in the PBMC from healthy adults. Furthermore, we confirmed GITR expression at the protein level by flow cytometry. CCR4 and CCR8 mRNA were also detected in almost all ATLL samples, at significantly higher levels than in the normal PBMC. Corresponding to the results of the primary cells, ATLL cell lines and HTLV-1-infected T-cell lines also expressed GITR mRNA, although HTLV-1-negative cell lines, Jurkat and Molt4, completely lack it. Next, we examined whether GITR affects ATLL cell proliferation using a GITR- expressing IL-2-dependent ATLL cell line, KK1. We found that GITR ligand induced proliferation of KK1 cells in an IL-2-negative condition. Thus, these results indicate the Treg origin of ATLL cells and show that GITR expression is possibly involved in the development of ATLL.

IL-23 and IFN-gamma deficiency in immunodeficient HIV patients who achieved a long-term increase in CD4 T-cell counts on highly active antiretroviral therapy.

The pathogenesis of HIV infection and the susceptibility to opportunistic infections has been associated with poor type 1 cytokine production. In severely immunodeficient HIV patients who achieved increased CD4 T-cell counts on longterm highly active antiretroviral therapy, we observed reduced expression of IL-23p19 and IFN-gamma messenger RNA. Impaired IL-23-induced IFN-gamma production by memory T cells might thus contribute to opportunistic infections in a minority of patients with substantial CD4 T-cell recovery.

Pneumocystis carinii pneumonitis in haemophagocytic lymphohistiocytosis

We report on a 10‐y‐old boy who developed Pneumocystis carinii pneumonitis (PCP) as the dominant symptom at the onset of haemophagocytic lymphohistiocytosis (HLH). PCP is a common infection in patients with combined primary immunodeficiencies or acquired immunodeficiency syndrome but it has rarely been observed at the onset of HLH. Typically, HLH presents as a febrile syndrome associated with cytopenia and hepatosplenomegaly. Repeated bone marrow aspirates, spleen or lymph node biopsies are sometimes required to reveal haemophagocytosis. Because of the significant immunosuppression during treatment of HLH, prophylaxis of PCP with co‐trimoxazole is recommended. However, de‐arranged immune response in HLH renders the patients susceptible to opportunistic infections, even before the introduction of immunosuppressants. Conclusion: We suggest that in patients with unclear respiratory symptoms, it is worth considering a differential diagnosis of HLH.

Guidelines for Prevention of Pneumocystis carinii Pneumonitis in Children and Adolescents with Cancer

Pneumocystis carinii pneumonitis (PCP) is one of the most important opportunistic infections in children and adolescents with cancer. Its high frequency and a considerable mortality have led to primary chemoprophylaxis in patients with hematological malignancies and following allogeneic hematopoietic stem cell transplantation. Although less well characterized, patients with autologous stem cell transplantation and patients with dose-intensive chemotherapy for pediatric solid tumors may have a similarly high risk for PCP based on their profound T-cell depletion. For more than two decades, effective chemoprophylaxis for PCP has been available. Trimethoprim and sulfamethoxazole (TMP/SMX) is the prophylactic modality of first choice. The combination has been shown to be almost 100 % efficacious in pediatric cancer patients at highest risk, and it is usually well tolerated in this setting. Secondary alternatives to TMP/SMX include oral dapsone, oral atovaquone, and aerosolized pentamidine-isethionate. These modalities are less effective than TMP/SMX, and have been evaluated predominantly in HIV-infected patients. This article reviews epidemiology and current approaches to chemoprophylaxis for PCP in children and adolescents with cancer and/or hematopoietic stem cell transplantation, and provides evidence-based guidelines for indications and modalities of PCP prophylaxis in this population.

Intensified therapy for infants with acute lymphoblastic leukemia

Infants with acute lymphoblastic leukemia (ALL) have a very poor prognosis. Since 1985, we have intensified therapy for infants with ALL by including a month of high dose multiagent chemotherapy after remission induction. Between 1985 and 1995, we treated 23 infants (age < 12 months). We compared the presenting characteristics and outcomes of these infants with the 11 infants treated on our protocols between 1973 and 1985, an era prior to the intensification of therapy. Available bone marrow samples from infants treated since 1985 were analyzed for the presence of MLL gene rearrangements by Southern blot analyses and for TEL-AML1 gene fusion by reverse transcriptase-polymerase chain reaction. With a median follow-up of 5.6 years, the 50-month event free survival (EFS) (+/- standard error) for the 23 infants was 54 +/- 11%, a significant improvement (P = 0.001) compared with the outcome for the 11 infants treated on our protocols prior to 1985 (EFS = 9 +/- 9%). Of the seven infants found to have a rearranged MLL gene, three (43%) remained in first complete remission. None of the nine infant bone marrow specimens tested had evidence of TEL-AML1 gene fusion. The intensified therapy was complicated by a high incidence of infections, including septicemia in 52% of patients and Pneumocystis carinii pneumonitis in 22% of patients. Late effects identified in the 13 long term survivors (median age, 6 years) included developmental delay and learning disabilities of varying severity (82% of evaluable patients), asymptomatic cataracts (67%), asymptomatic echocardiographic abnormalities (30%), obesity (27%), and short stature (18%). Intensification of therapy significantly improved the EFS of infants with ALL compared with previous, less intensive regimens and with the experience of other investigators. Future treatment for infants should attempt to improve efficacy while minimizing toxicity.

Intensified therapy for infants with acute lymphoblastic leukemia

BACKGROUND Infants with acute lymphoblastic leukemia (ALL) have a very poor prognosis. Since 1985, we have intensified therapy for infants with ALL by including a month of high dose multiagent chemotherapy after remission induction. METHODS Between 1985 and 1995, we treated 23 infants (age < 12 months). We compared the presenting characteristics and outcomes of these infants with the 11 infants treated on our protocols between 1973 and 1985, an era prior to the intensification of therapy. Available bone marrow samples from infants treated since 1985 were analyzed for the presence of MLL gene rearrangements by Southern blot analyses and for TEL-AML1 gene fusion by reverse transcriptase-polymerase chain reaction. RESULTS With a median follow-up of 5.6 years, the 50-month event free survival (EFS) (± standard error) for the 23 infants was 54 ± 11%, a significant improvement (P = 0.001) compared with the outcome for the 11 infants treated on our protocols prior to 1985 (EFS = 9 ± 9%). Of the seven infants found to have a rearranged MLL gene, three (43%) remained in first complete remission. None of the nine infant bone marrow specimens tested had evidence of TEL-AML1 gene fusion. The intensified therapy was complicated by a high incidence of infections, including septicemia in 52% of patients and Pneumocystis carinii pneumonitis in 22% of patients. Late effects identified in the 13 long term survivors (median age, 6 years) included developmental delay and learning disabilities of varying severity (82% of evaluable patients), asymptomatic cataracts (67%), asymptomatic echocardiographic abnormalities (30%), obesity (27%), and short stature (18%). CONCLUSIONS Intensification of therapy significantly improved the EFS of infants with ALL compared with previous, less intensive regimens and with the experience of other investigators. Future treatment for infants should attempt to improve efficacy while minimizing toxicity. Cancer 1997; 80:2285-95. © 1997 American Cancer Society.

Spontaneous pneumothorax in infants: a 10-year review.

To document the number of infants with spontaneous pneumothorax (SP) and determine the association of any underlying pathologic processes in the lung with SP. Retrospective chart review of infants admitted with SP from January 1985, to December 1994. Patients admitted to The Children's Medical Center, Dayton, Ohio. Children aged greater than 28 days but less than 1 year with the primary admitting diagnosis of SP. The number of infants with SP and description of underlying conditions associated with SP. Six infants were identified with the admitting diagnosis of SP. All of the patients had underlying conditions that predisposed to SP: febrile seizures, anatomic abnormalities (one with an intrathoracic cystic hygroma and one with a cystic adenomatoid malformation of the lung), bronchiolitis, and two patients with Pneumocystis carinii pneumonitis. The children with SP identified in this survey accounted for one admission per 10,000 hospitalized children and 3.4 admissions per 10,000 hospitalized infants. SP in infancy is uncommon. The data indicate that infants who present with SP have associated conditions predisposing to the development of a pulmonary air leak.

Paediatric HIV update.

Less than half of the paediatric HIV infections recorded in Australia have resulted from perinatal transmission, but in recent years this has been the predominant mode of infection. There are 136 infants who are known to have been exposed perinatally to HIV in Australia: 49 of these are infected. Caesarean section is thought now not to reduce the risk of perinatal transmission (PNT); rather, the risk increases with duration of membrane rupture and rises rapidly after 4 h of membrane rupture. However, no data exist to show that interventions to expediate delivery after membrane rupture reduce the risk of PNT. Data such as these suggest that the majority of perinatal infections (probably about 60%) occur close to the time of delivery. While the overall risk of PNT for non-breast fed infants is approximately 20-25%, the risk of infection for the infant is considerably increased when there is evidence of increased maternal viral burden. Advanced maternal disease predicts that if the infant is infected there is more likely to be early progression of HIV than is the case for the less frequently infected infants of mothers who are asymptomatic. Bottle feeding may prevent infection of 10% of children exposed perinatally. Use of zidovudine by the mother in the third trimester and i.v. zidovudine during labour, followed by oral zidovudine for the infant for 6 weeks can reduce the PNT rate by two thirds, to about 8%. Approximately 3% of uninfected infants with perinatal HIV exposure may be found to be transiently virus positive but eventually become antibody negative and thus appear to have eliminated the virus. The risk of Pneumocystis carinii pneumonitis (PCP) cannot be predicted on the basis of CD4 count and it is recommended that all children of infected mothers commence PCP prophylaxis around the age of 6 weeks-2 months and continue that therapy until the age of 12 months or until it becomes clear that the infant is uninfected. The cumulative risk of AIDS increases rapidly during the first year of life to about 20%, then more slowly at a rate of about 2 or 3% a year. The shape of this curve reveals the bimodal progression of HIV disease in children. About 15-20% of children rapidly develop a severe immune deficiency, opportunistic infections and, in most cases, encephalopathy. There is a very high morbidity rate in this group of children, most of whom die before the age of 3 or 4 years. In contrast, 80-85% of children only become immunodeficient after a relatively long period, which is similar to or perhaps even longer than that in adults. Recent studies indicate that zidovudine antiviral monotherapy is no longer appropriate. While no clear alternative to monotherapy has emerged most would, wherever possible, commence antiretroviral therapy with a combination of two or three drugs including zidovudine plus didanosine or lamivudine. If a third drug is used it would probably be a protease inhibitor.

Pneumocystis carinii Infection Alters GTP-Binding Proteins in the Lung

The GTP-binding regulatory proteins (G proteins) in the membranes of the lung parenchyma from normal, uninfected ferrets were compared to those from immunosuppressed animals with and without Pneumocystis carinii pneumonitis. In lung membranes, pertussis toxin (PT) catalyzed ADP ribosylation of a 41-kDa protein; treatment with cholera toxin (CT) led to ribosylation of a 44-kDa polypeptide. Compared to that in the normal ferrets, the level of the 44-kDa protein was dramatically suppressed in the P. carinii-infected animals. Western blot analysis with specific antibodies to alpha s (which recognized CT substrates), alpha common (which reacted to PT substrates), the alpha q/11 epitope, and the beta subunit demonstrated that these proteins were decreased in animals with P. carinii pneumonitis (PCP). Western blotting of PCP-free membranes with a pan-Ras antibody revealed a 21-kDa polypeptide (corresponding to small G proteins). The level of the 21-kDa protein in membranes from PCP-affected animals was only 30% of that in membranes from PCP-free animals. Finally, analogous studies performed with rat lung membranes revealed similar findings. These data suggest that, independent of its exacerbation of immunosuppression, PCP leads to extensive changes in the GTP-binding proteins in the lung.

Novel anti-Pneumocystis carinii effects of the immunosuppressant mycophenolate mofetil in contrast to provocative effects of tacrolimus, sirolimus, and dexamethasone.

The effects of three new immunosuppressive drugs used for organ transplantation, mycophenolate mofetil, tacrolimus, and sirolimus, were compared with those of dexamethasone in provocation of Pneumocystis carinii pneumonitis in virus-free Sprague-Dawley rats. Rats injected daily with tacrolimus showed a dose-related response to the point of severe P. carinii pneumonitis 4 weeks after initiation of drug administration identical to those animals treated with high-dose dexamethasone. Thirty percent of rats treated with sirolimus had mild P. carinii infection. Surprisingly, mycophenolate mofetil had an anti-P. carinii effect. None of the animals had discernible P. carinii infection when treated with mycophenolate mofetil alone or combined with dexamethasone. Mycophenolate mofetil is unique because of its dual activity as a potent immunosuppressant as well as an antimicrobial with action against P. carinii.

Pulmonary complications of bone marrow transplantation: A comparison of total body irradiation and cyclophosphamide to busulfan and cyclophosphamide

Purpose : To retrospectively compare the acute and long-term pulmonary toxicities of total body irradiation and busulfan in bone marrow transplantation. Methods and Materials : From March through February 1991, 144 patients received high-dose therapy with cyclophosphamide plus either total body irradiation (TBI-CY) or busulfan (BU-CY) followed by bone marrow rescue. Treatment protocols were based on disease type. Cyclophosphamide dose was 120–200 mg/kg, given in 2–4 days. Total body irradiation was given as 12 Gy in four fractions over 4 days, or 14.4 Gy in eight fractions over 4 days. Busulfan dose was 16 mg/kg given over 4 days. Results : Seventy-nine patients were treated with TBI-CY and 65 patients with BU-CY. More patients in the TBI group had allogeneic transplants (40 vs. 18). Pulmonary events occurred in 48 patients, 19 in BU-CY and 9 in TBI-CY. Of the 58 patients with allogeneic transplants, 21 (36%) developed chronic graft-vs.-host disease (GVHD), and 10 of those patients developed pulmonary complications (including 2 with obliterative bronchitis and 1 with asthma). Interstitial pneumonitis (IP) occurred in 14 patients, 12 in the TBI-CY group and 2 in the BU-CY group. Cytomegalovirus and pneumocytis infections were associated with IP in 11 of those patients. Fatal idiopathic IP occurred in one patient in each of the TBI-CY and BU-CY groups. Multivariate analysis showed that only chronic GVHD and prior bleomycin use were significant predictors of intersitial pneumonitis: no difference was seen between TBI-CY and BU-CY. Conclusion : Pulmonary complications were most commonly associated with GVHD and prior bleomycin use. The incidence of cytomegalovirus or pneumocystis carinii pneumonitis was greater in the patients receiving the TBI regimen; fatal pulmonary complications were not significantly different between TBI and nonTBI regimens.

Sequential changes in vital signs and acid-base and blood-gas profiles in Pneumocystis carinii pneumonitis in children with cancer. Basis for a scoring system to identify patients who will require ventilatory support.

Early reliable identification of patients with Pneumocystis carinii pneumonia (PCP) who will require ventilatory support would be desirable. To develop a predictive system to meet this need, we studied, prospectively, the sequential alterations in vital signs and acid-base and blood-gas profiles associated with this disease in 55 children with cancer, 29 of whom did not require ventilatory support (Group I) and 26 who did (Group II). None of the patients had acquired immunodeficiency syndrome (AIDS). On admission to the hospital the only feature that distinguished patients in Group I from those in Group II was the mean (+/- SD) respiratory rate (38.7 +/- 2.1 versus 49.1 +/- 3.5 breaths/min, p < 0.02). By 12 h after admission there was a significant difference in the partial pressure of oxygen (PaO2) between Groups I and II (75.1 +/- 3.2 mg Hg versus 65.4 +/- 3.1 mm Hg, p < 0.05), and also in the two groups' inspired fraction of oxygen (FIO2; 24.9 +/- 0.54% versus 29.6 +/- 1.6%, p < 0.01). Both alterations, as well as tachypnea, persisted for the remainder of the study period. The maximum FIO2 did not exceed 45% in Group I, and by 60 h after admission to the hospital, all patients in this group had persistent increases in PaO2 that exceeded 80 mm Hg, permitting decreases in FIO2 to that of room air. In Group II, hypoxemia was refractory despite an increase in FIO2 to 50%, at which point ventilatory support was begun (at a mean of 81.1 +/- 32.3 h after admission).(ABSTRACT TRUNCATED AT 250 WORDS)

Cytomegalovirus Infection Rate among Heart Transplant Patients in Relation to Anti-thymocyte Immunoglobulin Induction Therapy

During a 2-year period, 49 patients underwent heart transplantation at Rigshospitalet, Copenhagen. Nine (18%) were females and the mean age for all patients was 44 years (range 14-56 years). Immunosuppressive therapy included cyclosporin, azathioprine and steroids in all patients. 43 patients received in addition short-term (approx. 4 days) induction treatment with antithymocyte immunoglobulin (ATG). 17 patients received ATG Fresenius, 2.5 mg/kg/day or ATGAM, 12.5 mg/kg/day, whereas the remaining 26 patients received ATG Merieux, 2.5 mg/kg/day. Prophylactic antimicrobial chemotherapy included ceftriaxone, acyclovir (1 g daily), nystatin, and pyrimethamine in toxoplasmosis mismatch patients. Serological assays for cytomegalovirus (CMV), Epstein-Barr virus, varicella-zoster virus, herpes simplex virus, legionella and toxoplasmosis as well as CMV and bacterial culturing were carried out before transplantation, at regular intervals and when clinically indicated. Five patients developed septicaemia. Nine had pulmonary bacterial infections, including 2 cases of legionella pneumonia. Two had Clostridium difficile diarrhoea. Three patients had Pneumocystis carinii pneumonitis. 24 patients (49%) had evidence of CMV infection/reactivation. Seven out of 10 CMV mismatch (pos donor/neg recipient) patients and 3 out of 12 CMV match (pos donor/pos recipient) patients developed clinical CMV disease. The rate of CMV infection/reactivation was significantly higher among patients who had CMV-positive donors (p < 0.01) and among patients receiving ATG Merieux induction treatment (p < 0.0001). Logistic regression analysis showed that both positive CMV donor status and ATG Merieux induction treatment were significant independent predictors of CMV infection. Six patients (12%) died. Two out of 4 infection related deaths could be ascribed to CMV disease.

Acquired immunodeficiency syndrome-like illness associated with systemic Mycoplasma fermentans infection in a human immunodeficiency virus-negative homosexual man

A 35-year-old homosexual man developed a composite nodal Kaposi's sarcoma and peripheral T-cell lymphoma that were associated with a peripheral blood CD4-positive lymphocyle count of only 43/mm 3. The patient subsequently developed Pneumocystis carinii pneumonitis and eventually died due to disseminated Cryptococcus neoformans. Numerous premortem tests for the presence of human immunodeficiency virus (HIV) types 1 and 2 were negative by the enzyme-linked immunosorbent assay, Western blot, viral isolation, and polymerase chain reaction techniques. Postmortem evaluations for HIV-1, HIV-2, human T-cell lymphotropic virus (HTLV)-I, and HTLV-II also were negative by polymerase chain reaction, immunofluorescence assays, and viral isolation. A systemic infection by Mycoplasma fermentans, however, was documented by immunohistochemistry and polymerase chain reaction in premortem and post-mortem tissues. This recently recognized human pathogen has produced systemic infections in patients with the acquired immunodeficiency syndrome (AIDS) and in previously healthy non-AIDS patients who characteristically have a fulminant flu-like illness. Additionally, M fermentans has enhanced the cytopathic effect of HIV in in vitro studies and has produced fatal wasting illnesses with terminal lymphopenia in inoculated adult silvered leaf monkeys. This report is the first description of an association between M fermentans infection and an AIDS-like illness in an HIV-negative individual. The etiology of the severe immunosuppression in this patient and the associated role of M fermentans remain to be determined by further investigations.

ELISA of complement C3a in bronchoalveolar lavage fluid

Activated complement factors within the lung may induce several local biological effects. In order to investigate local complement activation we have developed non-competitive two-site ELISAs of C3a and total C3 in bronchoalveolar lavage fluid (BALF). For the assay of C3a, both C3 and C3(H2O) were removed from the samples by precipitation with polyethylene glycol. It was necessary to add carrier proteins to BALF to remove C3 and C3(H2O) fully. The ELISA of C3a has the lowest limit of detection reported thus far, namely 0.045 nM (= 0.405 ng/ml). In BALF from healthy persons (n = 9) the C3a concentration was 0.20 nM (0.12-0.31 nM) (median, range). C3a was higher in BALF from patients with asthma or with sarcoidosis; asthma (n = 10), 0.45 nM (0.20-5.79 nM); sarcoidosis (n = 19), 1.31 nM (0.095-5.65 nM) (Mann-Whitney U test, p less than 0.005). In BALF from patients with Pneumocystis carinii pneumonitis (n = 10) the C3a concentration was 0.18 nM (0.07-0.57 nM). C3a concentrations in BALF may reflect local complement activation in the lung and/or diffusion into the lumen. This was studied by normalizing C3a concentrations in BALF into values for epithelial lining fluid (ELF), and calculating serum-to-ELF quotients of C3a, and C3a/total C3 quotients.

Specific T-cell response to a Pneumocystis carinii surface glycoprotein (gp120) after immunization and natural infection

T cells have been shown to be important in recovery from Pneumocystis carinii pneumonitis, although no specific antigen of P. carinii has been defined as containing T-cell epitopes. P. carinii has an abundant mannosylated surface glycoprotein of approximately 120 kDa (gp120) which induces a prominent host antibody response in experimental animals after exposure to P. carinii in the environment or after recovery from P. carinii pneumonitis. P. carinii gp120 was purified from infected lungs by lectin affinity chromatography. Standard in vitro lymphocyte stimulation assays using purified gp120 and control normal lung preparations were performed on isolated T cells obtained from BALB/c mice after immunization with P. carinii-infected crude lung homogenates or lectin-purified gp120. Lymphocytes from reconstituted severe combined immunodeficient mice which had recovered from naturally acquired P. carinii pneumonitis were also tested. A specific T-cell response was elicited by gp120 after immunization with P. carinii gp120 and after recovery from P. carinii pneumonitis. In addition, the mice developed a strong antibody response to gp120 as ascertained by Western blot (immunoblot). These data suggest that gp120 may be important in the recognition of P. carinii by T cells.