Management of Pneumocystis pneumonia in patients with inflammatory disorders

Pneumocystis jirovecii is an atypical fungus that causes Pneumocystis pneumonia in immunocompromised patients. Underlying diseases associated with Pneumocystis pneumonia mainly consist of hematologic malignancies, solid tumors, organ transplant recipients and inflammatory disorders. Currently, inflammatory disorders represent 20% of underlying diseases. Corticosteroids are considered as a major risk factor. Recently introduced immunosuppressive drugs, such as antitumor necrosis factor monoclonal antibodies, could enhance the risk of Pneumocystis pneumonia. In patients with inflammatory disorders, lymphopenia is probably a determining factor but CD4+ T-cell count associated with the risk of Pneumocystis pneumonia remains unassessed. The diagnosis is based upon clinical, radiologic and biologic data. The identification of P. jirovecii usually requires a lower respiratory tract specimen, even if oral washes samples seem to be promising. According to recent data, immunofluorescent stains should be considered as the new gold standard, and specialized techniques such as PCR should be applied for sputum samples or oral washes. Recommendations on prophylaxis remains controversial except in patients with Wegener's granulomatosis and systemic lupus erythematosus. Cotrimoxazole is the preferred agent for prophylaxis as well as for treatment. An adjunctive corticosteroid therapy is usually prescribed despite the lack of evidence for utility in patients with inflammatory disorders. As person-to-person transmission is the most likely mode of acquiring P. jirovecii, isolation precautions should be advised.     

Do inhaled corticosteroids increase the risk of Pneumocystis pneumonia in people with lung cancer?

Pneumocystis pneumonia(PCP) is a life-threatening infection in immunocompromised patients. It is relatively uncommon in patients with lung cancer. We report a case of PCP in a 59-year-old man with a past medical history of chronic obstructive pulmonary disease treated with formoterol and a moderate daily dose of inhaled budesonide. He had also advanced stage non-small lung cancer treated with concurrent chemo-radiation with a cisplatin-etoposide containing regimen. The diagnosis of PCP was suspected based on the context of rapidly increasing dyspnea, lymphopenia and the imaging findings. Polymerase chain reaction testing on an induced sputum specimen was positive for Pneumocystis jirovecii. The patient was treated with oral trimethoprim-sulfamethoxazole and systemic corticotherapy and had showed clinical and radiological improvement. Six months after the PCP diagnosis, he developed a malignant pleural effusion and expired on hospice care. Through this case, we remind the importance of screening for PCP in lung cancer patients under chemotherapeutic regimens and with increasing dyspnea. In addition, we alert to the fact that long-term inhaled corticosteroids may be a risk factor for PCP in patients with lung cancer. Despite intensive treatment, the mortality of PCP remains high, hence the importance of chemoprophylaxis should be considered.     

Pneumonia, pneumocystis pneumonia

Pneumonia (almost equally bacterial) is the most common and serious adverse events of the patients with rheumatoid arthritis (RA) prescribing anti-tumor necrosis factor(TNF) agents. Furthermore, it has been shown that Pneumocystis jirovecii should be one of the important causal microorganisms by the results of postparketing all-patients registration surveillance in Japan. Older age, pulmonary comorbidities, diabetes mellitus, or dosage of co -prescribing glucocorticoid has been extracted as a predictable risk factor respectively and synergistically by the surveillance. When prescribing anti-TNF agents, it is possible that considering these risk factors might reduce the incidence of bacterial or Pneumocystis pneumonia in RA patients.     

Pneumocystis jirovecii testing by real-time polymerase chain reaction and direct examination among immunocompetent and immunosuppressed patient groups and correlation to disease specificity

We used real-time polymerase chain reaction (PCR) targeting the cdc2 gene and direct fluorescent microscopy examination (DFME) to evaluate the prevalence of Pneumocystis jirovecii among immunocompetent patients without clinical pulmonary infection and immunosuppressed patients evaluated for opportunistic pulmonary infections. Among 102 bronchoalveolar lavage samples collected from immunocompetent patients without infection, none tested positive for P. jirovecii by either DFME or real-time PCR despite the presence of other comorbidities. Among patients with suspected pulmonary infection and tested with either assay, real-time PCR produced a higher number of positive results compared to DFME and increased P. jirovecii detection by 7% when added to DFME-negative samples. Real-time PCR may have increased sensitivity for P. jirovecii detection over DFME and decrease the risk of sample contamination compared to conventional and nested PCR. The use of single-copy gene targets (e.g., cdc2) may lower the rate of "colonization" detection and confer a high predictive value for Pneumocystis pneumonia.     

Pneumocystis jirovecii multilocus genotyping in pooled DNA samples: a new approach for clinical and epidemiological studies

Specific single-nucleotide polymorphisms (SNPs) are recognized as important DNA sequence variations influencing the pathogenesis of Pneumocystis jirovecii and the clinical outcome of Pneumocystis pneumonia, which is a major worldwide cause of illness among immunocompromised patients. Genotyping platforms for pooled DNA samples are promising methodologies for genetic characterization of infectious organisms. We have developed a new typing strategy for P. jirovecii, which consisted of DNA pools prepared according to clinical data (HIV diagnosis, microscopic and molecular detection of P. jirovecii, parasite burden, clinical diagnosis and follow-up of infection) from individual samples using quantitative real-time PCR followed by multiplex-PCR/single base extension (MPCR/SBE). The frequencies of multiple P. jirovecii SNPs (DHFR312, mt85, SOD215 and SOD110) encoded at three distinct loci, the dihydrofolate reductase (DHFR), the mitochondrial large-subunit rRNA (mtLSU rRNA) and the superoxide dismutase (SOD) loci, were estimated in seven DNA pooled samples, representing a total of 100 individual samples. The studied SNPs were confirmed to be associated with distinct clinical parameters of infection such as parasite burden and follow-up. The MPCR/SBE-DNA pooling methodology, described in the present study, was demonstrated to be a useful high-throughput procedure for large-scale P. jirovecii SNPs screening and a powerful tool for evaluation of clinically relevant SNPs potentially related to parasite burden, clinical diagnosis and follow-up of P. jirovecii infection. In further studies, the candidate SNPs mt85, SOD215 and SOD110 may be used as molecular markers in association with MPCR/SBE-DNA pooling to generate useful information for understanding the patterns and causes of Pneumocystis pneumonia.     

Mutations of Pneumocystis jirovecii dihydrofolate reductase associated with failure of prophylaxis

Most drugs used for prevention and treatment of Pneumocystis jirovecii pneumonia target enzymes involved in the biosynthesis of folic acid, i.e., dihydropteroate synthase (DHPS) and dihydrofolate reductase (DHFR). Emergence of P. jirovecii drug resistance has been suggested by the association between failure of prophylaxis with sulfa drugs and mutations in DHPS. However, data on the occurrence of mutations in DHFR, the target of trimethoprim and pyrimethamine, are scarce. We examined polymorphisms in P. jirovecii DHFR from 33 patients diagnosed with P. jirovecii pneumonia who were receiving prophylaxis with a DHFR inhibitor (n = 15), prophylaxis without a DHFR inhibitor (n = 11), or no prophylaxis (n = 7). Compared to the wild-type sequence present in GenBank, 19 DHFR nucleotide substitution sites were found in 18 patients with 3 synonymous and 16 nonsynonymous mutations. Of 16 amino acid changes, 6 were located in positions conserved among distant organisms, and five of these six positions are probably involved in the putative active sites of the enzyme. Patients with failure of prophylaxis, including a DHFR inhibitor, were more likely to harbor nonsynonymous DHFR mutations than those who did not receive such prophylaxis (9 of 15 patients versus 2 of 18; P = 0.008). Analysis of the rate of nonsynonymous versus synonymous mutations was consistent with selection of amino acid substitutions in patients with failure of prophylaxis including a DHFR inhibitor. The results suggest that P. jirovecii populations may evolve under selective pressure from DHFR inhibitors, in particular pyrimethamine, and that DHFR mutations may contribute to P. jirovecii drug resistance.     

Prophylaxis of Pneumocystis pneumonia in immunocompromised non-HIV-infected patients: systematic review and meta-analysis of randomized controlled trials

OBJECTIVE: To assess the efficacy of prophylaxis for Pneumocystis pneumonia (PCP), caused by Pneumocystis jirovecii (formerly Pneumocystis carinii), for immunocompromised non-HIV-infected patients by conducting a systematic review and meta-analysis. METHODS: We searched for randomized controlled trials that compared prophylaxis using antibiotics effective against P jirovecii, given orally or intravenously, vs placebo, no intervention, or antibiotics with no activity against P jirovecii. In addition, we included trials that compared different PCP prophylactic regimens or administration schedules. The search included the Cochrane Central Register of Controlled Trials, PubMed, Latin American and Caribbean Health Sciences Literature, and conference proceedings. No language, year, or publication restrictions were applied. Two reviewers (H.G. and M.P.) independently searched, selected trials, extracted data, and performed methodological quality assessment. Relative risks (RRs) with 95% confidence intervals (CIs) are reported. Meta-analysis was performed using the random-effects model. RESULTS: Twelve randomized trials were identified, including 1245 patients (50% children) who had undergone autologous bone marrow or solid organ transplant or who had hematologic cancer. When trimethoprim-sulfamethoxazole was administered, a 91% reduction was observed in the occurrence of PCP (RR, 0.09; 95% CI, 0.02-0.32); the number needed to treat was 15 (95% CI, 13-20) patients, with no heterogeneity. Pneumocystis pneumonia-related mortality was significantly reduced (RR, 0.17; 95% CI, 0.03-0.94), whereas all-cause mortality did not differ significantly (RR, 0.79; 95% CI, 0.18-3.46). Adverse events that required discontinuation occurred in 3.1% of adults and none of the children, and all were reversible. No differences between once-daily and thrice-weekly administration schedules were found. CONCLUSION: Balanced against severe adverse events, PCP prophylaxis is warranted when the risk for PCP is higher than 3.5% for adults. Adverse events are less frequent in children, for whom prophylaxis might be warranted at lower PCP incidence rates.     

Symptomatic hyperbilirubinemia secondary to dapsone-induced hemolysis and atazanavir therapy

The antiretroviral agent atazanavir is associated with mild asymptomatic hyperbilirubinemia. We report two cases of symptomatic hyperbilirubinemia attributed to atazanavir in conjunction with the Pneumocystis jirovecii pneumonia prophylaxis agent dapsone. Symptoms and laboratory evidence of hemolysis resolved upon discontinuation of dapsone, enabling successful antiretroviral therapy. Symptomatic hyperbilirubinemia due to hemolytic anemia is a potential adverse event when using the combination of atazanavir and dapsone in the treatment of patients with the human immunodeficiency virus.     

Low prevalence of Pneumocystis jirovecii lung colonization in Ugandan HIV-infected patients hospitalized with non-Pneumocystis pneumonia

Pneumocystis jirovecii is an important opportunistic infection in human immunodeficiency virus (HIV)-infected patients. In the developed world, P. jirovecii epidemiology is marked by frequent colonization in immunosuppressed patients, but data on the prevalence of colonization are very limited in sub-Saharan Africa, where the majority of persons living with HIV reside. Our objective was to describe the epidemiology of P. jirovecii colonization among HIV-positive patients in a cross-sectional, hospital-based study of patients admitted with suspected pneumonia in Kampala, Uganda. P. jirovecii was detectable in bronchoalveolar lavage fluid from 7 (6%) of 124 consecutive patients with non-Pneumocystis pneumonia. Colonization was not associated with patient demographic or clinical information. This prevalence is substantially lower than in published studies in the developed world and suggests that there is a limited reservoir of organisms for clinical infections in this Ugandan population. These findings may partially explain the low incidence of Pneumocystis pneumonia in Uganda and other sub-Saharan African countries.     

The changing epidemiology of HIV-infected patients in the intensive care unit

With the introduction of highly active antiretroviral therapy (HAART), HIV has become a chronic disease. As HIV-infected patients are aging, they are at increased risk for comorbid diseases. These non-AIDS related diseases account for a growing proportion of intensive care unit (ICU) admissions in HIV-infected patients in recent studies. HIV-infected patients still present to the ICU with HIV-related conditions such as Pneumocystis jirovecii pneumonia (PCP), but these conditions are becoming less common. Respiratory failure remains the most common indication for ICU admission. Immune reconstitution inflammatory response syndrome and toxicities related to HAART may also result in ICU admission. While ICU survival has improved since the earliest era of the HIV epidemic, hospital mortality for HIV-infected patients admitted to the ICU remains around 30%. Risk factors for ICU mortality include poor functional status, weight loss, more than one year between HIV diagnosis and ICU admission, lower serum albumin, higher severity of illness, need for mechanical ventilation, and respiratory failure-particularly if due to PCP and accompanied by pneumothorax. The impact of HAART on ICU outcomes is unclear. HAART administration in the ICU can be challenging due to limited delivery routes, concern for viral resistance and medication toxicities. There are no data to determine the safety or efficacy of HAART initiation in the ICU. Future studies are needed to address the role of age, associated comorbidities and impact of HAART on outcomes of HIV-infected patients admitted to the ICU.     

Genetic characterization of the dihydrofolate reductase gene of Pneumocystis jirovecii isolates from Portugal

OBJECTIVES: The aim of the present study was to evaluate the genetic variation of Pneumocystis jirovecii dihydrofolate reductase (DHFR) gene in an immunocompromised Portuguese population and to investigate the possible association between DHFR genotypes and P. jirovecii pneumonia (PcP) prophylaxis with co-trimoxazole. METHODS: One hundred and thirty-eight P. jirovecii isolates were submitted to DHFR genetic characterization by PCR and sequencing. RESULTS: In the studied population, 72.7% of the patients presented sequences identical to the wild-type sequence of the P. jirovecii DHFR gene and 27.3% presented point substitutions. A total of nine substitution sites were identified; four synonymous substitutions at nucleotide positions 201, 272, 312 and 381 were detected in 31 patients. Five non-synonymous substitutions were observed, leading to the DHFR mutations Leu-13-->Ser, Asn-23-->Ser, Ser-31-->Phe, Met-52-->Leu and Ala-67-->Val. With the exception of the polymorphism at position 312 and the mutation at codon 52, all polymorphisms were reported in this study for the first time. CONCLUSIONS: Our results suggest that DHFR gene polymorphisms are frequent in the Portuguese immunocompromised population but do not seem to be associated with PcP prophylaxis failure (P = 0.748 and P = 0.730).     

Clinical review: Respiratory failure in HIV-infected patients - a changing picture

Respiratory failure in HIV-infected patients is a relatively common presentation to ICU. The debate on ICU treatment of HIV-infected patients goes on despite an overall decline in mortality amongst these patients since the AIDS epidemic. Many intensive care physicians feel that ICU treatment of critically ill HIV patients is likely to be futile. This is mainly due to the unfavourable outcome of HIV patients with Pneumocystis jirovecii pneumonia who need mechanical ventilation. However, the changing spectrum of respiratory illness in HIV-infected patients and improved outcome from critical illness remain under-recognised. Also, the awareness of certain factors that can affect their outcome remains low. As there are important ethical and practical implications for intensive care clinicians while making decisions to provide ICU support to HIV-infected patients, a review of literature was undertaken. It is notable that the respiratory illnesses that are not directly related to underlying HIV disease are now commonly encountered in the highly active antiretroviral therapy (HAART) era. The overall incidence of P. jirovecii as a cause of respiratory failure has declined since the AIDS epidemic and sepsis including bacterial pneumonia has emerged as a frequent cause of hospital and ICU admission amongst HIV patients. The improved overall outcome of HIV patients needing ICU admission is related to advancement in general ICU care, including adoption of improved ventilation strategies. An awareness of respiratory illnesses in HIV-infected patients along with an appropriate diagnostic and treatment strategy may obviate the need for invasive ventilation and improve outcome further. HIV-infected patients presenting with respiratory failure will benefit from early admission to critical care for treatment and support. There is evidence to suggest that continuing or starting HAART in critically ill HIV patients is beneficial and hence should be considered after multidisciplinary discussion. As a very high percentage (up to 40%) of HIV patients are not known to be HIV infected at the time of ICU admission, the clinicians should keep a low threshold for requesting HIV testing for patients with recurrent pneumonia.     

Antimicrobial prophylaxis in adults

Antimicrobial prophylaxis is used by clinicians for the prevention of numerous infections, including sexually transmitted diseases, human immunodeficiency virus infection, tuberculosis, rheumatic fever, recurrent cellulitis, meningococcal disease, recurrent uncomplicated urinary tract infections in women, spontaneous bacterial peritonitis in patients with cirrhosis, influenza, malaria, infective endocarditis, pertussis, plague, anthrax, early-onset group B streptococcal disease in neonates, and animal bite wounds. Certain opportunistic infections such as Pneumocystis carinii pneumonia in immunocompromised patients also can be effectively prevented with primary antimicrobial prophylaxis. Perioperative antimicrobial prophylaxis is recommended for various surgical procedures to prevent surgical site infection. Optimal antimicrobial agents for prophylaxis are bactericidal, nontoxic, inexpensive, and active against the typical pathogens that cause surgical site infection postoperatively. To maximize its effectiveness, intravenous perioperative prophylaxis should be given within 30 to 60 minutes before the time of surgical incision. Antibiotic prophylaxis should be of short duration to decrease toxicity, antimicrobial resistance, and excess cost.     

Mutations in the Pneumocystis jirovecii DHPS gene confer cross-resistance to sulfa drugs

Pneumocystis jirovecii is a major opportunistic pathogen that causes Pneumocystis pneumonia (PCP) and results in a high degree of mortality in immunocompromised individuals. The drug of choice for PCP is typically sulfamethoxazole (SMX) or dapsone in conjunction with trimethoprim. Drug treatment failure and sulfa drug resistance have been implicated epidemiologically with point mutations in dihydropteroate synthase (DHPS) of P. jirovecii. P. jirovecii cannot be cultured in vitro; however, heterologous complementation of the P. jirovecii trifunctional folic acid synthesis (PjFAS) genes with an E. coli DHPS-disrupted strain was recently achieved. This enabled the evaluation of SMX resistance conferred by DHPS mutations. In this study, we sought to determine whether DHPS mutations conferred sulfa drug cross-resistance to 15 commonly available sulfa drugs. It was established that the presence of amino acid substitutions (T(517)A or P(519)S) in the DHPS domain of PjFAS led to cross-resistance against most sulfa drugs evaluated. The presence of both mutations led to increased sulfa drug resistance, suggesting cooperativity and the incremental evolution of sulfa drug resistance. Two sulfa drugs (sulfachloropyridazine [SCP] and sulfamethoxypyridazine [SMP]) that had a higher inhibitory potential than SMX were identified. In addition, SCP, SMP, and sulfadiazine (SDZ) were found to be capable of inhibiting the clinically observed drug-resistant mutants. We propose that SCP, SMP, and SDZ should be considered for clinical evaluation against PCP or for future development of novel sulfa drug compounds.     

FlindersTechnology Associates (FTA) filter paper-based DNA extraction with polymerase chain reaction (PCR) for detection of Pneumocystis jirovecii from respiratory specimens of immunocompromised patients

We evaluated the diagnostic value of Flinders Technology Associates (FTA) filter paper together with polymerase chain reaction (PCR) for detection of Pneumocystis jirovecii (carinii) from induced sputum (IS) and bronchoalveolar lavage fluid (BALF) samples. The study involved 162 patients with clinical diagnosis of pneumocystis pneumonia (PcP) of human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS) patients and other immunocompromised patients. P. jirovecii cysts or trophozoites were detected in IS and BALF by cytological method. The mitochondrial 5S ribosomal ribonucleic acid (rRNA) gene of P. jirovecii was amplified from these samples by using FTA filters together with a one-step PCR method (FTA-PCR). With the FTA-PCR method, the sensitivity and specificity of the test compared to microscopic examination were 67% and 90% for IS, while they were 67% and 91% for BALF, respectively. The sensitivity and specificity of the FTA-PCR test was also comparable to PCR with the conventional deoxyribonucleic acid (DNA) extraction method. We concluded that FTA-PCR is useful to detect P. jirovecii in noninvasive IS.     

Clindamycin/primaquine therapy and secondary prophylaxis against Pneumocystis carinii pneumonia in patients with AIDS

We found a program of intravenous and subsequent oral clindamycin, combined with oral primaquine, to be effective for Pneumocystis carinii pneumonia in nine patients with AIDS. The pneumonias were either primary or recurrent and sometimes severe, with cavity formation and/or pneumothorax. Maintenance therapy at lowered dose by mouth was effective in preventing recurrence in seven patients. One patient died of other opportunistic infections on day 24, and therapy was discontinued in another on day 11 because of skin rash. We conclude that clindamycin/primaquine is effective for therapy of P carinii pneumonia in patients with AIDS, as well as for long-term secondary prophylaxis at lowered dosage.     

Pulmonary fungal infection with yeasts and pneumocystis in patients with hematological malignancy

Invasive fungal infections are an important cause of morbidity and mortality in patients with hematological malignancies, and in particular fungal pneumonia is the main clinical manifestation in this category of patients. The fungal agents responsible for this complication are various, but Aspergillus spp. and other molds such as Zygomycetes or Fusarium spp. represent the most frequently isolated micro-organisms. Less commonly, pneumonia could be due to other 'no-molds' fungal agents such as Candida spp, Cryptococcus spp, or Pneumocystis jirovecii . This review mainly focuses on practical aspects relevant to epidemiology, diagnosis and therapeutic management of the rare cases of pneumonia due to no-molds agents in patients affected by hematological malignancies.     

Cavitary Pneumocystis carinii pneumonia in patients receiving aerosol pentamidine prophylaxis

We have described two patients with AIDS who had cavitary Pneumocystis carinii pneumonia while receiving aerosolized pentamidine prophylaxis. This is the first report of this complication. Neither patient showed a clinical response to subsequent use of pentamidine either intravenously or by aerosol followed by intravenous use. Clinicians should be aware of the possibility that cavitary pneumonia in patients receiving aerosolized pentamidine may be due to P carinii.     

Pneumocystis carinii pneumonia in a 3-month-old infant receiving high-dose corticosteroid therapy for airway hemangiomas

Primary infection with Pneumocystis carinii usually occurs early in life, and young infants receiving prolonged treatment with high-dose corticosteroids may be at risk for the development of symptomatic disease. Prophylaxis with trimethoprim-sulfamethoxazole is safe and effective and should be considered for such infants, particularly those with underlying airway abnormalities. We describe a 3-month-old immunocompetent infant who developed severe P carinii pneumonia after 6 weeks of high-dose corticosteroid therapy for cervicofacial and airway hemangiomas.