INTRODUTION:

Pneumocystis pneumonia (PCP) is a form of pneumonia, caused by the yeast-like fungus Pneumocystis (previously known as Pneumocystis carinii). Pneumocystis pneumonia is not commonly found in the lungs of healthy people, but, being a source of opportunistic infection, it can cause a lung infection in people with a weak immune system. Pneumocystis jirovecii pneumonia (PCP) is a life-threatening infection in immunocompromised patients. Pneumocystis pneumonia is especially seen in people with cancer undergoing chemotherapy, HIV/AIDS, and the use of medications that suppress the immune system. Aliouat-Denis, C-M.; et al. [2008] Pneumonia is the leading infectious cause of death in developed countries. Among the vast diversity of respiratory pathogens, fungi account for only a small portion of community-acquired and nosocomial pneumonias [1,2]. However, fungal respiratory infections generate concern in the expanding population of immunosuppressed patients. Fungi may colonize body sites without producing disease or they may be a true pathogen, generating a broad variety of clinical syndromes.

Fungal pneumonia is an infectious process in the lungs caused by one or more endemic or opportunistic fungi. Fungal infection occurs following the inhalation of spores, after the inhalation of conidia, or by the reactivation of a latent infection. Hematogenous dissemination frequently occurs, especially in an immunocompromised host.

OBJECTIVE:

1 Identify risk factors for mortality in Pneumocystis jirovecii pneumonia.

2 Comparison of different clinical parameters of PCP with healthy controls.

REVIEW OF LITERATURE:

Pneumocystis is a genus of unicellular fungi found in the respiratory tracts of many mammals and humans. Distinct genomic variability exists between host-specific members of the genus. The organism was first described in 1909 by Chagas and then a few years later by Delanöes, who ultimately named the organism in honor of Dr. Carini after isolating it from infected rats. Years later, Dr. Otto Jirovec and his group isolated the organism from humans, and the organism responsible for PCP was renamed after him [3].

The taxonomic classification of the Pneumocystis genus was debated for some time. It was initially mistaken for a trypanosome and then later for a protozoan [4]. In the 1980s, biochemical analysis of the nucleic acid composition of Pneumocystis rRNA and mitochondrial DNA identified the organism as a unicellular fungus rather than a protozoan.

The organism is found in 3 distinct morphologic stages, as follows:

• The trophozoite (trophic form), in which it often exists in clusters

• The sporozoite (precystic form)

• The cyst, which contains several intracystic bodies (spores)

MATERIAL AND METHODS:

First cohort study to detect risk factors for developing Pneumocystis pneumonia:

We were observed data respectively analyzed 102 traceable patients with RA who had started treatment with biologic agents between April 2010 and September 2016 in the First Department of Pathology, Shyam Shah Medical College Rewa (M.P.). During the first step, we compared the clinical features and laboratory data between patients who developed PCP and the remaining patients who did not receive trimethoprim-sulfamethoxazole (TMP/SMX) prophylaxis. The following clinical parameters were evaluated to identify risk factors for the development of PCP: age, the duration of RA, the Disease Activity Score in 28 joints score and erythrocyte sedimentation rate (DAS28 ESR), coexisting pulmonary disease, diabetes mellitus (DM), ratio of patients who received glucocorticoid treatment, dose of glucocorticoid, dose of methotrexate (MTX), serum immunoglobulin G (IgG) and serum KL-6. Before starting biologic therapy, all patients underwent a bidirectional chest X-ray and/or chest computed tomography (CT) to identify coexisting pulmonary disease, including interstitial pneumonia, pleuritis, diffuse panbronchiolitis, bronchiectasia, old tuberculosis and inflammatory nodules. We excluded the patients who were proven soon after the initiation of biologic agents to have complications due to either malignancy or HIV, which influence the risk for PCP development. TMP/SMX prophylaxis was begun when each physician considered a patient to be at relatively high risk for PCP based on factors including age, dose of glucocorticoid, serum IgG level, coexisting pulmonary disease and complications of DM. We compared the characteristics of patients in the PCP group were compared with those in patients without PCP determined risk factors for PCP development. The sensitivity and specificity of the combination of risk factors were used to plan the primary prophylactic procedure, and that procedure was applied to patients with RA who initiated treatment with biologic agents starting in October 2015.

RESULTS:

First- study identified three risk factors for Pneumocystis pneumonia development:

In the study to develop the prophylactic procedure, we evaluated 102 patients with the rheumatoid arthritis (RA), who were being treated with biologic therapy (40 patients treated with IFX, 29 with ETN, 17 with adalimumab (ADA) and 16 with to cilizumab (TCZ)). The patient population comprised 83 females (81.7%) and 19 males (18.3%). The mean age of the patients when they received their first biologic agent was 58.0 years (range, 14 to 86 years) (Table 1). The mean observation period was 16.6 months (range,2 weeks to 60 months) and 21 patients (20.1%) received TMP/SMX prophylaxis. A total of 38 patients (37.7%) had coexisting pulmonary disease, 44 patients (43.2%) received glucocorticoid therapy and the mean dose (±SD) of glucocorticoid (converted to the prednisolone (PSL) equivalent) was 4.46 mg ± 3.64 mg. We included not only active lung disease but also non active lung lesions, including inactive pulmonary fibrosis as coexisting pulmonary disease, which resulted in the high ratio of patients with coexisting lung disease. A total of 78.5% of patients were given MTX, and the average dose of MTX in patients treated with MTX was 8.96 mg/wk. Nine (1.28%) of the seven hundred two patients developed PCP, and none of the patients in the group treated with TMP/SMX prophylaxis developed PCP. Four of nine patients with PCP were receiving the prophylactic treatment at the initiation of biologic therapy, although all of them stopped the prophylaxis (because of side effects of prophylaxis in two patients and for unknown reasons in two patients). The other five patients were not receiving the prophylaxis during the treatment with biologics. The mean interval between the first infusion of the biologic agent and the onset of PCP was 7.17 months (range, 2 weeks to 20 months). The mean age of patients with PCP at the start of biologic therapy was 69.5 years (range, 57 to 78 years), and the mean morbidity period of RA for the PCP patients was 76.3 months (Table 2). Coexisting pulmonary disease was detected in seven (77.8%) of the nine patients. Eight patients (88.9%) who developed PCP were receiving glucocorticoid therapy at a mean dose(±SD) of 8.83 mg ± 14.9 mg. Six (66.7%) of the nine patients were given MTX, and the average dose of MTX given to them was 9.83 mg/wk. The average in the nine patients was 6.56 mg/wk. Because TMP/SMX is known to inhibits the development of PCP almost completely cuared, we excluded from the analysis the 21 patients treated with the prophylaxis. We first analysed the characteristics of these 21 patients who were thought to be at high risk for the development of PCP and received the prophylaxis. Compared with the other 81patients, the mean age in their group was significantly older (68.9 years vs. 55.3 years); the serum level of IgG was significantly lower (1,496 mg/dl vs. 1,619 mg/dl);the dose of MTX was significantly lower (6.09 mg vs.7.28 mg); and the ratios of patients treated with glucocorticoids, PCP complicated with coexisting pulmonary disease and PCP complicated with DM were significantly higher (53.9% vs. 40.8%, 72.3% vs. 29.1% and 21.3% vs.10.5%, respectively). Next, we were observed the clinical and laboratory records of the 102 patients who did not receive TMP/SMX prophylaxis. If prophylaxis were given only to patients with three risk factors, we would have missed four of nine patients with PCP (sensitivity = 55.6%, specificity = 94.4%). On the basis of these results, we assumed that patients with two or three risk factors could benefit from prophylaxis with TMP/SMX (sensitivity = 77.8%, specificity = 76.1%). Assuming that TMP/SMX inhibits the development of PCP completely, the number needed to treat to prevent one case of PCP was 19.9 in the analysis of 102 patients.

Table 1 Comparison of baseline characteristics of two cohorts

Characteristics	Before	After	P-value
Patients, n	102	31
Females, n (%)	83 (82.3)	19(81.3)	0.851
Age (years)	58.0 ± 14.3	58.9 ± 15.5	0.642
RA duration (months)	112 ± 125	92.9 ± 119	0.037
DAS28 score (ESR)	5.83 ± 1.24	5.45 ± 1.27	0.001
Coexisting pulmonary disease (%)	37.7	65.8	0.001
Diabetes mellitus (%)	12.7	9.80	0.268
Glucocorticoids (%)b	43.2	22.9	0.001
Methotrexate (%)c	43.2	87.9	0.002
Dose of methotrexate (mg/wk)	8.96 ± 2.46	9.51 ± 2.51	0.007
Serum level of IgG (mg/dl)	1590 ± 522	1600 ± 876	0.131
Serum level of KL-6 (U/ml)	271 ± 147	250 ± 194	0.086

DISCUSSION:

It is well-known that HIV patients with a CD4+ cell counts less than 200 cells/mm3 are likely to develop PCP, and the most common identifiable risk factor for developing PCP in patients with autoimmune disease or malignancy is glucocorticoid use [36- 38]. Ogawa et al. Reported that the number of peripheral lymphocytes at 2 weeks after initiation of glucocorticoid treatment, not the number at the initiation of treatment, was a risk factor for PCP in patients with rheumatic diseases [3]. Other reports and some post marketing surveillance studies have revealed that a low lymphocyte count is not a risk factor for PCP in patients with RA. Thus, we excluded the number of lymphocytes as a risk factor from the analysis. The post marketing surveillance of IFX revealed that the development of PCP in RA patients treated with IFX was best predicted by an age of at least 65 years, dose of glucocorticoids (≥6 mg of PSL) and coexisting pulmonary disease [11, 12]. However, that report was restricted to patients treated with IFX and did not include patients receiving other TNFα inhibitors or an IL-6 inhibitor. After analysing the patients treated with biologic therapy who developed PCP in this study, we found that four of nine patients had fewer than two of the above-mentioned risk factors.

In our present study, we identified various risk factors for PCP in patients treated with biologics, including not only TNFα inhibitors but also the IL-6 inhibitor, to establish a new and useful prophylactic TMP/SMX procedure for PCP. We retrospectively compared a PCP group with a non-PCP group in patients who did not receive prophylaxis, and the multivariate analysis revealed that an age of at least 65 years, coexisting pulmonary disease and use of glucocorticoids were risk factors for PCP. An age of at least 65 years and coexisting pulmonary disease were also risk factors in the IFX post marketing surveillance report; however, in our present study, the use of glucocorticoids alone was abstracted as a risk factor without regard to the dose administered. Other researchers have shown that, among patients with interstitial pneumonia or autoimmune disease, the glucocorticoiddose (≥30 mg of PSL) was a risk factor for PCP development [30- 32]. In our study, eight of the nine patients who developed PCP were receiving glucocorticoids, but only two patients were given at least 6 mg of PSL. The other six patients were treated with less than6 mg of PSL (1.0 mg to 5.0 mg), suggesting that patient streated with glucocorticoids can benefit from primary TMP/SMX prophylaxis of PCP, regardless of glucocorticoiddose. A previous report revealed that patients treated with high-dose glucocorticoids, those receiving immunosuppressive agents and those with lower serum IgG levels hada significantly higher risk for developing PCP [13]. Another recent report identified an advanced radio graphic stage as a risk factor for PCP in RA patients treated with ADA [14]. In the present study, however, there were no significant differences in the serum IgG level or the radio graphic stage between the patients with versus without PCP. Although concomitant MTX treatment was identified as an independent risk factor for PCP in a report of RA patients in Japan who were treated with ETN [15]. The use (yes or no) or dose of MTX was not found to be a risk factor for the development of PCP in our patient cohort. The duration between the initiation of biologics and PCP development varied widely, from 2 weeks to 20 months. In previous reports of RA patients treated with biologics, 76%to 90% of the cases of PCP developed within 6 months after the initiation of biologics [14-16]. In our present study, PCP developed in two of nine patients more than12 months after biologics were started. That finding suggests that TMP/SMX prophylaxis needs to be continued for long periods. A total of 36 (35.6%) of the 102 patients had two or three risk factors for PCP in this study. If patients with at least one risk factor were started on TMP/SMX prophylaxis in our study, 74 (73.1%) of the patients would have been included in the prophylaxis group. This is why the percentage of pulmonary disease was much higher in the31 patients than that in the analysis of 102 patients [17 ].

There are some limitations associated with this study. First, we treated only nine patients with PCP. A larger number of patients and a longer observation period are necessary to confirm the effectiveness of our protocol. By the statistical calculation, we found that we needed 54 patients to confirm the statistical significance of the difference in the incidence of PCP in the first cohort (1.28%). Second, Pneumocystis colonization, which was previously reported to be a possible risk factor for PCP, was not analysed in this study. The number of lymphocytes also was not analysed. In the first cohort evaluated to identify the risk factors for PCP development, we excluded 21 patients who received TMP/SMX, although this exclusion might have led to biased results regarding the identification of risk factors.

CONCLUSIONS:

Pneumocystis pneumonia (PCP) is a major cause of morbidity and mortality among immune compromised persons, and it remains a leading acquired immune deficiency syndrome (AIDS)-defining opportunistic infection in human immune deficiency virus (HIV)-infected individuals throughout the world.

The results of the first analysis in this study show that there are three major risk factors for the development of PCP in patients with RA receiving biologics. They reveal that patients with two or three risk factors could benefit from TMP/SMX prophylaxis against PCP. We also show the prophylactic effectiveness and safety of the inclusion criteria. However, the number of patients was too low, so this prophylactic procedure needs to continue to be applied to further investigate its validity and safety.

SUGGESTION:

We report a molecular typing and epidemiologic analysis of Pneumocystis carinii pneumonia (PCP) cases diagnosed in our geographic area from 2015 to 2016. Our analysis suggests that transmission from patients with active PCP to susceptible persons caused only a few, if any, PCP cases in our setting.

REFERENCE:

[1]. Aliouat-Denis, C-M. et al. (2008). "Pneumocystis species, co-evolution and pathogenicpower". Infection, Genetics and Evolution; 8 (5): 708–726.

[2]. Romani L. Cell-mediated immunity to fungi: a reassessment. Medical Mycology. 2008; 46:515-29.

[3]. Ogawa J, Harigai M, Nagasaka K, Nakamura T, Miyasaka N: Prediction of andprophylaxis against Pneumocystis pneumonia in patients with connectivetissue diseases undergoing medium- or high-dose corticosteroid.

[4]. Cushion MT, Stringer JR. Has the name really been changed? It has for mostresearchers. Clin Infect Dis. 2005; 41(12):1756-8.

[5]. Slogrove AL, Cotton MF, Esser MM. Severe Infections in HIV-Exposed Uninfected Infants: Clinical Evidence of Immunodeficiency. J Trop Pediatr.2010; 56(2):75-81.

[6]. Fujii T, Nakamura T, Iwamoto A. Pneumocystis pneumonia in patients with HIV infection: clinical manifestations, laboratory findings, and radiological features. J Infect Chemother. 2007; 13(1):1-7.

[7]. Hui M, Kwok WT. Pneumocystis carinii pneumonia in Hong Kong: a 10 year retrospective study. J Med Microbiol. 2006; 55:85-8.

[8]. Safrin S, Finkelstein DM, Feinberg J, et al. Comparison of three regimens for treatment of mild to moderate Pneumocystis carinii pneumonia in patients with AIDS. A doubleblind, randomized, trial of oral trimethoprim-sulfamethoxazole, dapsone-trimethoprim,and clindamycin-primaquine. ACTG 108 Study Group. Ann Intern Med. 1996;124(9):792-802.

[9]. Schmoldt S, Schuhegger R, Wendler T, et al. Molecular evidence of nosocomial Pneumocystis jirovecii transmission among 16 patients after kidney transplantation. J Clin Microbiol. 2008;46(3):966-71.

[10]. De Boer MG, Bruijnesteijn van Coppenraet LE, Gaasbeek A, et al. An outbreak of Pneumocystis jiroveci pneumonia with 1 predominant genotype among renal transplant recipients: interhuman transmission or a common environmental source?. Clin Infect Dis. 2007; 44(9):1143-9.

[11]. Mori S, Polatino S, Estrada-Y-Martin RM. Pneumocystis-associated organizing pneumonia as a manifestation of immune reconstitution inflammatory syndrome in an HIV-infected individual with a normal CD4+ T-cell count following antiretroviral therapy. Int J STD AIDS. 2009;20(9):662-5.

[12]. Kolditz M, Halank M, Bandt D, Spornraft-Ragaller P, Höffken G. Early recurrence of Pneumocystis jiroveci pneumonia in two HIV-infected patients: linking infection relapse and immune reconstitution syndrome. Respirology. 2009; 14(6):910-2.

[13]. Mori S, Cho I, Sugimoto M. A followup study of asymptomatic carriers of Pneumocystis jiroveci during immunosuppressive therapy for rheumatoid arthritis. J Rheumatol. 2009;36(8):1600-5.

[14]. Ritter ML, Pirofski L. Mycophenolate mofetil: effects on cellular immune subsets, infectious complications, and antimicrobial activity. Transpl Infect Dis. 2009; 11(4):290-7.

[15]. Abouya YL, Beaumel A, Lucas S, et al. Pneumocystis carinii pneumonia. An uncommon cause of death in African patients with acquired immunodeficiency syndrome. Am Rev Respir Dis. 1992; 145(3):617-20.

[16]. Murray JF. Pulmonary complications of HIV-1 infection among adults living in Sub- Saharan Africa. Int J Tuberc Lung Dis. 2005; 9(8):826-35.

[17]. Grover SA, Coupal L, Suissa S, et al. The clinical utility of serum lactate dehydrogenase in diagnosing pneumocystis carinii pneumonia among hospitalized AIDS patients. Clin Invest Med. 1992; 15(4):309-17.

[18]. Alanio A, Desoubeaux G, Sarfati C, Hamane S, Bergeron A, Azoulay E, et al. Real-time PCR assay-based strategy for differentiation between active Pneumocystis jirovecii pneumonia and colonization in immune compromised patients. Clin Microbiol Infect. 2011; 17(10):1531-7.

[19]. Botterel F, Cabaret O, Foulet F, Cordonnier C, Costa JM, Bretagne S. Clinical

[20]. Kaplan JE,Masur H, Holmes KK. Guidelines for preventing opportunisticinfections among HIV-infected persons–2002. Recommendationsof the U.S. Public Health Service and the Infectious Diseases Societyof America. MMWR Recomm Rep 2002;51:1–52.

[21]. Palella FJ Jr, Delaney KM, Moorman AC, Loveless MO, Fuhrer J, SattenGA, Aschman DJ, Holmberg SD. Declining morbidity and mortalityamong patients with advanced human immunodeficiency virus infection:HIVOutpatient Study Investigators. N Engl JMed 1998;338:853–860.

[22]. Hirsch HH, Kaufmann G, Sendi P, Battegay M. Immune reconstitutionin HIV-infected patients. Clin Infect Dis 2004;38:1159–1166.

[23]. Shelburne SA, Visnegarwala F, Darcourt J, Graviss EA, Giordano TP,White AC Jr, Hamill RJ. Incidence and risk factors for immune reconstitutioninflammatory syndrome during highly active antiretroviraltherapy. AIDS 2005;19:399–406.

[24]. Wislez M, Bergot E, Antoine M, Parrot A, Carette MF, Mayaud C,Cadranel J. Acute respiratory failure following HAART introductionin patients treated for Pneumocystis carinii pneumonia. Am J RespirCrit Care Med 2001;164:847–851.

[25]. Thomas CF Jr, Limper AH. Pneumocystis pneumonia. N Engl J Med2004;350:2487–2498.

[26]. Wright TW, Notter RH, Wang Z, Harmsen AG, Gigliotti F. Pulmonaryinflammation disrupts surfactant function during Pneumocystis cariniipneumonia. Infect Immun 2001;69:758–764.

[27]. Shellito JE. Failure of host defenses in human immunodeficiency virus. semin Respir Crit Care Med 2004;25:73–84.

[28]. Zheng M, Shellito JE, Marrero L, Zhong Q, Julian S, Ye P, Wallace V,Schwarzenberger P, Kolls JK. CD4_ T cell-independent vaccinationagainst Pneumocystis carinii in mice. J Clin Invest 2001;108:1469–1474.

[29]. Koike T, Harigai M, Inokuma S, Ishiguro N, Ryu J, Takeuchi T, Tanaka Y,Yamanaka H, Fujii K, Yoshinaga T, Freundlich B, Suzukawa M: Postmarketingsurveillance of safety and effectiveness of etanercept in Japanesepatients with rheumatoid arthritis. Mod Rheumatol 2011, 21:343–351.

[30]. Ward MM, Donald F: Pneumocystis carinii pneumonia in patients withconnective tissue disease: the role of hospital experience in diagnosisand mortality. Arthritis Rheum 1999, 42:780–789.

[31]. Takabayashi K, Koike T, Kurasawa K, Yamazaki S, Sugiyama T, Matsumura R,Yoshida H, Tomioka H, Yoshida S, Oshima H: [Pulmonary opportunisticinfections in patients with autoimmune diseases] [in Japanese].Nihon Naika Gakkai Zasshi 1989, 78:1293–1298.

[32]. Thomas CF Jr, Limper AH: Pneumocystis pneumonia: clinical presentationand diagnosis in patients with and without acquired immune deficiencysyndrome. Semin Respir Infect 1998, 13:289–295.

[33]. Velayos FS, Sandborn WJ: Pneumocystis carinii pneumonia duringmaintenance anti-tumor necrosis factor-α therapy with infliximab forCrohn’s disease. Inflamm Bowel Dis 2004, 10:657–660.

[34]. Seddik M, Meliez H, Seguy D, Viget N, Cortot A, Colombel JF: Pneumocystisjirovecii (carinii) pneumonia following initiation of infliximab andazathioprine therapy in a patient with Crohn’s disease. Inflamm Bowel Dis2004, 10:436–437.

[35]. Kaur N, Mahl TC: Pneumocystis carinii pneumonia with oral candidiasisafter infliximab therapy for Crohn’s disease. Dig Dis Sci 2004, 49:1458–1460.

[36]. Takeuchi T, Tatsuki Y, Nogami Y, Ishiguro N, Tanaka Y, Yamanaka H,Kamatani N, Harigai M, Ryu J, Inoue K, Kondo H, Inokuma S, Ochi T, Koike T:Postmarketing surveillance of the safety profile of infliximab in 5000Japanese patients with rheumatoid arthritis. Ann Rheum Dis 2008,67:189–194.

[37]. Yale SH, Limper AH: Pneumocystis carinii pneumonia in patients withoutacquired immunodeficiency syndrome: associated illness and priorcorticosteroid therapy. Mayo Clin Proc 1996, 71:5–13.

[38]. Worth LJ, Dooley MJ, Seymour JF, Mileshkin L, Slavin MA, Thursky KA:An analysis of the utilisation of chemoprophylaxis against Pneumocystisjirovecii pneumonia in patients with malignancy receiving corticosteroidtherapy at a cancer hospital. Br J Cancer 2005, 92:867–872.

Received on 28.11.2016 Modified on 18.12.2016

Res. J. Pharmacognosy and Phytochem. 2017; 9(2): 59-63.

DOI: 10.5958/0975-4385.2017.00010.3