Clinical characteristics and risk factors associated with Pneumocystis jirovecii infection in patients with solid tumors: study of thirteen-year medical records of a large cancer center.

BACKGROUND: Pneumocystis jirovecii pneumonia (PCP)-related risk factors among patients with solid tumors are not completely defined. Thus, we aimed to characterize PCP cases with underlying solid tumors, to highlight the factors contributing to its development besides the prolonged use of moderate-to-high dose corticosteroids. METHODS: We retrospectively reviewed the medical records of patients with solid tumors diagnosed with PCP between 2006 and 2018 at a cancer center in Tokyo, Japan. Demographic and clinical data were collected, which included malignancy types, total lymphocyte count, coexisting pulmonary disease, chemotherapy, radiation therapy, corticosteroid use, and PCP-attributable mortality. RESULTS: Twenty cases of PCP with solid tumors were documented in 151,718 patients and 788,914 patient-years. Lung cancer (n = 6, 30%) was the most common underlying tumor, followed by breast cancer (n = 3, 15%). Only six (30%) patients were taking a dosage of ≥20 mg prednisone equivalents daily for ≥4 weeks from the onset of PCP. Among the remaining 14 patients, seven (50%) had coexisting pulmonary diseases, 10 (71%) had received chemotherapy within 90 days prior to PCP diagnosis, seven (50%) had undergone chest radiation therapy before PCP diagnosis, seven (50%) had received only intermittent corticosteroids, and one (7%) received no corticosteroids. Mortality attributable to PCP was 40%. CONCLUSIONS: More than half of the patients were not taking a dosage of ≥20 mg prednisone equivalents daily for ≥4 weeks. Multiple other factors (e.g., lymphocytopenia, radiation to chest) may have potentially contributed to PCP in patients with solid tumors in a composite manner. We need to establish a method for estimating the likelihood of PCP taking multiple factors into account in this patient population.

[Pneumocystis jirovecii and quantitative PCR: Pneumonia or colonization?] / Pneumocytis jirovecii et PCR quantitative : pneumonie ou colonisation à Pneumocystis jirovecii ?

BACKGROUND: Quantitative PCR to detect Pneumocystis jirovecii (Pj) is a new tool for the diagnosis of Pneumocystis jirovecii pneumonia (PJP). The yield of this technique, in cases of low fungal burden, when the standard technique using immunofluorescence (IF) is negative, needs to be evaluated. METHODS: We retrospectively reviewed the charts of all patients with a positive PCR but negative IF test (PCR+/IF-) in bronchoalveolar lavage (BAL) fluid performed over one year. We used an algorithm based on underlying immunosuppression, clinical picture, thoracic CT scan appearances, existence of an alternative diagnosis and the patient's outcome on treatment. Using this, each case was classified as probable PJP, possible PJP or colonization. RESULTS: Among the 416 BAL performed, 48 (12%) were PCR+/IF- and 43 patients were analyzed. Patients were mostly male (56%) with a median age of 60 years. Thirty-five (84%) were immunocompromised: 4 (9%) HIV-infected patients, 26 (60%) with hematologic or solid organ cancer, 3 (7%) were renal transplant recipients. Seven (16%) were classified as probable PPJ and 9 (21%) as possible PJP. Patients with a probable or possible PJP were more frequently admitted to the ICU (P<0.02) and had higher risk of death (P<0.01) when compared to those with colonization. Median PCR levels were very low and were not different between PJP or colonized patients (P=0.23). CONCLUSIONS: Among patients with a positive Pj PCR in BAL but with negative IF, only 37% had probable or possible PJP and PCR could not discriminate PJP from colonization.

Primary infection by Pneumocystis induces Notch-independent Clara cell mucin production in rat distal airways.

Clara cells are the main airway secretory cells able to regenerate epithelium in the distal airways through transdifferentiating into goblet cells, a process under negative regulation of the Notch pathway. Pneumocystis is a highly prevalent fungus in humans occurring between 2 and 5 months of age, a period when airways are still developing and respiratory morbidity typically increases. Pneumocystis induces mucus hyperproduction in immunocompetent host airways and whether it can stimulate Clara cells is unknown. Markers of Clara cell secretion and Notch1 activation were investigated in lungs of immunocompetent rats at 40, 60, and 80 days of age during Pneumocystis primary infection with and without Valproic acid (VPA), a Notch inducer. The proportion of rats expressing mucin increased in Pneumocystis-infected rats respect to controls at 60 and 80 days of age. Frequency of distal airways Clara cells was maintained while mRNA levels for the mucin-encoding genes Muc5B and Muc5ac in lung homogenates increased 1.9 and 3.9 times at 60 days of infection (P. = 0.1609 and P. = 0.0001, respectively) and protein levels of the Clara cell marker CC10 decreased in the Pneumocystis-infected rats at 60 and 80 days of age (P. = 0.0118 & P. = 0.0388). CC10 and Muc5b co-localized in distal airway epithelium of Pneumocystis-infected rats at day 60. Co-localization of Muc5b and Ki67 as marker of mitosis in distal airways was not observed suggesting that Muc5b production by Clara cells was independent of mitosis. Notch levels remained similar and no transnucleation of activated Notch associated to Pneumocystis infection was detected. Unexpectedly, mucus was greatly increased at day 80 in Pneumocystis-infected rats receiving VPA suggesting that a Notch-independent mechanism was triggered. Overall, data suggests a Clara to goblet cell transdifferentiation mechanism induced by Pneumocystis and independent of Notch.

Murine models of Pneumocystis infection recapitulate human primary immune disorders.

Despite the discovery of key pattern recognition receptors and CD4+ T cell subsets in laboratory mice, there is ongoing discussion of the value of murine models to reflect human disease. Pneumocystis is an AIDS-defining illness, in which risk of infection is inversely correlated with peripheral CD4+ T cell counts. Due to medical advances in the control of HIV, the current epidemiology of Pneumocystis infection is predominantly due to primary human immunodeficiencies and immunosuppressive therapies. To this end, we found that every human genetic immunodeficiency associated with Pneumocystis infection that has been tested in mice recapitulated susceptibility. For example, humans with a loss-of-function IL21R mutation are severely immunocompromised. We found that IL-21R, in addition to CD4+ T cell intrinsic STAT3 signaling, were required for generating protective antifungal class-switched antibody responses, as well as effector T cell-mediated protection. Furthermore, CD4+ T cell intrinsic IL-21R/STAT3 signaling was required for CD4+ T cell effector responses, including IL-22 production. Recombinant IL-22 administration to Il21r-/- mice induced the expression of a fungicidal peptide, cathelicidin antimicrobial peptide, which showed in vitro fungicidal activity. In conclusion, SPF laboratory mice faithfully replicate many aspects of human primary immunodeficiency and provide useful tools to understand the generation and nature of effector CD4+ T cell immunity.

[A Case of Pneumocystis Pneumonia Developed during Chemotherapy for Sigmoid Colon Cancer].

A 69-year-old man with multiple liver metastases from sigmoid colon cancer received mFOLFOX6 plus cetuximab(Cmab) chemotherapy. A partial response was observed; hence, we performed an extended left hepatectomy, 3 partial liver resections, and a sigmoidectomy. After 4 courses of CapeOX, a recurrent lesion occurred between S8 and S7 of the liver, and we changed the regimen to FOLFIRI plus bevacizumab(BV). Three months later, he had Grade 3 febrile neutropenia and CT scan findings showed ground glass opacity in the superior lobes of both lungs. We diagnosed pneumocystis pneumonia(PCP)and administered steroids and trimethoprim/sulfamethoxazole. The signs of PCP thus improved. PCP during chemotherapy for gastrointestinal cancer is rarely reported, but recently it has increased.

Granulomatous-lymphocytic interstitial lung disease and recurrent sinopulmonary infections in a patient with Good's syndrome.

Good's syndrome is a rare primary immunodeficiency associated with adult thymoma. Complications are mainly autoimmune manifestations and recurrent infections with encapsulated bacteria. Only one possible case of combined granulomatous-lymphocytic interstitial lung disease (GL-ILD) and Good's syndrome have been described earlier, but the patient died at the time of diagnosis. This is the first case of GL-ILD in Good's syndrome with a successful outcome. We present a case of a 43-year-old man with GL-ILD, who suffered from recurrent infections of Haemophilus influenzae and Pneumocystis jirovecii, with 8-year follow-up. After a thymectomy, he was diagnosed with Good's syndrome and GL-ILD. He was treated with prophylactic pivampicillin, quinolones and cephalosporins for his recurrent P. jirovecii and H. influenzae infections, an approach that proved unsuccessful due to resistance, with relapse after cessation. He was stabilised with oral diaminodiphenyl-sulfone for P. jirovecii and colistimethate-sodium inhalations for H. influenzae, which is a new approach to prophylactic treatment.

Respiratory Pathology and Pathogens in Wild Urban Rats (Rattus norvegicus and Rattus rattus).

Norway (Rattus norvegicus) and black rats (Rattus rattus) are common peridomestic species, yet little is known about wild rat ecology, including their natural diseases. We describe gross and histological lesions in the respiratory tract of a sample of 711 wild urban rats. A subset was examined for 19 distinct categories of histological lesions in the respiratory tract. Testing for known respiratory pathogens included serology and polymerase chain reaction (PCR) of lung samples. Grossly evident lesions were rare (8/711; 1%). Upper respiratory tract inflammation was present in 93 of 107 (87%) rats and included rhinitis, submucosal and periglandular lymphoplasmacytic tracheitis, and/or tracheal intraluminal necrotic debris and was significantly associated (P < .05) with the presence of cilia-associated respiratory bacillus (CARB), Mycoplasma pulmonis, and increased body mass (odds ratio [OR] = 1.09; 95% confidence interval [CI] = 1.05-1.14 per 10 g). Within the lungs, peribronchiolar and/or perivascular lymphoplasmacytic cuffs were present in 152 of 199 rats (76%) and were also significantly associated (P ≤ .02) with CARB, M. pulmonis, and increased body mass (OR = 1.20; 95% CI = 1.14-1.27 per 10 g). Rats were frequently coinfected with M. pulmonis and CARB, and lesions associated with these pathogens were histologically indistinguishable. Pneumocystis sp was detected in 48 of 102 (47%) rats using PCR but was not significantly associated with lesions. This description of pathology in the respiratory system of wild rats demonstrates that respiratory disease is common. Although the impact of these lesions on individual and population health remains to be investigated, respiratory disease may be an important contributor to wild rat morbidity and mortality.

Trimethoprim-sulfamethoxazole treatment does not reverse obstructive pulmonary changes in pneumocystis-colonized nonhuman primates with SHIV infection.

BACKGROUND: Despite antiretroviral therapy and trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis, Pneumocystis pneumonia remains an important serious opportunistic infection in HIV-infected persons. Pneumocystis (Pc) colonization in HIV-infected individuals and in HIV-uninfected smokers is associated with chronic obstructive pulmonary disease (COPD). We previously developed a nonhuman primate model of HIV infection and Pc colonization and demonstrated that Pc colonization correlated with COPD development. In the present study, we examined kinetics of COPD development in non-human primate and tested the effect of Pc burden reduction on pulmonary function by TMP-SMX treatment. METHODS: Cynomolgus macaques (n = 16) were infected with simian/human immunodeficiency virus (SHIV89.6P), and natural Pc colonization was examined by nested polymerase chain reaction of serial bronchoalveolar lavage fluid and anti-Pc serology. RESULTS: Eleven of 16 monkeys became Pc colonized by 16 weeks post simian-human immunodeficiency virus (SHIV) infection. Pc colonization of SHIV-infected monkeys led to progressive declines in pulmonary function as early as 4 weeks after Pc detection. SHIV-infected and Pc-negative monkeys maintained normal lung function. At 25 weeks post-SHIV infection, TMP-SMX treatment was initiated in 7 Pc-positive (Pc+) (TMP: 20 mg/kg and SMX: 100 mg/kg, daily for 48 weeks) and 5 Pc-negative (Pc-) monkeys. Four SHIV+/Pc+ remained untreated for the duration of the experiment. Detection frequency of Pc in serial bronchoalveolar lavage fluid (P < 0.001), as well as plasma Pc antibody titers (P = 0.02) were significantly reduced in TMP-SMX-treated macaques compared with untreated. CONCLUSIONS: Reduction of Pc colonization by TMP-SMX treatment did not improve pulmonary function, supporting the concept that Pc colonization results in early, permanent obstructive changes in the lungs of immunosuppressed macaques.

The Pneumocystis Ace2 transcription factor regulates cell wall-remodeling genes and organism virulence.

Pneumocystis carinii (Pc) ß-glucans are major components of the organism cell wall; yet, the regulation of Pc cell wall genesis and remodeling is not well understood. Ace2 transcription factors, which are present in many fungi, regulate glucanases and other enzymes needed for cell wall remodeling. The cloning and heterologous expression of PcAce2 in ace2Δ Saccharomyces cerevisiae demonstrated that PcAce2 can restore the defective glucanase and endochitinase gene expression of the mutant as well as regulate cell wall ß-glucan biosynthetic genes. Furthermore, when a reconstructed yeast system was used, PcAce2 activated the transcription of the Pneumocystis gsc1 ß-glucan synthetase, confirming the activity of a Pc transcription factor on a native Pneumocystis promoter and gene for the first time. We further observed that Pneumocystis binding to host extracellular matrix proteins and lung epithelial cells induced the phosphorylation (activation) of the PcAce2 transcription factor. Finally, we present a novel method that confirms the role of PcAce2 in modulating organism virulence using ace2Δ Candida glabrata infection in neutropenic mice. Together, these results indicate that the adherence of Pc to lung matrix proteins and epithelial cells leads to the activation of the Ace2 transcription factor, which regulates cell wall degradation and biosynthesis genes that are required for cell wall remodeling.

Clinical significance of Pneumocystis jiroveci in patients with active tuberculosis.

Pneumocystis colonization has been associated with airway inflammation and obstruction. We conducted a retrospective cohort study to investigate the clinical significance of Pneumocystis in the airway of patients with active tuberculosis. Of the 108 respiratory specimens tested positive for M. tuberculosis by polymerase chain reaction (PCR), 11 (10.2%) were also positive for Pneumocystis by PCR. Compared with patients tested negative for Pneumocystis, those with Pneumocystis had a higher serum alanine transaminase level, a greater likelihood of requiring oxygen supplementation, and a worse 30-day mortality. The proportion of patients with chronic obstructive pulmonary disease was not significantly different between the 2 groups, but lung malignancy was more prevalent among patients with Pneumocystis. Multivariate analysis showed that Pneumocystis was independently associated with oxygen supplementation. Our study has shown an association between the detection of Pneumocystis in lower respiratory tract specimens and greater impairment of pulmonary function among patients with active tuberculosis.

Mixed Pneumocystis and Cryptococcus cutaneous infection histologically mimicking xanthoma.

Cutaneous Pneumocystis jirovecii infection is rare. It is thought that the disease emerges from a latent infection delivered via hematogenous and/or lymphatic dissemination from a primary lung infection in immunocompromised individuals. A 32-year-old human immunodeficiency virus-positive male was admitted for headache and vomiting. He was diagnosed with meningitis due to Cryptococcus neoformans and sputum tested positive for Pneumocystis. Six months later, he presented with a slightly crusted yellowish brown plaque and 2 similar but smaller papules with telangiectasia near the right angle of the mouth. Biopsy of the area featured histiocytes expanded by foamy cytoplasm as in a xanthoma except that the vacuoles were coarser. Special stains ultimately demonstrated the characteristic disks of Pneumocystis accompanied by a minor component of budding yeasts (Cryptococcus) in the same fields. This case illustrates the utility of adequate special stains in recognizing a mixed cutaneous infection, particularly in human immunodeficiency virus-positive patients, when microscopy presents an odd xanthoma-like lesion.

Pneumocystis infection and the pathogenesis of chronic obstructive pulmonary disease.

With increases in the immunocompromised patient population and aging of the HIV+ population, the risk of serious fungal infections and their complications will continue to rise. In these populations, infection with the fungal opportunistic pathogen Pneumocystis jirovecii remains a leading cause of morbidity and mortality. Infection with Pneumocystis (Pc) has been shown to be associated with the development of chronic obstructive pulmonary disease (COPD) in human subjects with and without HIV infection and in non-human primate models of HIV infection. In human studies and in a primate model of HIV/Pc co-infection, we have shown that antibody response to the Pc protein, kexin (KEX1), correlates with protection from colonization, Pc pneumonia, and COPD. These findings support the hypothesis that immunity to KEX1 may be critical to controlling Pc colonization and preventing or slowing development of COPD.

Pneumocystis: from a doubtful unique entity to a group of highly diversified fungal species.

At the end of the 20th century the unique taxonomically enigmatic entity called Pneumocystis carinii was identified as a heterogeneous group of microscopic Fungi, constituted of multiple stenoxenic biological entities largely spread across ecosystems, closely adapted to, and coevolving in parallel with, mammal species. The discoveries and reasoning that led to the current conceptions about the taxonomy of Pneumocystis at the species level are examined here. The present review also focuses on the biological, morphological and phylogenetical features of Pneumocystis jirovecii, Pneumocystis oryctolagi, Pneumocystis murina, P. carinii and Pneumocystis wakefieldiae, the five Pneumocystis species described until now, mainly on the basis of the phylogenetic species concept. Interestingly, Pneumocystis organisms exhibit a successful adaptation enabling them to dwell and replicate in the lungs of both immunocompromised and healthy mammals, which can act as infection reservoirs. The role of healthy carriers in aerial disease transmission is nowadays recognized as a major contribution to Pneumocystis circulation, and Pneumocystis infection of nonimmunosuppressed hosts has emerged as a public health issue. More studies need to be undertaken both on the clinical consequences of the presence of Pneumocystis in healthy carriers and on the intricate Pneumocystis life cycle to better define its epidemiology, to adapt existing therapies to each clinical context and to discover new drug targets.

Airway obstruction is increased in pneumocystis-colonized human immunodeficiency virus-infected outpatients.

We investigated the relationship of Pneumocystis colonization, matrix metalloprotease levels in sputum, and airway obstruction in a cohort of human immunodeficiency virus (HIV)-infected outpatients. Pneumocystis-colonized subjects had worse obstruction of airways and higher levels of matrix metalloprotease-12 in sputa, suggesting that Pneumocystis colonization may be important in HIV-associated chronic obstructive pulmonary disease.

Pneumocystis species, co-evolution and pathogenic power.

The genus Pneumocystis comprises uncultured, highly diversified microfungal organisms able to attach specifically to type-I alveolar epithelial cells and to proliferate in pulmonary alveoli provoking severe pneumonitis. The pathogenic potential of Pneumocystis species, especially of the human-associated Pneumocystis jirovecii, has stimulated a growing interest in these peculiar microfungi. However, a comprehensive understanding of basic biology and pathogenic power of Pneumocystis organisms calls for their recognition as natural, complex entities, without reducing them to their pathogenic role. For many years, the entity named "Pneumocystis carinii" was considered like an anecdotal pulmonary pathogen able to cause pneumonia in immunosuppressed hosts. Only for the last years, marked genetic divergence was documented among the Pneumocystis strains of different mammals. Cross-infection experiments showed that Pneumocystis species are stenoxenous parasites. Mainly on the basis of the Phylogenetic Concept of Species, Pneumocystis strains were considered as genuine species. Five species were described: P. carinii and Pneumocystis wakefieldiae in rats, P. jirovecii in humans, Pneumocystis murina in mice, and Pneumocystis oryctolagi in rabbits. They also present distinctive phenotypic features. Molecular techniques have revealed a high prevalence of Pneumocystis colonization in wild mammals, probably resulting from active airborne horizontal and vertical (transplacental or aerial) transmission mechanisms. Cophylogeny is the evolutionary pattern for Pneumocystis species, which dwelt in the lungs of mammals for more than 100 million years. Consistently, Pneumocystis organisms exhibit successful adaptation to colonize the lungs of both immunocompromised and healthy hosts that can act as infection reservoir. Pneumocystis pneumonia, rarely reported in wild mammals, seems to be a rather unfrequent event. A larger spectrum of Pneumocystis infections related to the heterogeneous level of immune defence found in natural populations, is, however, expected. Pneumocystis infection of immunocompetent hosts emerges therefore as a relevant issue to human as well as animal health.

Otic pneumocystosis in acquired immune deficiency syndrome.

AIDS-associated otic pneumocystosis is rare. Of 14 cases documented mainly as case reports up to now, only 1 has been reported in the surgical pathology literature. We report 6 males, mean age of 32.3 years, with external auditory canal masses and otorrhea. Two biopsies contained a predominance of granulation tissue with a mixed inflammatory cell infiltrate and elusive foci of foamy exudate. In contrast, 4 biopsies demonstrated conspicuous angiocentric mantles of stippled, foamy exudate. Fibrin was noted in intravascular, perivascular, and intervascular locations. One biopsy demonstrated bordering of the foamy exudate by a palisaded granulomatous reaction, with adjacent discrete giant cell-containing granulomas. Special stains confirmed trophozoites and cysts within the foamy exudate. Review of 2 initial "nondiagnostic" biopsies confirmed granulation tissue and necrotic debris in which Pneumocystis jiroveci was identified in focal foamy exudate. After the diagnosis of otic pneumocystosis, all patients were initiated on trimethoprim-sulfamethoxazole. One patient also had dapsone. Two patients succumbed to pulmonary tuberculosis and 2 were lost to follow-up. One patient with pneumocystis pneumonia did not return for follow-up after 6 weeks. One patient experienced complete resolution of the mass on medical therapy, and is disease free for 4 years. Heightened recognition of the characteristic foamy exudate in an unconventional location remains the gold standard in the timely diagnosis of this eminently treatable disease. In all patients, otic pneumocystosis served as the sentinel of underlying HIV infection and AIDS.

Botryomycosis caused by Staphylococcus aureus and Pneumocystis carinii in a patient with acquired immunodeficiency disease.

Botryomycosis is an uncommon, chronic, granulomatous and/or suppurative, opportunistic infection affecting the skin and viscera, primarily caused by bacteria. The exact pathogenesis of this infection is not well understood. However, both the host's immune status and microbial infectivity have been implicated in the pathogenesis of this unusual clinical condition. To date, botryomycosis caused by a nonbacterial pathogen has not been reported in the literature. We report a case of cutaneous botryomycosis caused by combined Staphylococcus aureus and Pneumocystis carinii. Cutaneous P. carinii infection without pulmonary involvement is extremely rare.

[Primary cerebellar T-cell lymphoma]. / Primäres zerebelläres T-Zell-Lymphom.

Primary central nervous system T-cell lymphomas are rare and have to be differentiated from reactive lesions. It is therefore essential to use all possible tools to establish the diagnosis, including immunohistochemistry, molecular genetic analysis, and/or cytogenetic methods. In this paper we present the case of a primary cerebellar T-cell lymphoma in a 50-year-old man; a clonal T-cell receptor gene rearrangement was documented. After two cycles of methotrexate therapy the patient developed Pneumocystis carinii-induced pneumonia, dying 10 weeks after his diagnosis. The autopsy did not reveal any residual tumour.