Treatment Of Pneumocystis Carinii Pneumonia Research Articles

Diagnosis and treatment of pneumocystis pneumonia - a review article

This study aims to comprehensively evaluate the literature on recent advances in the diagnosis and treatment of Pneumocystis Pneumonia (PCP). A thorough review of relevant literature was conducted. Data were sourced from electronic databases such as PubMed, Scopus, Google Scholar, and Medline, focusing on articles published within the last ten years. The review included 41 articles. The diagnosis of PCP has evolved with the development of molecular techniques, advanced imaging modalities, and artificial intelligence models. Trimethoprim-sulfamethoxazole (TMP-SMX) remains the mainstay of treatment. Corticosteroid adjunctive therapy (CAT) has demonstrated efficacy in improving outcomes, while emerging research suggests a potential role for immunomodulatory agents. Chemoprophylaxis with TMP-SMX remains the main stay of prevention in populations at risk. Despite advances in diagnostic technologies, treatment options for PCP have largely remained unchanged. There are currently no vaccines, and chemoprophylaxis remains the mainstay of prevention. Practical Immediate treatment is essential. New ELISA techniques are viable, while real-time PCR proves superior to nested PCR. Clinical judgment plays a critical role in supporting laboratory diagnoses. High-resolution CT scans may be warranted for evaluating immunosuppressed patients with suspected pneumonia when chest X-rays appear normal. Radiomics can assist in distinguishing PCP from other types of pneumonia in non-HIV patients. Trimethoprim-sulfamethoxazole remains the preferred treatment, with alternative options including dapsone with trimethoprim, clindamycin with primaquine, atovaquone, or pentamidine. Corticosteroid adjunct therapy (CAT) is beneficial in treating PCP, and chemoprophylaxis is essential for high-risk populations.

A Mathematical Model for the Co-infection Dynamics of Pneumocystis Pneumonia and HIV/AIDS with Treatment

The control of opportunistic infections among HIV infected individuals should be one of the major public health concerns in reducing mortality rate of individuals living with HIV/AIDS. In this study a deterministic co-infection mathematical model is developed to provide a quantification of treatment at each contagious stage against Pneumocystis Pneumonia (PCP) among HIV infected individuals on ART. The goal is to minimize the co-infection burden by putting the curable PCP under control. The disease-free equilibria for the HIV/AIDS sub-model, PCP sub-model and the co-infection model are shown to be locally asymptotically stable when their associated disease threshold parameter is less than a unity. By use of suitable Lyapunov functions, the endemic equilibria corresponding to HIV/AIDS and PCP sub-models are globally asymptotically stable whenever the HIV/AIDS related basic reproduction number <I>R</I><sub>0<I>H</I></sub> and the PCP related reproduction number <I>R</I><sub>0<I>P</I></sub> are respectively greater than a unity. The sensitivity analysis results implicate that the effective contact rates are the main mechanisms fueling the proliferation of the two diseases and on the other hand treatment efforts play an important role in reducing the incidence. The model numerical results reveal that PCP carriers have a considerable contribution in the transmission dynamics of PCP. Furthermore, treatment of PCP at all contagious phases significantly reduces the burden with HIV/AIDS and PCP co-infection.

Sulfamethoxazole-trimethoprim for pneumocystis pneumonia prophylaxis, causes of discontinuation and thrombocytopenia observed during administration: A single-center retrospective study

IntroductionThe development of pneumocystis pneumonia (PCP) has recently become a growing concern; thus, its prevention has become increasingly important. Sulfamethoxazole-trimethoprim (ST) is a cost-effective first-line and prophylactic treatment for PCP. However, ST administration criteria for PCP prophylaxis remain unclear and are often discontinued because of adverse events (AEs). In this study, we aimed to investigate the causes of ST discontinuation and the associated AEs using objective data. MethodsWe retrospectively analyzed the data of 162 patients admitted to Kansai Medical University Hospital between January 2018 and December 2020, who received ST for PCP prophylaxis. We compared clinical characteristics, laboratory data, and incidence of AEs between ST non-discontinuation and ST discontinuation groups. Additionally, we divided the patients into non-developing and developing thrombocytopenia (≥ Grade 1) groups based on the investigation results. ResultsNo patients developed PCP while receiving ST. The most common causes of ST discontinuation were thrombocytopenia (37%), liver dysfunction (20%), and rash (18%). Multivariate analysis revealed thrombocytopenia (≥ Grade 1) as a factor significantly associated with ST discontinuation. Furthermore, we identified three factors correlated with thrombocytopenia (≥ Grade 1): age ≥50 years, lymphocyte count <1000/μL, and platelet count <180,000/μL. ConclusionsPatients with the aforementioned factors are at higher risk of developing thrombocytopenia (≥ Grade 1) during ST administration for PCP prophylaxis. Therefore, platelet count monitoring is essential to enhance safety and efficacy of ST treatment. Nonetheless, further research is warranted to explore additional implications and interventions.

Drug repurposing of Mito-Atovaquone for cancer treatment.

Repurposing of approved drugs in a new strategy to combat cancer that leads to savings in time and investment. Atovaquone is a US FDA approved drug for treatment of Pneumocystis carinii pneumonia and malaria. Patent US2023017373 describe the use of mito-atovaquone for the treatment of several types of cancer. Mito-Atovaquone demonstrated antiproliferative activity in cell lines of pancreatic cancer, lung cancer and brain cancer and inhibited tumor growth in syngeneic mouse models and in animals genetically prone to breast cancer. Mito-Atovaquone has the potential to be used successfully in the treatment of various types of tumors.

Efficacy of initial caspofungin plus trimethoprim/sulfamethoxazole for severe PCP in patients without human immunodeficiency virus infection

BackgroundThe number of pneumocystis pneumonia (PCP) cases is increasing in immunocompromised patients without human immunodeficiency virus infection (HIV), causing serious morbidity with high mortality. Trimethoprim/sulfamethoxazole (TMP/SMZ) monotherapy has limited effectiveness in the treatment of PCP. Clinical data on whether initial caspofungin plus TMP/SMZ for this disease is superior to monotherapy in non-HIV-infected patients are limited. We aimed to compare the clinical effectiveness of these regimens for severe PCP in non-HIV patients.MethodsA retrospective study reviewed 104 non-HIV-infected patients with confirmed PCP in the intensive care unit between January 2016 and December 2021. Eleven patients were excluded from the study because TMP/SMZ could not be used due to severe hematologic disorders or clinical data were missing. All enrolled patients were divided into three groups according to different treatment strategies: Group 1 received TMP/SMZ monotherapy, Group 2 received caspofungin combined with TMP/SMZ as first-line therapy, and Group 3 initially received TMP/SMZ monotherapy and later received caspofungin as salvage therapy. The clinical characteristics and outcomes were compared among the groups.ResultsA total of 93 patients met the criteria. The overall positive response rate of anti-PCP treatment was 58.06%, and the overall 90-day all-cause mortality rate was 49.46%. The median APACHE II score was 21.44. The concurrent infection rate was 74.19%, among whom 15.05% (n = 14) of those patients had pulmonary aspergillosis, 21.05% (n = 20) had bacteremia, and 23.65% (n = 22) had CMV infections. The patients who received initial caspofungin combination with TMP/SMZ had the best positive response rate (76.74%) compared to others (p = 0.001). Furthermore, the group that received initial caspofungin combined with TMP/SMZ had a 90-day all-cause mortality rate (39.53%) that was significantly different from that of the shift group (65.51%, p = 0.024), but this rate showed no statistically significant difference compared with that in the monotherapy group (48.62%, p = 0.322). None of the patients had serious adverse events from caspofungin therapy.ConclusionsFor non-HIV-infected patients with severe PCP, initial combination therapy with caspofungin and TMP/SMZ is a promising first-line treatment option compared with TMP/SMZ monotherapy and combination therapy as salvage therapy.

Anidulafungin Treatment Blocks the Sexual Cycle of Pneumocystis murina and Prevents Growth and Survival without Rescue by an Alternative Mode of Replication.

The proposed life cycle of fungi in the genus Pneumocystis has typically included both an asexual cycle via binary fission and a sexual cycle. Until recently, the strategy used for sexual replication was largely unknown, but genomic and functional assays now support a mode known as primary homothallism (self-fertilization). The question of whether an asexual cycle contributes to the growth of these fungi remains. Treatment of Pneumocystis pneumonia in immunosuppressed rodent models with the class of drugs known as echinocandins is challenging the historical concept of asexual replication. The echinocandins target 1,3-β-D-glucan (BG) synthesis resulting in death for most fungi. Because Pneumocystis species have both non-BG expressing life cycle stages (trophic forms) and BG-expressing asci, treatment with anidulafungin and caspofungin resulted in elimination of asci, with large numbers of non-BG expressing organisms remaining in the lungs. Transcriptional analyses of anidulafungin treated Pneumocystis murina-infected lungs indicated that these agents were blocking the sexual cycle. In the present study, we explored whether there was an asexual or alternative method of replication that could rescue P. murina survival and growth in the context of anidulafungin treatment. The effects of anidulafungin treatment on early events in the sexual cycle were investigated by RT-qPCR targeting specific mating genes, including mam2, map3, matMi, matPi, and matMc. Results from the in vivo and gene expression studies clearly indicated there was no rescue by an asexual cycle, supporting these fungi's reliance on the sexual cycle for survival and growth. Dysregulation of mating-associated genes showed that anidulafungin induced effects early in the mating process. IMPORTANCE The concept of a sexually obligate fungus is unique among human fungal pathogens. This reliance can be exploited for drug development and here we show a proof of principle for this unusual target. Most human fungal pathogens eschew the mammalian environment with its battery of immune responses. Pneumocystis appear to have evolved to survive in such an environment, perhaps by using sexual replication to help in DNA repair and to introduce genetic variation in its major surface antigen family because the lung is the primary environment of these pathogens. The concept of primary homothallism fits well into its chosen ecosystem, with ready mating partners expressing both mating type receptors, and a sexual cycle that can introduce beneficial genetic variation without the need for outbreeding.

Clinical Characteristic, Diagnosis and Treatment of Acute Lymphoblastic Leukemia Combined with Pneumocystis Carinii Pneumonia in Children

To investigate the clinical characteristics and treatment of pneumocystis carinii pneumonia (PCP) in children with acute lymphoblastic leukemia (ALL), in order to improve the early diagnosis and effective treatment. Clinical data of five children with ALL developing PCP in the post-chemotherapy granulocyte deficiency phase were analyzed retrospectively. The clinical manifestations, laboratory tests, imaging findings, treatment methods and effect were summarized. The male-to-female ratio of the five children was 1∶4, and the median age was 5.5 (2.9-8) years old. All patients developed PCP during granulocyte deficiency phase after induction remission chemotherapy. The clinical manifestations were generally non-specific, including high fever, tachypnea, dyspnea, non-severe cough, and rare rales in two lungs (wet rales in two patients). Laboratory tests showed elevated C-reactive protein (CRP), serum procalcitonin (PCT), (1,3)-β-D-glucan (BDG), lactate dehydrogenase (LDH) and inflammatory factors including IL-2R, IL-6 and IL-8. Chest CT showed diffuse bilateral infiltrates with patchy hyperdense shadows. Pneumocystis carinii(PC) was detected in bronchoalveolar lavage fluid (BALF) or induced sputum by high-throughput sequencing in all patients. When PCP was suspected, chemotherapy was discontinued immediately, treatment of trimethoprim-sulfame thoxazole (TMP-SMX) combined with caspofungin against PC was started, and adjunctive methylprednisolone was used. Meanwhile, granulocyte-stimulating factor and gammaglobulin were given as the supportive treatment. All patients were transferred to PICU receiving mechanical ventilation due to respiratory distress during treatment. Four children were cured and one died. PCP should be highly suspected in ALL children with high fever, dyspnea, increased LDH and BDG, and diffuse patchy hyperdense shadow or solid changes in lung CT. The pathogen detection of respiratory specimens should be improved as soon as possible. TMP/SMZ is the first-line drug against PCP, and the combination of Caspofungin and TMP/SMZ treatment for NH-PCP may have a better efficacy. Patients with moderate and severe NH-PCP may benefit from glucocorticoid.

Pneumocystis in the era of prophylaxis: do the guidelines have to change?

In the era of effective prophylaxis, the objective of this study was to describe pneumocystis pneumonia (PCP) patients' profile and evaluate the consistency of clinical situations encountered with the recommended indications for prophylaxis. This was a single-centre, retrospective study. All adults (> 18years) with a definitive diagnosis of PCP were included. Data were collected from patients' electronic medical files. The study examined the medical files of 225 patients diagnosed with PCP and treated between 1 January, 2015, and 30 June, 2020. More than 95% of the patients were not on anti-PCP prophylaxis at the time of PCP diagnosis. There were 32 (14%) deaths before the end of PCP treatment, mainly in auto-immune disease (30%) and solid tumours (38%) groups unlike the solid-organ transplants group, among whom deaths were infrequent. Indeed, 48% of our cohort (n = 107) had both corticosteroid (CS) therapy, immunosuppressive or immunomodulatory treatment, and lymphopaenia and could have been considered at high risk for PCP. Trimethoprim/sulfamethoxazole was administered as first-line PCP curative treatment in 95% of the patients. Toxicities of this drug led to treatment interruption in 25% of the patients (except death). This study found a high number of PCP cases over 5years. Unsurprisingly, most of the patients were immunosuppressed, with risk factors for PCP already described in the literature. This large number of PCP cases should be avoidable and, consequently, questions arise. Faced with these data, prophylaxis should be common sense for immunocompromised patients with risk factors, even if formalised recommendations do not exist.

Retrospective Analysis of the Efficacy of Early Antiretroviral Therapy in HIV-1-Infected Patients Coinfected with Pneumocystis jirovecii.

The early initiation of antiretroviral therapy (ART) in HIV-infected patients shortly after the initiation of treatment for Pneumocystis pneumonia (PCP) has not been fully validated in a clinical setting. We retrospectively extracted all patients diagnosed with HIV-related PCP (HIV-PCP), including those with severe cases, who were treated with first-line ART in our hospital. The HIV-PCP patients were divided into two groups: an early ART group (patients who commenced ART within 21 days after the start of PCP treatment) and a deferred ART group (patients who started ART after 22 days). We compared the incidence of AIDS progression or death, the virological suppression rate, and changes in the CD4+ cell count at 24 weeks after the initiation of ART between the two groups. In addition, we analyzed the incidences of immune reconstitution inflammatory syndrome and grade 3 or 4 laboratory and clinical adverse events within 24 weeks as safety outcomes. Ninety-one HIV-PCP patients (36 in the early ART group and 55 in the deferred group) were included in this study. We found no significant difference in the incidence of AIDS progression or death between the two groups. Virological outcomes tended to be better in the early ART group but were not significantly different. Increases in the CD4+ cell counts at 24 weeks were comparable in both groups, suggesting that the safety was not significantly different. Analysis of the propensity-score matched cohort was performed to adjust for selection bias, and no significant difference was found in any outcome. Our results suggest that early ART introduction can be considered for untreated HIV-positive patients with PCP on the basis of efficacy and safety.

Pneumocystis Pneumonia: Immunity, Vaccines, and Treatments.

For individuals who are immunocompromised, the opportunistic fungal pathogen Pneumocystis jirovecii is capable of causing life-threatening pneumonia as the causative agent of Pneumocystis pneumonia (PCP). PCP remains an acquired immunodeficiency disease (AIDS)-defining illness in the era of antiretroviral therapy. In addition, a rise in non-human immunodeficiency virus (HIV)-associated PCP has been observed due to increased usage of immunosuppressive and immunomodulating therapies. With the persistence of HIV-related PCP cases and associated morbidity and mortality, as well as difficult to diagnose non-HIV-related PCP cases, an improvement over current treatment and prevention standards is warranted. Current therapeutic strategies have primarily focused on the administration of trimethoprim-sulfamethoxazole, which is effective at disease prevention. However, current treatments are inadequate for treatment of PCP and prevention of PCP-related death, as evidenced by consistently high mortality rates for those hospitalized with PCP. There are no vaccines in clinical trials for the prevention of PCP, and significant obstacles exist that have slowed development, including host range specificity, and the inability to culture Pneumocystis spp. in vitro. In this review, we overview the immune response to Pneumocystis spp., and discuss current progress on novel vaccines and therapies currently in the preclinical and clinical pipeline.

Clinically amyopathic dermatomyositis presenting with isolated facial edema complicated by acute respiratory failure: a case report

BackgroundIn clinically amyopathic dermatomyositis, the hallmark cutaneous manifestations are the key to diagnosis. We report a case of clinically amyopathic dermatomyositis which presented with facial edema as the sole cutaneous manifestation and was later complicated by acute respiratory failure leading to death.Case presentationA 58-year-old woman presented with edema of the face that had developed approximately one year ago. There was no weakness in the extremities, and the serum creatine kinase level was within normal range. On MRI, there was diffuse edematous change in the bilateral masticator and extra-ocular muscles, accompanied by subcutaneous fat infiltration in the face. A shared decision was made to defer muscle biopsy in the facial muscles. The facial swelling almost resolved with medium-dose glucocorticoid therapy but relapsed in days at glucocorticoid doses lower than 15 mg/day. Combination therapy with either azathioprine, mycophenolate, or methotrexate was not successful in maintaining clinical remission, and the swelling became more severe after relapses. A US-guided core-needle biopsy was subsequently performed in the right masseter muscle. On pathologic examination, there was a patchy CD4 + T cell-dominant lymphoplasmacytic infiltration in the stroma, necrosis of the myofibrils and prominent perifascicular atrophy. Based on those findings, a diagnosis of clinically amyopathic dermatomyositis was made. Therapy with gamma-globulin was not effective in maintaining remission. In the sixth week after starting rituximab, she presented to emergency room with altered mental state from acute respiratory failure. Despite treatment with antibiotics, glucocorticoid pulse, cyclosporin, and polymyxin B-immobilized fiber column direct hemoperfusion, she died three weeks later from persistent hypoxemic respiratory failure.ConclusionsThis case showed the full spectrum and severity of internal organ involvement of dermatomyositis, although the patient presented exclusively with subcutaneous edema limited to the head. The prognosis may be more closely associated with a specific auto-antibody profile than the benign-looking initial clinical manifestation. Close follow-up of lung involvement with prophylactic treatment for Pneumocystis pneumonia and prompt implementation of emerging therapeutic regimens may improve the outcome.

Dihydropteroate Synthase (DHPS) Gene Mutations and Mitochondrial Large Subunit (mtLSU) rRNA Genotype Variations in Pneumocystis jirovecii Strains

Pneumocystis jirovecii is an atypical fungus that causes Pneumocystis pneumonia (PCP) in HIV/AIDS and immunocompromised patients. Antibiotics containing sulfa and sulfone groups are widely used in PCP prophylaxis and treatment. Especially, long-term use of trimethoprim sulfamethoxazole (TMP-SMX) is known to cause certain point mutations associated with drug resistance in the P.jirovecii dihydropteroate synthase (DHPS) gene. In addition, DHPS and mitochondrial large subunit (mtLSU) rRNA genotype characterization provides important data on the epidemiology of P.jirovecii. In this study, it was aimed to investigate the DHPS and mtLSU rRNA gene polymorphisms of P.jirovecii strains isolated from immunocompromised patients in Mersin University Hospital. In this study, 16 P.jirovecii positive samples, which isolated from 96 patients samples, between August 2016 and February 2018, were included. P.jirovecii mtLSU rRNA genotypes were determined by sequence analysis according to polymorphisms at the 85th and 248th nucleotide positions. Nested PCR and RFLP method was applied for mutation analysis of DHPS locus, 165th and 171st nucleotide positions. In the DHPS mutation analysis, 12/16 (75%) wild type (W165/W171) and 4/16 (25%) mutant type (M165/W171) were detected. Two mutant types belonged to HIV/AIDS positive patients with PCP and had a history of prophylaxis; the other 2 mutant types belonged to patients with colonization. In the study, a history of prophylaxis in 3 (19%) of the 16 patients were recorded, and mutant type was detected in these 2 of 3 patients. According to mtLSU-rRNA analysis, 3 different genotypes were obtained from 16 P.jirovecii isolates. In our region, genotype 2 (43.75%; n= 7) was the most common genotype, genotype 1 (37.5%; n= 6) was the second common and genotype 3 (18.75%; n= 3) was the least one. Genotype 4 was not detected in our region. When DHPS and mtLSU-rRNA were evaluated as multilocus, five different genotypes were observed. As a result, these findings provided important data on P.jirovecii epidemiology in our region and potential drug-resistant strains showed a risk of transmission in immunosuppressive patients. Multicenter studies involving more P.jirovecii isolates are needed to better define the epidemiology of P.jirovecii in our region and in our country.

Caspofungin combined with TMP/SMZ as a first-line therapy for moderate-to-severe PCP in patients with human immunodeficiency virus infection.

ObjectivesThe effectiveness of trimethoprim/sulfamethoxazole (TMP/SMZ) for pneumocystis pneumonia (PCP) is limited with adverse events. Caspofungin, by inhibiting the cyst form of Pneumocystis jirovecii, may be an alternative therapy for PCP. However, the availability of clinical data about caspofungin combined with TMP/SMZ in the treatment of PCP in HIV‐infected patients is limited. Thus, we aimed to examine the clinical effectiveness and safety of caspofungin combined with TMP/SMZ as a first‐line therapy for moderate‐to‐severe PCP in HIV‐infected patients.MethodsFrom January 2017 to December 2019, data of HIV‐infected patients with moderate‐to‐severe PCP who received either TMP/SMZ alone or caspofungin combined with TMP/SMZ as first‐line therapy were retrospectively reviewed to assess the effectiveness and safety of each regimen. The Kaplan–Meier curve and log‐rank test were used for survival analysis.ResultsA total of 278 patients met the criteria. The overall positive response rate of PCP treatment was 48.92%, and the overall all‐cause in‐hospital mortality rate was 33.09%. Patients who received combination therapy consisting of caspofungin and TMP/SMZ had a better positive response rate (59.44% vs. 37.78%, P < 0.001) and lower all‐cause in‐hospital mortality rate (24.48% vs. 42.22%, P = 0.003). Also, patients who received combination therapy had higher survival rate during a hospital stay (75.52% vs. 57.78%, P = 0.004), and those who received longer combination therapy were more likely to have higher survival rate (P = 0.042). We found that age (P = 0.019), CD4 cell count (P = 0.001) and therapeutic regimen (P = 0.002) were significant risk factors for all‐cause in‐hospital mortality rate in univariate analysis. In multivariate analysis, only CD4 cell count and therapeutic regimen were statistically significant factors associated with all‐cause in‐hospital mortality rate. Patients with a CD4 count of > 30 cells/µL and patients who received combination therapy consisting of caspofungin and TMP/SMZ were more likely to survive from PCP (P = 0.011 and P = 0.002, respectively). There were no additional severe adverse events caused by adding caspofungin.ConclusionsFor HIV‐infected patients with moderate‐to‐severe PCP, combination therapy with caspofungin and TMP/SMZ is an effective and promising first‐line therapy with no greater number of adverse events compared with TMP/SMZ monotherapy. Patients who received caspofungin had better positive response rates and lower all‐cause in‐hospital mortality rates. Also, we recommend early initiation of caspofungin.

Single-Center Retrospective Analysis of Prophylaxis and Treatment of Pneumocystis carinii Pneumonia in Patients with Renal Dysfunction After Renal Transplantation.

BackgroundPneumocystis carinii is an opportunistic pathogen that can cause severe lung infections after renal transplantation. Trimethoprim-sulfamethoxazole (TMP-SMX) has been recognized as a first-line treatment for chemoprophylaxis of Pneumocystis carinii pneumonia (PCP). This study aimed to establish a personalized chemoprophylaxis prescription specifically for those recipients with renal insufficiency.Material/MethodsThis retrospective study included 68 patients with confirmed PCP after renal transplantation. Patients were divided into 2 groups: an abnormal renal function (ARF) group (creatinine ≥1.5 ng/dl; n=37) and a normal renal function (NRF) group (creatinine <1.5 ng/dl; n=31). Clinical characteristics and prognosis of PCP in both groups were compared and analyzed.ResultsPatients in the ARF group had more prophylaxis after transplantation (15 [40.5%] vs. 2 [6.5%], p=0.047), had more biopsy-proven rejections (10 [27%] vs. 1 [3.2%], p=0.008), and had lower lymphocyte counts (0.6 [05–0.9] vs. 1.1 [0.7–1.6], p<0.01). Renal function after treatment was obviously improved in the ARF group, which had a significant decrease rate in creatinine (−13.2% [−22~4.8%] vs. −4.4% [−12.6~20.9%], p=0.043).ConclusionsPCP prophylaxis regimens for recipients after renal transplantation are still needed regardless of whether the renal functions were normal or abnormal, especially for recipients with persistent lymphopenia or rejection after transplantation.

Clinical characteristics and prevalence of dihydropteroate synthase gene mutations in Pneumocystis jirovecii-infected AIDS patients from low endemic areas of China.

Pneumocystis pneumonia (PCP) is an opportunistic and potentially life-threatening infection of AIDS patients caused by the fungus Pneumocystis jirovecii (P. jirovecii). Trimethoprim-sulfamethoxazole (TMP-SMX) is the most commonly used drug combination in the treatment and prophylaxis of PCP. However, with long-term use of this combination, mutations in the dihydropteroate synthase (DHPS) gene of P. jirovecii bring about the development of resistance. Data on the prevalence of P. jirovecii and its DHPS mutants in China, especially in low endemic areas, are still limited. Thus, in the present study, we measured the P. jirovecii infection rate among HIV-positive and AIDS (HIV/AIDS) patients with suspected PCP and investigated the relationship between CD4+ T cell count and PCP occurrence. As well as the polymerase chain reaction (PCR) analysis and sequencing, the restriction fragment length polymorphism (RFLP) method was used to analyze DHPS point mutation in P. jirovecii strains. P. jirovecii was detected in 40.82% of cases. The clinical symptoms and signs of PCP were not typical; with decreasing CD4+ T cell counts, PCP infection in HIV/AIDS patients increased. In only one case (1.67%), the patients’ DHPS gene could not be cut by the Acc I restriction enzyme. Furthermore, mutation at codon 171 was detected in 11 cases and no mutation was found at codon 57. Patients treated with sulfamethoxazole combined with Voriconazole or Caspofungin exhibited favorable results. After treatment, the symptoms of dyspnea were alleviated, and chest computed tomography findings showed the improvement of lung shadows. These indicated that the prevalence of DHPS mutations in P. jirovecii isolates in AIDS-PCP patients in the region was low. Thus, the contribution of gene mutations to treatment failure requires further research.

Management of community-acquired pneumonia in children: South African oracic Society guidelines (part 3)

Background. Pneumococcal conjugate vaccine (PCV) administration and other advances have been associated with a shift in the aetiological spectrum of community-acquired pneumonia, necessitating reconsideration of empiric antibiotic treatment guidelines. Management strategies have also evolved in the last decade. Objectives. To produce revised guidelines for the treatment of pneumonia in South African (SA) children, including ambulatory, hospital and intensive care management. Methods. An expert subgroup, reviewing evidence on the management of childhood pneumonia, was convened as part of a broader group revising SA guidelines. Evidence was graded using the British Thoracic Society (BTS) grading system and recommendations were made. Results. Antibiotic treatment depends on the child’s age, possible aetiology, antimicrobial resistance patterns, previous treatment, as well as factors affecting host susceptibility, including HIV, and nutritional and vaccination status. All children with signs of severe pneumonia should receive antibiotics. Children 1 month of age, high-dose amoxicillin remains the preferred antibiotic. For severe pneumonia in this age group, hospitalisation and empiric treatment with amoxicillin-clavulanate orally is recommended; if oral therapy is not tolerated, intravenous therapy is recommended. Generally, 5 days of therapy is proposed, but longer duration may be needed in cases of severe or complicated disease. A macrolide antibiotic should be used if pertussis, mycoplasma or chlamydia pneumonia is suspected. Most hypoxic children can receive oxygen via nasal cannulae, but respiratory support should be individualised and extends to non-invasive and invasive ventilation in some cases. Children should be fed enterally; if this is not possible, administer intravenous isotonic fluids at <80% of maintenance, with monitoring of sodium levels. Empiric antibiotic treatment is the same in HIV-infected, HIV-exposed uninfected and HIV-uninfected children, although treatment for pneumocystis pneumonia and/or cytomegalovirus pneumonia should be considered in HIV-infected infants, especially in the absence of combination antiretroviral therapy. Conclusions. Updated guidelines optimise the management of childhood pneumonia in the context of changing epidemiology, improvements in HIV prevention and new evidence on management.

Prognostic impact of pre-existing interstitial lung disease in non-HIV patients with Pneumocystis pneumonia.

BackgroundThe increasing incidence of life-threatening Pneumocystis pneumonia (PCP) in non-HIV immunocompromised patients is a global concern. Yet, no reports have examined the prognostic significance of pre-existing interstitial lung disease (ILD) in non-HIV PCP.MethodsWe retrospectively reviewed the medical records of non-HIV PCP patients with (ILD group) or without (non-ILD group) pre-existing ILD. The clinical features and outcomes of the ILD group were compared with those of the non-ILD group. Cox regression models were constructed to identify prognostic factors.Results74 patients were enrolled in this study. The 90-day mortality was significantly higher in the ILD group than in the non-ILD group (62.5% versus 19.0%, p<0.001). In the ILD group, patients with a higher percentage of bronchoalveolar lavage fluid neutrophils had worse outcomes compared to those having a lower percentage (p=0.026). Multivariate analyses revealed that pre-existing ILD (p=0.002) and low levels of serum albumin (p=0.009) were independent risk factors for 90-day mortality. Serum levels of β-d-glucan were significantly reduced after treatment of PCP in both groups, whereas levels of Krebs von den Lungen-6 (KL-6) significantly increased in the ILD group. In the ILD group, the 90-day mortality of patients with increasing KL-6 levels after treatment was significantly higher than those with decreasing levels (78.9% versus 0%, p=0.019).ConclusionIn non-HIV PCP patients, pre-existing ILD is associated with a poorer prognosis. Prophylaxis for PCP is needed in patients with pre-existing ILD under immunosuppression.

Niflumic Acid Reverses Airway Mucus Excess and Improves Survival in the Rat Model of Steroid-Induced Pneumocystis Pneumonia.

Although the role of adaptive immunity in fighting Pneumocystis infection is well known, the role of the innate, airway epithelium, responses remains largely unexplored. The concerted interaction of innate and adaptive responses is essential to successfully eradicate infection. Increased expression of goblet-cell-derived CLCA1 protein plus excess mucus in infant autopsy lungs and in murine models of primary Pneumocystis infection alert of innate immune system immunopathology associated to Pneumocystis infection. Nonetheless, whether blocking mucus-associated innate immune pathways decreases Pneumocystis-related immunopathology is unknown. Furthermore, current treatment of Pneumocystis pneumonia (PcP) relying on anti-Pneumocystis drugs plus steroids is not ideal because removes cellular immune responses against the fungal pathogen. In this study, we used the steroid-induced rat model of PcP to evaluate inflammation and mucus progression, and tested the effect of niflumic acid (NFA), a fenamate-type drug with potent CLCA1 blocker activity, in decreasing Pneumocystis-associated immunopathology. In this model, animals acquire Pneumocystis spontaneously and pneumonia develops owing to the steroids-induced immunodeficiency. Steroids led to decreased animal weight evidencing severe immunosuppression and to significant Pneumocystis-associated pulmonary edema as evidenced by wet-to-dry lung ratios that doubled those of uninfected animals. Inflammatory cuffing infiltrates were noticed first around lung blood vessels followed by bronchi, and both increased progressively. Similarly, airway epithelial and lumen mucus progressively increased. This occurred in parallel to increasing levels of MUC5AC and mCLCA3, the murine homolog of hCLCA1. Administration of NFA caused a significant decrease in total mucus, MUC5AC and mCLCA3 and also, in Pneumocystis-associated inflammation. Most relevant, NFA treatment improved survival at 8 weeks of steroids. Results suggest an important role of innate immune responses in immunopathology of steroid-induced PcP. They warrant evaluation of CLCA1 blockers as adjunctive therapy in this condition and describe a simple model to evaluate therapeutic interventions for steroid resistant mucus, a common condition in patients with chronic lung disease like asthma, chronic obstructive pulmonary disease (COPD) and cystic fibrosis.

Echinocandins as alternative treatment for HIV-infected patients with Pneumocystis pneumonia.

Treatment with trimethoprim-sulfamethoxazole for Pneumocystis pneumonia (PCP) is often associated with adverse effects. Echinocandins, by inhibiting the cyst form of Pneumocystis jirovecii, may be an alternative therapy for PCP. However, clinical experience with echinocandins in the treatment of PCP remains limited among HIV-infected patients. From August 2013 to April 2018, data of HIV-infected patients with confirmed PCP who received echinocandins as alternative treatment because of intolerance or unresponsiveness to trimethoprim-sulfamethoxazole were retrospectively reviewed to assess the effectiveness and safety of echinocandins alone or in combination with other agents. In total, 34 patients were included, with a median CD4 count of 27 cells/μl [interquartile range (IQR), 20-93). Twenty-four patients (70.6%) presented with moderate-to-severe PCP. The most common adverse effects leading to withdrawal of trimethoprim-sulfamethoxazole were hepatotoxicity (29.4%), gastrointestinal upset (23.5%), and rash (17.6%). Nine patients (26.5%) were switched to echinocandins after failure of trimethoprim-sulfamethoxazole. The median interval before switch from trimethoprim-sulfamethoxazole to echinocandins was 9.0 days (IQR 5.0-14.0). The all-cause and PCP-related in-hospital mortality rate of patients receiving echinocandins as alternative therapy was 20.6% (7/34) and 14.7% (5/34), respectively. The all-cause in-hospital mortality was 0% in mild PCP cases and 29% (7/24) in moderate-to-severe PCP cases. Patients who had failed to respond to first-line trimethoprim-sulfamethoxazole treatment tended to have a higher in-hospital mortality rate than those without first-line trimethoprim-sulfamethoxazole failure (44.4% versus 12.0%, P = 0.06). Echinocandin therapy might serve as an alternative option for HIV-infected patients with PCP who are intolerable to trimethoprim-sulfamethoxazole.

Serial change in serum biomarkers during treatment of Non-HIV Pneumocystis pneumonia

BackgroundFor patients with non–human immunodeficiency virus (HIV) Pneumocystis pneumonia (PCP), data are limited on serial changes in serum biomarkers and the correlations with clinical outcomes. ObjectiveThis study evaluated serial change in serum biomarkers and clinical outcomes of non-HIV PCP. MethodsWe retrospectively reviewed data from 63 patients treated for non-HIV PCP at Toho University Omori Medical Center. The patients were classified as survivors and nonsurvivors on the basis of 60-day PCP mortality. The groups were compared for clinical course and levels of serum biomarkers (β-D glucan, Krebs von den Lungen-6 antigen [KL-6], and surfactant protein-D [SP-D]), which were measured at baseline, and 7 days and 14 days after starting treatment. In addition, serial changes in serum biomarkers were analyzed in survivors and nonsurvivors. ResultsThere were 14 PCP nonsurvivors and 49 survivors. Biomarker values were not different between groups at baseline. At 7 and 14 days after starting treatment, the proportions of patients with elevated β-D glucan and KL-6 did not significantly differ between groups; however, the proportion of patients with elevated SP-D was significantly lower among survivors than among nonsurvivors (57.1% vs. 100%, p = 0.009; 30% vs. 100%, p < 0.001; respectively). SP-D on day 14 was significantly lower than that at baseline among survivors (99.6 [61.0–190.3] vs. 156 [100.8–283.5]; p = 0.045) but significantly higher among nonsurvivors (974 [744.5–1565] vs. 317 [211–448]; p = 0.03). ConclusionSerum SP-D value continues to increase after failure of treatment for non-HIV PCP and may thus be associated with outcomes for non-HIV PCP patients.