Severe Pneumocystis Carinii Pneumonia Research Articles

Pharmacokinetics of Trimetrexate and Dapsone in AIDS Patients with Pneumocystis carinii Pneumonia

The objective of this study was to determine the pharmacokinetics of trimetrexate and dapsone in AIDS patients with moderate to severe pneumocystis pneumonia. Trimetrexate, leucovorin, and dapsone were administered for 21 +/- 3 days in the following doses: trimetrexate glucuronate, 45 mg/m2; leucovorin, 20 mg/m2; and dapsone, 100 mg daily. The pharmacokinetics of trimetrexate, dapsone, and dapsone's metabolite, monoacetyldapsone, were determined at three separate periods over the course of treatment. Serial blood samples were obtained over 24 hours after dosing and analyzed for trimetrexate, dapsone, and monoacetyldapsone, and pharmacokinetic parameters were determined. The mean parameters obtained for the early, mid-, and late collection periods were the following: trimetrexate: t1/2 = 8.29, 9.15, 10.00 hr; AUC = 16.85, 22.38, 24.49 mg.hr/l; CI = 5.58, 4.14, 3.96 l/hr, respectively. DDS: t1/2 = 14.99, 16.59, 15.13 hr; AUC = 30.60, 35.29, 36.08 mg.hr/l; CI = 3.82, 3.49, 3.01 l/hr, respectively. Monoacetyldapsone: t1/2 = 20.25, 18.66, 16.32 hr; AUC = 24.05, 24.06, 23.86 mg.hr/l, respectively. No statistically significant changes in pharmacokinetics for trimetrexate or dapsone were observed over the 21 +/- 3 day course of treatment. The results suggest that there are no major interactions between trimetrexate and dapsone when administered together in acutely ill patients.

Successful extracorporeal membrane oxygenation in four children with malignant disease and severe Pneumocystis carinii pneumonia

Background Toxic deaths due to intensified treatment are of increasing concern in view of the generally improved prognosis for children with malignancies. Pneumocystis carinii pneumonia (PCP) during immunosuppressive treatment in children with malignancies is a severe complication with a poor prognosis if mechanical ventilation is required. Extracorporeal membrane oxygenation (ECMO) is a recognized technique that provides temporary respiratory support for patients with intractable respiratory failure. Procedure We here report successful ECMO support in four children with PCP, secondary to chemotherapy-induced immunosuppression, in whom the respiratory situation deteriorated despite pharmacological treatment and mechanical ventilation. The duration of ECMO was 7–43 days. Results Three children with acute lymphoblastic leukemia recovered from their PCP to continue chemotherapy and are now in complete continuous remission. Their pulmonary function normalized completely during 6–12 months after ECMO therapy. One child with a primitive neuroectodermal tumor survived the PCP and was off ECMO for 11 days before succumbing to unrelated complications. Conclusions We conclude that ECMO offers an important means of respiratory support in children with severe PCP that can also be adopted during treatment for malignant disease. Med. Pediatr. Oncol. 32:25–31, 1999. © 1999 Wiley-Liss, Inc.

Use of Adjunctive Corticosteroids in Severe Adult Non-HIV Pneumocystis carinii Pneumonia

To examine the use of adjunctive corticosteroids in cases of severe Pneumocystis carinii pneumonia (PCP) in non-HIV-infected adult patients. Retrospective review of medical records. Tertiary care urban teaching hospital. Review identified 31 consecutive histologically confirmed primary cases of adult non-HIV-related PCP. Complete records were available for 30 patients, including 20 male and 10 female patients with a mean age of 58.3+/-15 years (+/-SD). Underlying conditions included organ transplantation (n=13), long-term immunosuppressive therapy (n=9), and chemotherapy for malignancy (n=8). All patients had documented PO2 <65 mm Hg or arterial oxygen saturation <90% on room air. Following the identification of P carinii, in addition to trimethoprim-sulfamethoxazole or pentamidine therapy, 16 patients received increased steroids (> or =60 mg prednisone daily equivalent; increased high-dose steroid group), whereas 14 patients were maintained on a regimen of low doses (< or =30 mg prednisone equivalent daily) or had steroid therapy tapered (low-dose steroid group). The increased high-dose steroid group demonstrated a shorter required duration for mechanical ventilation (6.3+/-6 days vs 18.0+/-21 days; p=0.047), a shorter duration of ICU admission (8.5+/-7 days vs 15.8+/-8 days; p=0.025), and a shorter duration of supplemental oxygen use (10.0+/-4 vs 32.2+/-33; p=0.05). The hospital duration to discharge for the nine survivors in each group favored the use of corticosteroids (15.4+/-5 days vs 36.3+/-33 days; p=0.077). Similar rates were observed for intubation (75% vs 57%; p=0.442) and in-hospital mortality (44% vs 36%; p=0.722). These preliminary data suggest that high-dose adjunctive corticosteroids may accelerate recovery in cases of severe adult non-HIV PCP.

Successful oral desensitization to trimethoprim-sulfamethoxazole in acquired immune deficiency syndrome.

To study the outcome of a modified oral desensitization protocol for trimethoprim-sulfamethoxazole in human immunodeficiency virus infected patients with Pneumocystis carinii pneumonia and acquired immune deficiency syndrome. A prospective study. Tertiary care referral center. Thirteen human immunodeficiency virus infected patients with Pneumocystis carinii pneumonia and allergy to sulfonamides who failed alternative therapy. Oral desensitization to trimethoprim-sulfamethoxazole. Nature of allergic reactions, toxicity of alternate medications, indication as well as outcome of trimethoprim-sulfamethoxazole desensitization and routine laboratory determinations. The most common reaction to trimethoprim-sulfamethoxazole was generalized, pruritic maculopapular rash (n = 10, 76.9%) followed by urticaria/angioedema in two patients (15.38%). Two patients had generalized pruritus without rash. All patients (n = 13) tolerated oral desensitization to trimethoprim-sulfamethoxazole without any adverse reactions including three patients who were critically ill and on mechanical ventilation. Thus the success rate of our protocol was 100%. No patient had received antihistamines prior to or during the protocol. Four patients (5, 6, 7, and 9) were receiving prednisone for severe Pneumocystis carinii pneumonia. Total followup has ranged from 4 to 84 weeks. Two patients died during followup due to causes unrelated to desensitization. All other patients are tolerating trimethoprim-sulfamethoxazole without any allergic reactions. Oral desensitization to trimethoprim-sulfamethoxazole, as per this protocol is safe, in that there were no systemic or cutaneous reactions during desensitization as well as followup. It is well tolerated in all patients, including the three critically ill patients. As judged by the outcome and ability to tolerate trimethoprim-sulfamethoxazole after desensitization, the procedure is successful in all patients in this study. Equipped with this protocol one can evaluate possible mechanisms of desensitization such as oral tolerance or mediator depletion in a controlled fashion.

Does Cytomegalovirus Predict a Poor Prognosis in Pneumocystis carinii Pneumonia Treated With Corticosteroids?: A Note for Caution

To examine the importance of cytomegalovirus (CMV) in bronchoalveolar lavage (BAL) fluid of patients with HIV-associated Pneumocystis carinii pneumonia (PCP) treated with adjunctive corticosteroids (CS). Analysis of clinical data during a 5-year period. Department of infectious diseases where clinical and paraclinical data on patients suspected of having PCP have been sampled prospectively. 148 consecutive patients with a first episode of PCP in a 5-year period. Vital status 3 months after diagnosis of PCP. Patients with PCP treated with adjunctive CS who had CMV cultured from BAL fluid had a two times higher mortality within 3 months from bronchoscopy than others (p = 0.08). This difference could not be explained by differences in CD4 count, PO2 or PCO2 at time of bronchoscopy. With the accepted usage of adjunctive CS in severe PCP, the role of CMV as a pulmonary copathogen may have changed. Active CMV infection may be an important cause of failing treatment of severe PCP in those treated with adjunctive CS.

A Multicenter Randomized Double-Blind Placebo-Controlled Trial of Adjunctive Corticosteroids in the Treatment of Pneumocystis carinii Pneumonia Complicating the Acquired Immune Deficiency Syndrome

A multicenter placebo-controlled trial of early short-term high-dose methylprednisolone enrolled 78 patients with moderate to severe Pneumocystis carinii pneumonia (PCP) complicating HIV infection. The mean pressure of oxygen (PO2) at study entry was 55 mm Hg for the 71 patients who had blood gases monitored while breathing room air. Patients were randomized to receive methylprednisolone (40 mg) or placebo parenterally twice daily for 10 days, and the first dose of study medication was given within 24 h of the first dose of antimicrobial therapy for PCP. The primary end point included death, need for mechanical ventilation for > 6 days, or a partial PO2 < 70 mm Hg while breathing room air 10 days after initiation of treatment. There was no statistically significant difference in the primary end point between patients randomized to corticosteroid (CS) or placebo (PL) (p = 0.522; 95% CI = -0.30, 0.16). The incidence of superinfections during therapy or of other HIV-associated infections or malignancies in the 6 months following treatment for PCP was not significantly different between the two groups. More patients randomized to placebo had to discontinue treatment with trimethoprim-sulfamethoxazole because of hypersensitivity than those randomized to corticosteroids (p = 0.039). We conclude that addition of corticosteroids does not significantly affect the outcome of PCP in patients with HIV and a PO2 < 70 mm Hg on room air at presentation but lowers the incidence of hypersensitivity reactions to trimethoprim-sulfamethoxazole.

Interleukin-8 and eicosanoid production in the lung during moderate to severe Pneumocystis carinii pneumonia in AIDS: a role of interleukin-8 in the pathogenesis of P. carinii pneumonia

Pneumocystis carinii pneumonia (PCP) may cause severe respiratory distress. This is believed to be partly caused by the accumulation of neutrophils in the lung. Interleukin-8 (IL-8) and leukotriene B 4 (LTB 4) are potent neutrophil chemo-attractants and activators. Eicosanoids [i.e. prostaglandins (PG) and leukotrienes (LT)] are pro-inflammatory mediators released from arachidonic acid by action of phospholipase A 2 (PLA 2) and have been implicated in the host response to micro-organisms. Bronchoalveolar lavage (BAL) was performed on patients with PCP as part of a randomized study of adjuvant corticosteroids vs. placebo, in addition to standard antimicrobial therapy. Re-bronchoscopy was offered at day 10. BAL fluid was available for 26 patients who had follow-up bronchoscopy performed. At diagnosis, IL-8 levels were elevated in patients with PCP, compared to healthy controls, and correlated with relative BAL neutrophilia and P(A-a)O 2. LTB 4 was also elevated in PCP, but failed to correlate with either BAL neutrophilia or P(A-a)O 2. PLA 2 activity in patients correlated with IL-8 levels and BAL neutrophilia, but not with P(A-a)O 2. A trend towards a decrease in IL-8 levels in BAL fluid was detected in the corticosteroid-treated patients from days 0–10, whereas no change was detected in the placebo group. No change in levels of LTB 4, LTC 4, PGE 2, PGF 2α and PLA 2 were detected over time in either treatment group. This study establishes a correlation between IL-8, BAL neutrophilia and P(A-a)O 2, and suggests a role of IL-8 as a mediator in the pathogenesis of PCP, whereas the role of eicosanoids seems less clear.

Evaluation of a Prognostic Score: Pneumocystis carinii Pneumonia in HIV-Infected Patients

(1) To evaluate a clinical score predicting the early death from Pneumocystis carinii pneumonia (PCP) in HIV-infected patients and to compare it with lactate dehydrogenase (LDH) levels and Karnofsky's performance score. (2) To compare the association of this score and partial oxygen pressure (PaO2) at baseline (at ambiant air) with change in therapy. This clinical score was based on respiratory rate, degree of fever, cough, dyspnea, chest tightness, and chest radiographic findings. It was prospectively assessed in patients enrolled in two clinical trials for primary therapy of PCP. A university hospital with a large AIDS population. PCP scores (PCPSc) were assessed on treatment days (D) 0, D3, D7, D14, and D21 for 78 patients with mild to moderately severe PCP (PaO2 > 50 mm Hg at entry at room air). Regardless of the treatment received, these patients were stratified into two groups (survivors and nonsurvivors) within 45 days after the beginning of therapy. The PCPSc was associated with 45 days survival at treatment D3 (p = 0.03) and D14 (p < 0.001). Its decrease was significant between D0 and D7 and between D7 and D14 for survivors only. The LDH levels during the treatment course did not correlate with outcome. The fall in LDH values was significant only for survivors between D7 and D14 of therapy. The PaO2 at hospital admission was associated with death at 45 days and was well correlated with the PCPSc on D0 by single and multiple linear regression (R = 0.60, p < 0.0001). The PCPsc on D0 was associated with the change of initial therapy due to failure or drug adverse effects whereas PaO2 on D0 was associated only with treatment failure. For HIV-infected patients with mild to moderately severe PCP, this clinical score is easy to assess and has a prognostic value for survivors. It could be helpful to predict both treatment failure and occurrence of severe adverse drug reactions. The PCPSc should be validated in a larger number of patients, including those with more severe forms of PCP.

Reconsidering the Use of Adjunctive Corticosteroids in Pneumocystis Pneumonia?

Editorial comment on a study of the use of adjunctive corticosteroid therapy in moderate to severe Pneumocystis pneumonia.

Disseminated Cryptococcal Disease Complicating Steroid Therapy for Pneumocystis carinii Pneumonia in a Patient With AIDS

Recent studies have suggested that steroid therapy may reduce the morbidity and mortality of HIV-associated Pneumocystis carinii pneumonia (PCP) in a select population of patients. However, the risks of steroid therapy for this group have not been well defined. We describe the case of a patient admitted with severe PCP whose treatment included high-dose steroids. During his hospitalization, overwhelming cryptococcal disease developed, contributing to his death. We postulate that the rapidity of progression was due, in part, to the steroid therapy. We have also reviewed the literature. We recommend screening for cryptococcal infection before beginning steroid therapy.

Pharmacokinetics and Adverse Reactions of Various Dosage Regimens of Intravenous Pentamidine in the Treatment of HIV-Associated Pneumocystis carinii Pneumonia

The aim of this study was to compare various dosage regimens of intravenous pentamidine in the treatment of severe HIV-associated Pneumocystis carinii pneumonia. In a prospective open nonrandomised pilot study, we investigated the pharmacokinetics, efficacy and adverse reactions of different maintenance dosages of pentamidine in the treatment of Pneumocystis carinii pneumonia (PcP).

Effect of Corticosteroids on IL1β and TNFα Release by Alveolar Macrophages From Patients With AIDS and Pneumocystis carinii Pneumonia

The mechanisms by which corticosteroids (CCs) improve the outcome of AIDS patients with severe Pneumocystis carinii pneumonia (PCP) are unclear. We studied IL1 beta and TNF alpha release from alveolar macrophages (AMs) of patients receiving CCs for the treatment of PCP and also the effect of in vitro hydrocortisone on this release. Cytokine release from AMs of AIDS patients with pulmonary complications not receiving CCs (group 1) was compared with that from AM of those receiving CCs for PCP (group 2). The AMs of HIV-negative normal subjects (group 3) served as controls. All participants were nonsmokers or exsmokers. We found that lipopolysaccharide-stimulated AM from group 2 released significantly less interleukin-1 beta (IL1 beta) and tumor necrosis factor alpha (TNF alpha) than AM from group 1 and was similar to that from group 3. There was a significant positive correlation between the amount of TNF alpha and IL1 beta released. The presence of HC in the culture medium reduced in vitro IL1 beta and TNF alpha release from stimulated AM of the three groups. Thus, stimulated AMs from AIDS patients who receive CCs for treatment of PCP release significantly less IL1 beta and TNF alpha than AM from patients not receiving CCs. These findings suggest a mechanism by which CCs improve the outcome of AIDS patients with PCP.

Corticosteroids improve survival of children with AIDS and Pneumocystis carinii pneumonia.

To determine if corticosteroids administered in addition to antimicrobials improve survival in children with acquired immunodeficiency syndrome and severe Pneumocystis carinii pneumonia (PCP). Before-after, nonrandomized, case-comparison study. Pediatric intensive care unit of a tertiary care teaching hospital in Florida. Eleven children infected with the human immunodeficiency virus (HIV) with confirmed PCP. Infants with HIV infection and acute respiratory failure due to PCP were studied sequentially. The first seven infants were treated with antimicrobials alone while the next four received a 2-week course of methylprednisolone sodium succinate in addition to antimicrobials. The two groups were similar with respect to age, route of HIV infection, stage of HIV disease, CD4 T-cell count, antiretroviral therapy, and respiratory parameters at intubation. All children treated with antimicrobials alone died while receiving mechanical ventilation. Survival of the children who received corticosteroid therapy was significantly improved (P < .05), and all were weaned from the ventilator. Corticosteroids administered in addition to antimicrobials and supportive care improve the short-term survival of HIV-infected children who have acute respiratory failure due to PCP.

Pneumocystis carinii pneumonia in patients with systemic lupus erythematosus.

At the University Hospital, Kuala Lumpur, Malaysia, nine patients with systemic lupus erythematosus (SLE) were treated for Pneumocystis carinii pneumonia (PCP) between January 1987 and December 1988. When they developed PCP all the patients' SLE disease course was active and eight of them were on prednisolone. Four of these eight patients were also receiving cyclophosphamide. Patients who were on more intensive immunosuppressive therapy were found to develop more severe PCP. All the patients except one were treated with high-dose cotrimoxazole. Four patients responded to antipneumocystis treatment and survived, while PCP was responsible for the death of the five non-survivors.

Reduction of Pulmonary Surfactant in Patients with Human Immunodeficiency Virus Infection and Pneumocystis carinii Pneumonia

We assessed qualitative and quantitative differences in surfactant lipid composition of bronchoalveolar lavage (BAL) fluid in patients with acquired immune deficiency syndrome (AIDS) and Pneumocystis carinii (PC) pneumonia. Five normal volunteers and 27 patients with human immunodeficiency virus (HIV) infection underwent BAL for evaluation of possible pulmonary infection. Bronchoalveolar lavage studies in eight patients were negative for PC organisms, and 19 were positive. Pneumocystis carinii pneumonia was graded (mild vs moderate to severe) by initial alveolar-arterial oxygen gradient. Bronchoalveolar lavage fluid was centrifuged, the lipids were extracted from the supernatant, and total lipid profiles of dephosphorylated glycerolipids were analyzed as trimethylsilylether derivatives by high temperature gas-liquid chromatography. Phospholipase A2 levels were determined using a radiolabeled E coli membrane method. Compared to the normal volunteers (109 +/- 13 micrograms/5 ml) and the PC negative group (107 +/- 13 micrograms/5 ml), total BAL lipid was reduced for both the mild PC pneumonia group (73 +/- 10 micrograms/5 ml) and the moderate to severe PC pneumonia group (46 +/- 4 micrograms/5 ml). There was a parallel reduction of diacylglycerol lipids: normal volunteers, 52 +/- 7 micrograms/5 ml; PC negative, 52 +/- 9 micrograms/5 ml; mild PC pneumonia, 35 +/- 7 micrograms/5 ml; and moderate to severe PC pneumonia, 15 +/- 2 micrograms/5 ml. Phospholipase A2 activity in moderate to severe PC pneumonia was twice that of the PC negative patients, and 30 times that for normals. The data demonstrate a marked diminution in surfactant glycerophospholipid in patients with AIDS and PC pneumonia and suggest a potential role for surfactant abnormality in the pathophysiology of this disease.

Length of Stay and Survival after Intensive Care for Severe Pneumocystis carinii Pneumonia: A Prospective Study

Survival rates for persons receiving intensive care for Pneumocystis carinii pneumonia have improved. However, the utility of prolonged intensive care for patients who do not show initial improvement remains unclear. We assessed survival in a nested cohort study of patients receiving intensive care while participating in a randomized trial of early adjunctive corticosteroids for Pneumocystis pneumonia. Twenty-eight of 251 (11 percent) participants were admitted to an intensive care unit. Fourteen (50 percent) of these were discharged alive from the intensive care unit and 11 (39 percent) were discharged alive from the hospital. Survivors and nonsurvivors were similar demographically and with respect to treatment received but differed in the mean days of intensive care received (4.5 vs 8.6 [p = 0.02]). The conditional probability surviving to hospital discharge after intensive care dropped steadily from 39 percent at intensive care unit admission to 17 percent after one week and to 0 percent after two weeks.

Improvement of pulmonary gas exchange after surfactant replacement in rats with Pneumocystis carinii pneumonia.

The effect of intratracheal surfactant instillation on pulmonary function in rats with pneumocystis carinii pneumonia (PCP) was investigated. In these animals which developed PCP with severe respiratory failure after s.c. administration of cortisone acetate over 8-12 weeks, pulmonary function could be improved by surfactant instillation, as measured by an increase in PaO2. Histological examination showed that alveoli of rats with PCP which received no surfactant treatment are filled with foamy edema, whereas after surfactant treatment alveoli are stabilized and well-aerated. These results indicate that surfactant therapy could be used in patients with severe PCP to overcome an acute stage of respiratory distress while at the same time surfactant could serve as a carrier substance for antimicrobial drugs to attain high intra-alveolar and low systemic antimicrobial drug concentrations.

Severe combined immune deficiency presenting with cyclic hematopoiesis

At age 2 months a male infant presented with a cyclic clinical syndrome every 14–21 days that included pharyngeal aphthous ulcers, high fever, lymphadenopathy, pallor, and malaise. Serial blood studies indicated cycling of all blood cell elements, compatible with a diagnosis of cyclic hematopoiesis (CH). He also manifested a progressively severe immune deficiency, not described before in human CH. When first studied at age 5 months, he was hypogammaglobulinaemic with normal B lymphocyte numbers. By 6.5 months, he was agammaglobulinaemic. At age 8 months, he developed severe pneumocystis carinii pneumonia, and studies showed a state of severe combined immune deficiency. The patient received a bone marrow transplant from his HLA-identical sister with no preconditioning therapy. Subsequently, normal immune function developed and the cyclic hematopoiesis resolved. The majority of lymphocytes is of donor origin. Persistence of erythrocytes and neutrophils of recipient origin suggests that the hematopoietic stem cells were not abnormal. We speculate that this patient had a primary deficiency of a differentiation factor affecting maturation of lymphoid and myeloid progenitor cells.

Efficacy of clindamycin/primaquine versus trimethoprim/sulfamethoxazole in primary treatment ofPneumocystis carinii pneumonia

Mild to moderately severe Pneumocystis carinii pneumonia in patients with AIDS was treated in a clinical trial with a combination regimen of primaquine and clindamycin, and the efficacy of this regimen was compared with that of the conventional treatment regimen of trimethoprim/sulfamethoxazole. The results revealed that primaquine/clindamycin appears to be an equally effective alternative to trimethoprim/sulfamethoxazole. The spectrum of side-effects was similar for the two regimens; side-effects occurred with equal frequency but appeared to be less severe in patients given primaquine/clindamycin. Because therapy with primaquine and clindamycin was limited to patients with mild to moderate Pneumocystis carinii pneumonia, studies with this regimen in more severe cases are warranted.

Methylprednisolone decreased mortality and respiratory failure in severe Pneumocystis carinii pneumonia

Source Citation Gagnon S, Boota AM, Fischl MA, et al. Corticosteroids as adjunctive therapy for severe Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. A double-blind, placebo-controlled trial. N Engl J Med. 1990;323:1444-50.