Pneumocystis carinii pneumonia: a review of current issues in diagnosis and management.

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

Diagnosis of Pneumocystis carinii Pneumonia

Pneumocystis Pneumonia in Solid Organ Transplant Recipients

Sixty children aged between 1 and 23 months admitted to Queen Elizabeth Central Hospital in Blantyre, Malawi for diagnosis of acute lower respiratory tract infections (ALRI) were investigated for laboratory diagnosis of Pneumocystis carinii pneumonia (PCP) by indirect immunofluorescence assay on nasopharyngeal secretions. P. carinii was found in five of the 60 children. Three PCP cases had AIDS. The clinical presentation of children with PCP was of little diagnostic value and all the children were infants. Arterial oxygen saturation was significantly lower in PCP cases. Of the five PCP cases, four died, indicating that the marked hypoxaemia was associated with poor prognosis. These results indicate that an immunofluorescence assay on nasopharyngeal secretions could be used for first-line diagnosis of PCP in Africa.

Cases of paradoxical worsening of opportunistic infections shortly after the beginning of highly active antiretroviral therapy (HAART) prompted questions on the optimal timing of introduction of HAART in patients with inaugural AIDS-related opportunistic infections. We describe three cases of acute respiratory failure after early introduction of HAART in patients treated for Pneumocystis carinii pneumonia (PCP). The three patients had severe PCP that initially improved with anti-PCP and adjunctive steroid therapy. HAART was introduced 1 to 16 d after diagnosis of PCP, and steroids were stopped on Day 15. Seven to 17 d after HAART introduction, the three patients developed a second episode of severe acute respiratory failure with high-grade fever and patchy alveolar opacities on the chest roentgenogram. PCP resistant to cotrimoxazole, pulmonary superinfection, and drug-related pneumonitis were suspected but subsequently ruled out. Bronchoalveolar lavage and lung pathologic findings showed severe nonspecific pulmonary inflammatory foci surrounding a few persistent P. carinii cysts. All three patients recovered after HAART interruption or steroid reintroduction. We conclude that acute respiratory failure can recur after initiation of antiretroviral therapy in patients being treated for severe PCP. This phenomenon could result from rapid pulmonary recruitment of fully competent immune and inflammatory cells responding to a few persistent P. carinii cysts. A short course of steroid therapy may suppress this reaction.

Pneumocystis Pneumonia: Miles to Go

Purpose : To analyze the radiographic and HRCT findings of Pneumocystic carinii pneumonia. Materials and Methods : We reviewed the medical records and retrospectively analysed the chest radi-ographs(n=31) and HRCT scans(n=17) of 31 patients with Pneumocystis carinii pneumonia who had been fol-lowed up at our institute between, 1993 and March 1998. Pneumocystis carinii pneumonia was confirmed by cytologic evaluation of sputum stained with methenamine silver(n=25) or on the basis of clinical history(n=6). The study group included 17 men and 14 women aged 28 -78(average, 53.6) years. Twenty-eight patients had underlying conditions such as hematologic diseases(n=13), AIDS(n=8), malignancy(n=2), DM(n=2) and mal-nutrition(n=1), and three were free from underlying diseases. Results : Twenty patients had pure Pneumocystis carinii pneumonia and 11 had combined lung diseases, namely pulmonary tuberculosis(n=4), pulmonary metastasis(n=2), bacterial pneumonia(n=2), atypical my-cobacterial infection(n=1), pulmonary edema(n=1), and Kaposi ’s sarcoma(n=1). Chest radiographic findings of 20 cases of pure Pneumocystis carinii pneumonia included consolidation(n=12), l inear-reticular opacity(n=8), ill defined haziness(n=7), and nodules(n=6), with bilaterality in is cases and zonal predomi-nance in ten [central(n=5), lower(n=5)]. Ancillary findings included pleural effusion(n=10), cysts(n=5), lym-phadenopathy(n=4) and pneumothorax(n=1). In two patients, findings were entirely normal. HRCT findings in ten cases of pure Pneumocystis carinii pneumonia included ground-glass opacity(n=6), consolidation(n=6), linear-reticular opacity(n=8), and nodules(n=5), with bilaterallity in seven cases and zonal predominance in five [central(n=5), lower(n=2)]. Ancillary findings among these cases included pleural effusion(n=4), lym-phadenopathy(n=2), cysts(n=1), and pneumothorax(n=1). HRCT findings in seven cases of Pneumocystis carinii pneumonia combined with other lung diseases included nodules(n=6), ground-glass opacity(n=5), lin-ear-reticular opacity(n=4), and consolidation(n=3). Conclusion : Although ground-glass opacity in both pure Pneumocystis carinii pneumonia and this same con-dition combined with other lung diseases is a common radiologic finding, the possibility of variable radiologic findings in cases of Pneumocystis carinii pneumonia and other lung diseases with which it frequently com-bines is essential for approximate diagnosis of Pneumocystis carinii pneumonia.

Pneumocystis pneumonia (PCP) is a well-known compli-cation in AIDS patients, but it is also frequently diagnosedin hemato-oncological patients [1]. High-dose cotrimoxa-zole is the first-line treatment for PCP, but some patientsshow contraindications and drug resistance may appear[2]. Since Pneumocystis jirovecii cannot be cultivated invitro, mutations in the genes involved in folate metabo-lism have been investigated as a possible expression ofcotrimoxazole resistance [3], but the search for a clinicalcorrelate has so far led to equivocal results [4]. There issome doubt as to what may be the best alternative tocotrimoxazole in the treatment of PCP [5]. The presentreport refers to the use of caspofungin to treat a patientwith PCP undergoing bone marrow transplantation (BMT)in whom cotrimoxazole had to be discontinued because ofits myelotoxicity.A 45-year-old male patient with T-lymphoblastic leu-kemia in second complete remission was scheduled to re-ceive an allogeneic BMT from an unrelated HLA-matcheddonor in October 2004. In September, he was admitted tohospital because of acute respiratory failure. Subsequentexamination of bronchoalveolar lavage (BAL) led to thediagnosis of PCP, and a computed tomography (CT) scanshowed diffuse, bilateral, interstitial disease with “groundglass”parenchymaandthickeningoftheinterlobularsepta.Molecular, cultural and cytological investigations of theBAL failed to identify any other pathogen. Transbronchialbiopsy was not performed. High-dose cotrimoxazole wasstarted in combination with methylprednisolone. A bonemarrow aspirate revealed signs of an initial leukemic re-lapse that was treated with weekly vincristine and dailyoral 6-mercaptopurine, which led to a stable bone marrowblast count and the maintenance of normal peripheralhematometry.During cotrimoxazole treatment, the CT findings im-proved significantly but did not normalize, and the drugwas discontinued after 2 weeks because of patient refusal.On 7 October, the patient was discharged for personalreasons, and he continued taking oral cotrimoxazole at adaily dose of 3,840 mg. Two weeks later, a further CTscanshowed persistence of significant lung infiltrates.On 11 November, when the patient was admitted toundergoBMT,apositronemission tomography(PET)scanrevealed the presence of diffuse, active, alveolar disease(Fig. 1) and high-dose intravenous cotrimoxazole wasresumed. On 22 November, standard-dose caspofungin(70mgonthefirstday,followedby50mg/day)wasadded,and a conditioning regimen was started including thio-tepa (15 mg/kg divided into three equal doses on days −8and−7),andcyclophosphamide(50mg/kg/dayondays−4,−3 and −2). A bone marrow aspirate showed a raised butstable blast count. On 29 November, the CT findings wereunchanged, and cotrimoxazole was discontinued. On 30November, BMT was performed, with standard-dose cy-closporine-Aandmethotrexatebeingadministeredasgraft-versus-host disease prophylaxis. During pancytopenia,mixed Enterobacter/coagulase-negative Staphylococcusbacteremia was observed. Polymorphonuclear recoverywasachievedonpost-BMTday25,andplateletrecoveryonday 34, after being delayed by mild microangiopathichemolytic anemia responsive to defibrotide therapy. On22 December, a CT scan showed complete resolution ofthe lung infiltrates. On 5 January, caspofungin was dis-continued and a bone marrow aspirate showed completeremission and full donor chimerism. On 12 January thepatient was discharged. One month later, the leukemiarelapsed; a CTscan did not show any lung infiltrates.A diagnosis of PCP is frequently established in BMTrecipients,inwhomimmunodepressionmayplayaprimaryrole, and also in hematological patients receiving che-motherapy alone [1]. In such cases, cotrimoxazole mayinterfere with the possibility of delivering the subsequent

Second and subsequent episodes of acute Pneumocystis carinii pneumonia (PCP) are reported to have a worse prognosis than initial episodes in patients with the acquired immunodeficiency syndrome. We tested the hypothesis that survival rates of first, second, and subsequent episodes of acute PCP in patients with the acquired immunodeficiency syndrome are equal. Analysis of the outcomes in prospective series of patients with the acquired immunodeficiency syndrome treated for acute PCP over 5 years. Survival rates of 222 PCP occurrences by episode number were: first, 86%; second, 84%; third, 88%; and fourth, 67%. Survival rates for the first, second, and third episodes were not significantly different. Second and third episodes had a larger proportion of patients with mild disease than initial episodes. Survival rates for first, second, and third episodes of PCP in patients with the acquired immunodeficiency syndrome are not different. In contrast to earlier articles, treatment for second and third episodes of acute PCP may be as successful as in initial episodes.

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.

HIV Disease and Aging

In a recent issue of AIDS, Morris and co-workers [1] reported improved survival with highly active antiretroviral therapy (HAART) in HIV-infected patients with severe Pneumocystis carinii pneumonia (PCP). The explanation for a possible survival benefit from HAART include decreased viral fitness, an attenuated rise in viral titre during PCP, or the anti-Pneumocystis properties of protease inhibitors (PI). We demonstrated that several PI exert an in-vitro aspecific anti-Pneumocystis effect at concentrations clinically achievable in plasma in vivo during HAART [2–4]. Other authors did not reproduce our results in a different in-vitro axenic model, although reporting in vivo a slight decrease in P. carinii cyst counts in the lungs of animals experimentally treated with PI [5]. The clinical relevance of these observations remains to be investigated, especially for a microrganism harbouring in lung alveoli, such as P. carinii. No data were available on the concentration of PI in epithelial lining fluid (ELF). Reliable methods to measure drug concentrations in ELF have been developed and successfully applied also for the detection of antipneumocystic drugs such as pentamidine [6]. Lopinavir exerts in-vitro dose-dependent anti-Pneumocystis activity, and very high concentrations are detected in plasma during therapy, so we preliminarily chose this drug in order to screen for the possible presence of PI in ELF. We hereby report the detection of lopinavir in the ELF of one patient treated with lopinavir/ritonavir oral tablets. Heparanized and unheparinized blood was collected for plasma separation and biochemistry. Standardized bronchoscopy and blood collection were performed after informed consent 13 h after the administration of the evening dose of lopinavir/ritonavir in a fasted, male, HIV-infected patient. He had been receiving HAART, including lopinavir/ritonavir (400/100 mg twice a day), lamivudine (300 mg/day) and stavudine (80 mg/day), for 6 months. No systemic sedation was used. A total of 2 × 50 ml normal saline were instilled and promptly aspirated. Pooled specimens of bronchoalveolar lavage (BAL) fluid were processed as follows: aliquots were sent for microbiological, biochemical and microscopic examination, centrifuged at 400g for 5 min and the supernatant frozen at −80°C until used. The volume (V) of ELF recovered was calculated using the urea dilution method: VELF = VBAL × (ureaBAL/ureaserum) and the concentration of lopinavir (LPV) was obtained by the following relationship: LPVBAL × VBAL/VELF. Samples were analysed according to a validated high-performance liquid chromatography assay with ultraviolet detection and liquid–liquid extraction. The cut-off for lopinavir detection was 50 ng/ml. On 70 ml of recovered BAL fluid, the ELF volume was 0.9 ml. The concentration of lopinavir was 8.1 μg/ml in plasma and 14.4 μg/ml in ELF. BAL fluid was microbiologically sterile, and internal transcribed spacers-nested polymerase chain reaction to detect P. carinii DNA was negative. The microscopic evaluation of BAL (cyto-spinned cells) demonstrated a non-inflammatory, normal pattern of alveolar cells, with prevalent macrophages and few lymphocytes, and no granulocytes. The apparent accumulation of lopinavir in the ELF is not surprising because PI intracellular and efflux pumps have been described in macrophages, cells commonly harbouring and trafficking in alveoli [7]. We cannot exclude the possibility that BAL centrifugation could have caused some ‘spilling’ of lopinavir from inside the cells; however, our preliminary demonstration of lopinavir penetration in human ELF deserves attention: such a high micromolar PI concentration supports the hypothesis that the anti-Pneumocystis effects described in vitro, starting from a 0.5 μg/ml lopinavir concentration, could also be relevant in vivo, possibly explaining the dramatic decrease in PCP during the early phase of HAART, before immune reconstitution, in addition to the improved survival of HIV-infected patients with severe PCP treated with PI-based HAART. The non-viral aspecific beneficial effect exerted by PI, in addition to the direct inhibition of P. carinii proteases, may include the modulation of host cell proteasome [8].

In spite of the high prevalence of Pneumocystis carinii (PC) pneumonia in immunocompromised patients, little is known about the epidemiological characteristics of this infection, and whether the cases of PC pneumonia in immunosuppressed patients are the result of a reactivation of a latent infection or a due to a recent infection is unknown. The aim of this study was to provide information about the epidemiological characteristics of PC pneumonia in a cohort of heart transplant (HT) recipients when compared with the epidemiology of PC infection in a cohort of chronic sputum producers (CSP) representative of the general population of the same geographical area. We identified all the cases of PC pneumonia in the cohort of 72 subjects who underwent cardiac transplantation at our institution between January 1991 and December 1996 and compared them with the cases of PC infection identified in a non-selected cohort of 34 CSP. This second group was included to obtain an approximation of the frequency of PC carriers in the general population. Identification of PC was accomplished through customary stain techniques and immunofluorescence with monoclonal antibodies. Of the 72 HT recipients four (5.5%) developed PC pneumonia, but one had two episodes. Only one had received primary chemoprophylaxis, but developed PC pneumonia 2 months after discontinuing prophylactic therapy. PC pneumonia episodes were produced 53, 102, 230, 181 and 772 days after the moment of transplant, respectively. PC was identified in two (5.8%) of the 34 CSP. No significant differences were found when the accumulative incidences of PC pneumonia in HT patients and PC infection in CSP were compared (P=0.7). The frequency of PC pneumonia among HT patients is the same as the frequency of PC infection in the general population. This observation and the long interval between transplantation and the development of PC pneumonia observed in the study support the hypothesis that the occurrence of PC pneumonia in immunocompromised patients might be from a new infection rather than from the reactivation of latent organisms. Therefore, continuous prophylaxis might be indicated in areas with a high prevalence of PC for patients at highest risk.

By means of serial lung function tests we examined the changes in lung function and possible pulmonary long-term sequelae in AIDS patients with a primary episode of Pneumocystis carinii pneumonia (PCP). A total of 19 patients had lung function tests performed prospectively from the time of PCP diagnosis, at 7 days, 14 days, 1, 2, 3, 4.5, 6 and 9 months after PCP. Forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV1) were both reduced to a median of 61% of predicted at PCP diagnosis, and were normalized within 1 month and 1 week respectively. The median pulmonary diffusing capacity for carbon monoxide (DLCO) was severely reduced to 43% of predicted during the acute infection. Although DLCO improved significantly during the first 2 months, it remained reduced at a median DLCO of 64% of predicted 9 months after PCP. We conclude that despite a general improvement in lung function during the first 2 months following the PCP diagnosis, ther was a persistent reduction in DLCO up to 9 months following PCP. The pathological mechanisms causing this reduction remain to be established.

Radiation pneumonitis complicated by Pneumocystis carinii in patients with thoracic neoplasia: a clinical analysis of 7 cases