Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
The treatment guidelines for Pneumocystis pneumonia (PCP) suggest adding 40mg of prednisone (or its equivalent in methylprednisolone) twice per day on days 1 through 5, 40 mg days 6 through 10, and 20 mg daily on days 11 through 21 in subjects with moderate and serious PCP. Steroids have shown to improve clinical outcome and reduction in mortality in HIV-infected patients the effectiveness of adjuvant steroid treatment for PCP has been observed if it starts within the first 24 to 48 hours. Possibly, there is a long-term benefit with their use in the recovery of function and limitation of chronic pulmonary complications; recently, benefits have been observed in decreasing the incidence of Inflammatory Immune Reconstitution Syndrome (IRIS) due to Mycobacterium tuberculosis. On the other hand, steroids could increase the morbidity related to adverse reactions as well as paradoxical worsening of associated herpes virus infection, which are attributed to IRIS or as a result of immunosuppression generated by their use. Recently, it has been shown that gradually steroids withdrawal is not necessary in patients who have received less than 21 days of treatment.
This non-inferiority work aims to confirm the null hypothesis that a reduced steroid scheme in patients with moderate PCP (8 days) and severe pneumonia (14 days) is sufficient to limit long-term ventilatory complications and acute postinflammatory syndrome, compared to the conventional 21-day scheme. It also has been hypothesized that it could be associated with fewer cases of IRIS due to herpes virus type 1,2,3 and 8.
The investigators selected hospitalized subjects with confirmed or suspected moderate or severe PCP: the diagnostic certainty will be based on the following criteria:
Proved PCP. Defined as cases with presence of P. jirovecii cysts in bronchial alveolar lavage (BAL) exams or lung biopsy.
Possible PCP. Defined by the following two criteria: 1) the presence of three of four items: cough, fever, dyspnea and compatible radiological or tomographic findings 2) associated clinical improvement after the onset of trimethoprim/sulfamethoxazole (TMP / SMX).
Probable PCP. Defined as the presence of one of the two previous criteria, without other identified microorganisms.
The radiological or tomographic findings compatible with PCP are: presence of bilateral reticular infiltrate, ground glass, crazy paving pattern and presence of bullae, cysts or spontaneous pneumothorax.
The microbiological findings will be the identification of cysts in the Grocott stain or a positive immunofluorescence test (IFA).
Patients will be classified as moderate PCP when the partial pressure of oxygen (PaO2) is less than 70 mmHg and the alveolar arterial difference (Da-a) is greater than 35 mmHg and severe PCP when it is greater than 45 mmHg.
The sample size was calculated for non-inferiority tests to a tail with an estimated mortality of 16% for both groups; using a Z alpha in 1.65 and Z beta in 1.645, with a non-inferiority margin of 0.6; resulting in 98 subjects per group.
After obtaining the informed consent, patients will be randomized accordingly to their CD4+ T cell count (less or more than 50 cells/mm3 and assigned to each group:
The equivalent prednisone doses of systemic steroids will be recorded, as well as the duration of their administration since it could be modified according to the criteria of the treating physicians; demographic data, the start date of ART (Antiretroviral Therapy), and the presence of other opportunistic, nosocomial and co-infections will also be recorded.
The laboratory data that will be recorded at the time of diagnostic suspicion of PCP will be: CD4+ T cell count, HIV viral load, lactate dehydrogenase (LDH), C-reactive protein (PCRe), pAO2, Da-aO2.
Once the patient has been discharged, the patient will be scheduled to continue ambulatory, conventional follow-up at 90, 180 and 360 days after starting the ART and to evaluate secondary outcomes.
Once 50% of the sample size has completed 30 days of follow-up, a preliminary analysis will be conducted to assess safety and efficacy; if differences in the mortality are observed, the study will be terminated.
Not provided
Not provided
Not provided
Not provided
| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Group A conventional steroid regimen | Active Comparator | Subjects will receive the conventional steroid regimen with prednisolone or equivalent (with methylprednisolone): Day 1 to 5: 40 mg orally every 12 h; Day 6 to 10: 40 orally every 24 hours; and Day 11 to 21: 20 mg orally every 24 h. |
|
| Group B shortened steroid regimen | Experimental | Subjects will receive the shortened steroid regimen for the severity of pneumonia with prednisone or equivalent with methylprednisolone, depending the severity of pneumonia:
|
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Conventional steroid regimen | Drug | Subjects will receive the conventional steroid regimen with prednisolone or equivalent (with methylprednisolone): Day 1 to 5: 40 mg orally every 12 h; Day 6 to 10: 40 orally every 24 hours; and Day 11 to 21: 20 mg orally every 24 h. |
| Measure | Description | Time Frame |
|---|---|---|
| Cumulative incidence of Mortality at 30 days | To compare 30-day cumulative incidence of mortality in subjects with moderate and severe PCP and HIV infection in patients receiving the shortened steroid scheme or the conventional 21-day schedule. | 30 days |
| Measure | Description | Time Frame |
|---|---|---|
| Cumulative incidence of Mortality at 90 days | To compare cumulative incidence of mortality in patients receiving the shortened steroid scheme or the conventional 21-day schedule, at 90 days | 90 days |
| Cumulative incidence of mortality at 360 days |
Not provided
Inclusion Criteria:
Exclusion Criteria:
Not provided
Not provided
Not provided
Not provided
Not provided
| Name | Affiliation | Role |
|---|---|---|
| Gustavo Reyes-Teran, M.D. | Instituto Nacional de Enfermedades Respiratorias | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Centro de Investigacion en Enfermedades Infecciosas | México | State of Mexico | 14080 | Mexico |
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
| ID | Term |
|---|---|
| D011020 | Pneumonia, Pneumocystis |
| D000163 | Acquired Immunodeficiency Syndrome |
| ID | Term |
|---|---|
| D008172 | Lung Diseases, Fungal |
| D009181 | Mycoses |
| D001423 | Bacterial Infections and Mycoses |
| D007239 | Infections |
Not provided
Not provided
| ID | Term |
|---|---|
| D003365 | Costs and Cost Analysis |
| ID | Term |
|---|---|
| D004467 | Economics |
| D004472 | Health Care Economics and Organizations |
Not provided
Not provided
After obtaining the informed consent. The subjects will be randomized 6 days after starting treatment for PCP with trimethoprim/ sulfamethoxazole plus prednisone or methylprednisolone. Stratified randomization will be generated by an electronic system, in blocks of 6 and 8, and a 1:1 ratio, according to the CD4+ T cell count (less or more than 50 cells/mm3 and assigned to each group:
Not provided
Not provided
Not provided
Not provided
|
| Shortened steroid regimen | Drug |
|
|
|
To compare mortality in patients receiving the shortened steroid scheme or the conventional 21-day schedule
| 360 days |
| Cumulative incidence of mortality by CMV pneumonitis | To compare cumulative incidence of mortality stratified by the CMV pneumonitis (yes or not) in patients receiving the shortened steroid scheme or the conventional 21-day schedule, at 360 days | 360 days |
| Cumulative incidence of mortality by CD4+T cell count | To compare cumulative incidence of mortality stratified by the CD4+ T cell count (less of or more than 50 cells per mm3), in patients receiving the shortened steroid scheme or the conventional 21-day schedule | 360 days |
| Cumulative incidence of mortality by PCP severity | To compare cumulative incidence of mortality stratified by the PCP severity (moderate or severe), according with the gasometric parameters (AIDSinfo), in patients receiving the shortened steroid scheme or the conventional 21-day schedule | 360 days |
| Time of intubation | To compare the time of intubation expressed in days of intubation,in subjects receiving the shortened steroid scheme or the conventional 21-day schedule | 90 days |
| Time of intubation stratified by PCP severity | To compare the time of intubation expressed in days of intubation, in patients receiving the shortened and conventional steroid scheme, stratified by the PCP severity (moderate or severe), according with the gasometric parameters (AIDSinfo) | 90 days |
| Number of participants with ventilatory requirements, stratified by the CD4+ T cell count | To compare the ventilatory requirements expressed by need for reintubation or intubation during hospitalization, in patients receiving the shortened and conventional steroid scheme, stratified by the CD4+ T cell count (less or more than 50 cells per mm3). | 90 days |
| Number of participants with ventilatory requirements stratified by the CMV coinfection | To compare the ventilatory requirements, expressed by need for reintubation, in patients receiving the shortened and conventional steroid scheme, stratified by the CMV coinfection (yes or not) | 90 days |
| Media of arterial oxygenation | To compare the arterial oxygenation thresholds using the media of arterial partial pressure of oxygen (PaO2) in arterial blood gasometry, obtained at admission, and 21 days in subjects receiving the shortened and conventional steroid scheme | 90 days |
| Media of arterial oxygenation, stratified by PCP severity | To compare the arterial oxygenation thresholds using the media of arterial partial pressure of oxygen (PaO2) in arterial blood gasometry, obtained at admission, and 21 days in subjects receiving the shortened and conventional steroid scheme, stratified by the PCP severity (moderate or severe) | 90 days |
| Media of arterial oxygenation, stratified by CD4+ T cell Count | To compare the arterial oxygenation thresholds using the media of arterial partial pressure of oxygen (PaO2) in arterial blood gasometry, obtained at admission, and 21 days in subjects receiving the shortened and conventional steroid scheme, stratified by the CD4+ T cell count (less or more than 50 cells per mm3) | 90 days |
| Media of arterial oxygenation, stratified by the CMV pneumonitis | To compare the arterial oxygenation thresholds using the media of arterial partial pressure of oxygen (PaO2) in arterial blood gasometry, obtained at admission, and 21 days in subjects receiving the shortened and conventional steroid scheme, stratified by the presence or absence of CMV pneumonitis | 90 days |
| Pulmonary function | To compare the pulmonary function, expressed by the spirometric pattern (normal, or obstructive, or restrictive), in pre and post-bronchodilator spirometry at 360 days in patients receiving the shortened and conventional steroid scheme. | 360 days |
| Pulmonary function changes | To compare the changes in the spirometry pattern (normal, or obstructive, or restrictive), between baseline and 360 days in subjects receiving the shortened and conventional steroid scheme. | 360 days |
| Pulmonary function by spirometry, stratified by CD4+ T cell count | To compare the pulmonary function, expressed by the spirometric pattern (normal, or obstructive, or restrictive), in pre and post-bronchodilator spirometry, in patients receiving the shortened and conventional steroid scheme, stratified by the CD4+ T cell count (less or more than 50 cells per mm3) | 360 days |
| Pulmonary function by spirometry, stratified by PCP severity | To compare the pulmonary function, expressed by the spirometric pattern (normal, or obstructive, or restrictive), in pre and post-bronchodilator spirometry, in patients receiving the shortened and conventional steroid scheme, stratified by the PCP severity (moderate or severe) | 360 days |
| Pulmonary function by spirometry, stratified by CMV pneumonitis | To compare the pulmonary function, expressed by the spirometric pattern (normal, or obstructive, or restrictive), in pre and post-bronchodilator spirometry, in patients receiving the shortened and conventional steroid scheme, stratified by the presence or absence of CMV pneumonitis | 360 days |
| Changes in diffusing lung capacity of carbon monoxide | To compare the changes in the diffusing lung capacity of carbon monoxide (DLCO) in patients receiving the shortened and conventional steroid scheme | 360 days |
| Changes in diffusing lung capacity of carbon monoxide by CMV coinfection | To compare the changes in the diffusing lung capacity of carbon monoxide (DLCO) in patients receiving the shortened and conventional steroid scheme, stratified by the CMV coinfection | 360 days |
| Changes in diffusing lung capacity of carbon monoxide by the PCP severity | To compare the changes in the diffusing lung capacity of carbon monoxide (DLCO) in patients receiving the shortened and conventional steroid scheme, stratified by the PCP severity | 360 days |
| Changes in diffusing lung capacity of carbon monoxide by CD4+ cell count | To compare the changes in the diffusing lung capacity of carbon monoxide (DLCO) in patients receiving the shortened and conventional steroid scheme, stratified by the CD4+ T cell count less or more than 50 cells per mm3 | 360 days |
| IRIS | Compare the cumulative incidence of IRIS associated with herpes virus infection 1, 2, 3, and 8, in patients receiving the shortened and conventional steroid scheme | 360 days |
| Herpes virus dynamic | Measure the replication of herpes virus with the plasma viral load of Epstein-Barr Virus (EBV), Cytomegalovirus (CMV) and human herpes-virus 8 (HHV8) in blood | 90 days |
| D016720 |
| Pneumocystis Infections |
| D012141 | Respiratory Tract Infections |
| D011014 | Pneumonia |
| D008171 | Lung Diseases |
| D012140 | Respiratory Tract Diseases |
| D015658 | HIV Infections |
| D000086982 | Blood-Borne Infections |
| D003141 | Communicable Diseases |
| D015229 | Sexually Transmitted Diseases, Viral |
| D012749 | Sexually Transmitted Diseases |
| D016180 | Lentivirus Infections |
| D012192 | Retroviridae Infections |
| D012327 | RNA Virus Infections |
| D014777 | Virus Diseases |
| D012897 | Slow Virus Diseases |
| D000091662 | Genital Diseases |
| D000091642 | Urogenital Diseases |
| D007153 | Immunologic Deficiency Syndromes |
| D007154 | Immune System Diseases |