Board of Th e Egyptian Journal of Bronchology (EJB)

Editor-in-ChiefTarek Safwat (Ain Shams)

Deputy Editors

Associate Editors

Adel Kattab(Ain Shams Univ.)

Adel Saeed(Ain Shams Univ.)

Ashraf Hatem(Cairo Univ.)

Essam Gouda(Alex. Univ.)

Ashraf Madkour (Ain Shams Univ.)

EJB BOARDAbd El Hakim Mahmoud (Cairo Univ.)Abd El Moneim Rabie (Alex. Univ.)Abd El Rehim Yousef (Zakazik Univ.)Adel Salah (Zakazik Univ.)Ahmed Abdel Rahman (Monoufeya Univ.)Ahmed Al Halfawy (Cairo Univ.)Ahmed El Gazzar (Benha Univ.)Ahmed El Noury (Ain Shams Univ.)Amgad Abdel Raouf (Tanta Univ.)Amr Badr El Din (Banha Univ.)Ehab Atta (Alex. Univ.)Emad Koraa (Ain Shams Univ.)Gamal El Khouly (Tanta Univ.)Gamal Rabie Agmy (Assiut Univ.)Hafez Abdel Hafeez (Azhar Univ.)Hatem El Mallawany (Alex. Univ.)Hesham Tarraf (Cairo Univ.)Hoda Abou Yousef (Cairo Univ.)Ibrahim Radwan (Azhar Univ.)Khaled Eid (Cairo Univ.)Khaled Wagih (Ain Shams Univ.)Magda Yehia Elseify (Ain Shams Univ.)Magdy Abou Rayan (Alex. Univ.)Magdy Zedan (Mansoura Univ.)

Malak Shaheen (Ain Shams Univ.)Mamdouh Mahfouz (Cairo Univ.)Maysa Sharaf El Din (Cairo Univ.)Medhat Abdel Khalek (Cairo Univ.)Medhat Negm (Benha Univ.)Mohamed Abdel Sabour (Ain Shams Univ.)Mohamed Awad Ibrahim (Zagazig Univ.)Mohamed Dosouky Abou Shehata (Mansoura Univ.)Mohamed Khairy (Mansoura Univ.)Mohamed Metwally (Assiut Univ.)Nader Fasseeh (Alex. Univ.)Neveen Abd El Fattah (Ain Shams Univ.)Olfat El Shinawy (Assiut Univ.)Raef Hosni (Cairo Univ.)Ramadan Nafea (Zagazig Univ.)Salah Sorour (Alex. Univ.)Samiha Ashmawy (Ain Shams Univ.)Sayed Oraby (Ain Shams Univ.)Suzan Salama (Assiut Univ.)Tarek Mohsen (Cairo Univ.)Wafaa El Sheimy (Tanta Univ.)Walid El Sorougy (Cairo Univ.)Yasser Mostafa (Ain Shams Univ.)

ADVISORY BOARD INTERNATIONAL FACULTY BOARD

Mokhtar Madkour (Ain Shams Univ.)Mohamed Awad Tag El Din (Ain Shams Univ.)

Ahmed Boseila (Germany)Alaa El Gendy (USA)Atul Mehta (USA)Heinrich D. Becker (Germany)Henri G. Colt (USA)James R. Jett (USA)Majdy M. Idrees (KSA)Petr Pohunek (Czech Republic)Richard W. Light (USA)Roland M. du Bois (UK)

http://www.ejbronchology.eg.net/

Editorial CoordinatorAmr Shoukri (Ain Shams Univ.)

GUIDELINES FOR AUTHORS

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ReferencesTh e Egyptian Journal of Bronchology reference style follows the Uniform Requirements for Manuscripts Submitted to Biomedical Journals which is based largely on an ANSI standard style adapted by the National Library of Medicine (NLM) for its databases www. nlm.nih.gov/bsd/uniform_requirements.html Example for standard journal article:Halpern SD, Ubel PA, Caplan AL. Solid-organ transplantation in HIV-infected patients. N Engl J Med. 2002;347:284-7.For articles with more than six authors: List the fi rst six authors followed by et al.Rose ME, Huerbin MB, Melick J, Marion DW, Palmer AM, Schiding JK, et al. Regulation of interstitial excitatory amino acid concentrations after cortical contusion injury. Brain Res. 2002;935:40-6. Wherever possible should be chosen by the author.

ANNUAL SUBSCRIPTION

Th e Egyptian Journal of Bronchology is will be published thrice a year, January, May and September to start with.

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Information about the Journal is also available at the Egyptian Scientifi c Society of Bronchology website at:http://www.ejbronchology.eg.net/

Th e Egyptian Journal of BronchologyThe Offi cial Journal of the Egyptian Scientifi c Society of Bronchology

Vol. (12), No. (1), January-March, 2018

Review Article

Pulmonary Infections1 What does pulmonary–renal syndrome stand

for? Taghreed S. Farag, Abeer S. Farag

Original articles

Airway diseases14 Magnetic resonance spectroscopy in evaluating

cerebral metabolite imbalance in chronic obstructive pulmonary disease

Olfat M. El-Shinnawy, Eman M. Khedr, Mohamed M. Metwally, Alaa EL-din Th abiet Hassan, Ahmad M. Shaddad, Radwa Kamel Soliman

Airway diseases20 Study of voice disorders in patients with

bronchial asthma and chronic obstructive pulmonary disease

Adel M. Saeed, Nermine M. Riad, Nehad M. Osman, Ahmed Nabil Khattab, Shymaa E. Mohammed

Airway diseases27 Transthoracic ultrasonographic evaluation of

diaphragmatic excursion in patients with chronic obstructive pulmonary disease

Ayman Amin, Moustafa Zedan

Airway diseases33 Medication adherence and treatment satisfaction

in some Egyptian patients with chronic obstructive pulmonary disease and bronchial asthma

Iman H. Galal, Yasser M. Mohammad, Abeer A. Nada, Yosra E. Mohran

Critical Care41 The effect of triggering type on post-triggering

pressure variations during pressure support venti lat ion: a simpli f ied surrogate for dyssynchrony

Maher M. H. Al-Najjar, Tamer S. Fahmy, Mohamed A. Al-Shafee, Hatem Al-Atroush

Critical Care

49 Predictors of failure of early shift from invasive to noninvasive ventilation in weaning chronic obstructive pulmonary disease patients who have failed the initial spontaneous breathing trial: a prospective cohort study

Sameh A. Moneim, Tamer S. Fahmy, Nashwa Abed

Critical Care

57 Predictors and outcome of prolonged stay in the respiratory ICU

Adel M. Khattab, Ahmed Abd Elgawad El-Masry, Ashraf A. El Maraghy, Noha O. Ahmed

Interstitial lung diseases

69 Serum interleukin 23 and its associations with interstitial lung disease and clinical manifestations of scleroderma

Gamal A. Hammad, Refaat M. Eltanawy, Rasha M. Fawzy, Tahany M.A. Gouda, Mona A. Eltohamy

Interstitial lung diseases

76 Combined pulmonary fi brosis and emphysema syndrome: clinical, functional, and radiological assessment

Maha K. Ghanem, Hoda A. Makhlouf, Ali A. Hassan, Heba A. Hamed

Interventional Pulmonology83 Use of videobronchoscopic narrow band imaging

compared with white light in diagnosing some bronchopulmonary diseases

Ehab M. Atta, Suzan M.F. Helal, Rasha G.A. Daabis, Alaa A. Abdallah, Amr M.I. Yehya

Interventional Pulmonology

92 Assessment of severe dyspnea in critically ill patients by transthoracic sonography: Fayoum experience of the Bedside Lung Ultrasonography in Emergency protocol

Gamal R. Agmy, Sherif Hamed, Mohamed A. Saad, Randa Ibrahim, Aliaa A. Mohamed

Pleural diseases98 Efficacy and safety of intrapleural cisplatin

versus silver nitrate in treatment of malignant pleural effusion

Mohammad K. El Badrawy, Raed El-Metwally Ali, Asem A. Hewidy, Mohamed A. El-Layeh, Fatma M.F. Akl, Abdelhadi Shebl

Pulmonary Infection105 Study of addiction in newly diagnosed patients

with pulmonary tuberculosis in Abbasia Chest Hospital

Adel M. Saeed, Riham H. Raafat, Eman M. Elbaz

Seep Medicine114 Pulse transit time in patients with sleep-

disordered breathing Marwa El-Sayed El-Naggar

(Miscellaneous)119 Frequency of hepatopulmonary syndrome and

portopulmonary hypertension in cirrhotic liver patients

Abbas S. El-Maraghy, Ahmed A. Abu Naglah, Ayman Amin, Kamal A. Merghany, Mohamed M. Khalil

Case report129 Broncial stump aspergillosis, an unusual cause

of hemoptysis, and review of the literature Dipesh Maskey, Ritesh Agrawal

Review article 1

What does pulmonary–renal syndrome stand for?Taghreed S. Faraga, Abeer S. Faragb

Pulmonary–renal disorder (PRS) is an emergency situationdescribed by a rapidly progressive course without an earlyintervention. It is appropriate time to review this disorder, thisis may be attributable to frequent patients’ attendance topulmonologist with both vague pulmonary and/or renalsymptoms with disproportionate lack of informationconcerning consequent care. In addition, the outcome datafor PRS still confined to little studies with limited follow-up. Anupdated working knowledge of PRS including the diseasepathogenesis, complications as well as quickly advancingfield focused on current new immunomodulatory therapieswhich offer life-saving options for refractory disease. An often-multi-disciplinary team is required for management. Earlyrapid identification relies upon a high index of clinicalsuspicious, carful medical evaluation, accessible laboratoryinvestigations, imaging study, histopathology, with exclusionof differential diagnosis. An accurate diagnosis, exclusion of

© 2018 Egyptian Journal of Bronchology | Published by Wolters Kluwer - Medknow

infection, close monitoring of the patient as well as timelyinitiation of aggressive therapy are crucial for the patient’soutcome. The mortality rate of PRS, reach up to 25–50 % [1].Egypt J Bronchol 2018 12:1–13© 2018 Egyptian Journal of Bronchology

Egyptian Journal of Bronchology 2018 12:1–13

Keywords: diffuse alveolar hemorrhage, glomerular filtration rate, pulmonary-renal syndromes, rapid progressive glomerulonephritis:

Departments of, aChest Diseases, bPathology, Faculty of Medicine for Girls,

Al-Azhar University, Cairo, Egypt

Correspondance to Taghreed S. Farag, MD, Chest Diseases Department,

Faculty of Medicine for Girls, Al-Azhar University, Al-Zahraa University

Hospital, 02-26854947– 11517 Al-Abbassia, Cairo, Egypt;

e-mail: drtaghreedsaied@gmail.com

Received 18 January 2017 Accepted 14 May 2017

IntroductionPulmonary–renal syndrome (PRS) is an emergencysituation described by a rapidly progressive coursewithout an early intervention. It is an appropriate timeto review this disorder; this may be attributable tofrequent attendance of patients to the pulmonologistwith both vague pulmonary and/or renal symptomswithdisproportionate lack of information of consequent care.In addition, the outcome data for PRS are still confinedto a few studies with limited follow-up. An updatedworking knowledge of PRS will be useful including thedisease pathogenesis, complications as well as quicklyadvancing field focused on current new immuno-modulatory therapies that offer life-saving options forrefractory disease.

An often-multidisciplinary team is required formanagement. Early rapid identification relies on a highindex of clinical suspicious, carful medical evaluation,accessible laboratory investigations, imaging study, andhistopathology, with exclusion of a differential diagnosis.

An accurate diagnosis, exclusion of infection, closemonitoring of the patient as well as timely initiationof aggressive therapy are crucial for the patient’soutcome. The mortality rate of PRS reaches up to25–50% [1].

This is an open access article distributed under the terms of the Creative

Commons Attribution-NonCommercial-ShareAlike 3.0 License, which

allows others to remix, tweak, and build upon the work

noncommercially, as long as the author is credited and the new

creations are licensed under the identical terms.

Pulmonary–renal syndromePRS are defined as clinical syndromes characterizedby diffuse alveolar hemorrhage (DAH) combinedwith rapid progressive glomerulonephritis (RPGN)[2–4].

The DAH is characterized by hemoptysis, lowhematocrit with bilateral diffuse alveolar infiltrate,and hypoxemic respiratory failure [5]. However,RPGN is a kidney disorder described on a clinicalbasis by a rapid decrease in glomerular filtration rate ofno less than 50% within a brief period of time, whichvaries from days up to 3 months [6].

Causes and differential diagnosis of thepulmonary–renal syndromeThere is a broad list of etiologies that can cause thissyndrome (Table 1). Systemic small-vessel vasculitis isthe main underlying causal factor of PRS, mainly smallrenal as well as pulmonary vessels vasculitis. PRS can beclassified according to the following [2–7]:

(1)

Morphological criteria (size of the affected vessels,presence or absence of granulomas).

(2)

Etiological criteria (idiopathic or secondary forms).

(3)

Immunological criteria [anti-neutrophilic-

cytoplasmic antibodies (ANCA)-associatedvasculitis, immune-complex vasculitis, or causedby antibasement antibodies).

Pathogenesis of pulmonary–renal syndromeA variety of mechanisms are implicated in thepathogenesis of PRS syndrome:

DOI: 10.4103/ejb.ejb_6_17

mailto:drtaghreedsaied@gmail.com

Table 1 Pulmonary–renal syndromes: clinical entities

2 Egyptian Journal of Bronchology, Vol. 12 No. 1, January-March 2018

(1)

ANCA-mediated injury.

classified according to the pathogenesis [4,7,10,11]

(2)

1: ANCA associated systemic vasculitis, make up 60% of all

Injury induced by anti-glomerular basementmembrane (anti-GBM) antibodies.

PRS**

ANCA positive vasculitis

(3)

• Wegener’s granulomatosis (WG): C-ANCA or Anti-PR3

Immune-complex-mediated vasculitis of smallvessels.

• Churg–Strauss syndrome (CSS): P-ANCA or Anti-MPO

(4)

Drug-induced vasculitides.

• Microscopic polyangiitis (MPA): P-ANCA or Anti MPO• Drug-associated ANCA-positive vasculitis (Propylthiouracil,D-Penicillamine, Hydralazine, Allopurinol, Sulfasalazine)

2: Non-ANCA associated systemic vasculitis

a) ANCA-negative systemic vasculitis

• Behçet’s disease

Multiple centers have proposed that the developmentof PRS in 60–70% of patients is related toautoantibodies to ANCAs; however, 20% is relatedto anti-GBM antibodies [7–10].

• Henoch–Schönlein purpura• Cryoglobulinemic vasculitis

(1)

• IgA nephropathyb) Anti-GBM antibodies, make up 20% of all PRS

• Goodpasture’s syndromec) Autoimmune connective tissue disease

• Autoimmune rheumatic diseases (immune complexes and/orANCA mediated)

• Systemic lupus erythematosis(SLE)(Immune-complex mediatedvasculitis)

• Scleroderma• Rheumatoid arthritis• Mixed collagen vascular disease (systemic sclerosis,polymyositis)

d) Thrombotic microangiopathy

• Antiphospholipid syndrome• Thrombotic thrombocytopenic purpura• Infectious diseases• Neoplasm• DAH complicating idiopathic pauci-immune glomerulo-nephritise) Miscellaneous

• Paraneoplastic Vasculitis• Inflammatory Bowel Disease

CSS: Churg–Strauss syndrome; C-ANCA: cytoplasmic anti-neutrophilic-cytoplasmic antibodies; DAH: diffuse alveolarhemorrhage; p-ANCA, perinuclear anti-neutrophilic-cytoplasmicantibodies; MPA: Microscopic polyangiitis; SLE: Systemic lupuserythematosis; WG, Wegener’s granulomatosis. **They receivesimilar treatments – but the prognosis is worse if anti-Pr3 is present.

ANCA are antibody groups that interact withcytoplasmic antigens in human neutrophils. Despitea large variety of ANCA directed against abundantneutrophilic components, only two forms of ANCA[proteinase 3 (Pr3) andmyeloperoxidase (MPO)] areconsidered to be interrelated to small-vessel vasculitis[3]. Pr3 and MPO are detected in the azurophilicgranule of neutrophils and canbe expressedon the cellsurface in stimulated polymorphonuclear leukocytecells. MPO are considered the target antigens forperinuclear anti-neutrophilic-cytoplasmic antibodies(P-ANCA) however, Pr3 are the target antigens forcytoplasmicANCA (C-ANCA). Binding ofANCAwithPr3on the endothelial surface induces the releaseof lytic enzymes, interleukin-8 chemoattractant, andreactive oxygen species. Neutrophils subsequentlyaggregate on the endothelium, causing inflam-mation and damage to the vasculature; finally, cellnecrosis and apoptosis and occur that contributetoward the vascular inflammatory process[4,11–14]. Identification of ANCA could be bothby indirect immunofluorescence (IF) and by enzyme-linked immunosorbent assay (ELISA) [4,8]. By anindirect IF test on ethanol-fixed neutrophils forANCA, three types of antibodies can be observedon the basis of their cellular staining pattern: aperinuclear pattern, a diffuse cytoplasmic granularpattern, and an atypical pattern [4,10,11].(a) PRS in ANCA-positive systemic vasculitis:

ANCA antibodies are identified in nearly60–70% of patients presenting with PRS[7–10]. ANCA do not prove a definiteetiology, but enable a differential diagnosis ofthree main systemic vasculitides syndromes:Wegener’s disease or Wegener’s granulo-matosis (WG), microscopic polyangiitis(MPA), and Churg–Strauss syndrome (CSS)(Tables 1 and 2) [4].

(b) Recently, there have been attempts to changethe eponym of WG to ANCA-associatedgranulomatous vasculitis, which describesthe pathology and the disease process [15].

The triad of systemic necrotizing vasculitisdescribes WG, that is, necrotizing granulo-matous inflammation of the upper and/or thelower respiratory tract, focal necrotizingvasculitisof medium and small arteries, including venulesand arterioles, and necrotizing immuneglomerulonephritis [16]. The incidence of thedisease has been predicted to be up to 8.5/million(range: 5.2–12.9/million), with amale-to-femaleratio of 1 : 1.Thedisease frequently affectswhites(80–97%), with a mean age at the time ofpresentations of 40–55 years, although it canoccur at any age [17]. The lungs are affected in90% of cases. In a small percentage of patients, alimited WG that spares the kidney and with noevidence of systemic vasculitis has been reported[17,18].C-ANCA is found inmore than 85%of

Table 2 Clinical presentations, laboratory investigations, and histopathological features of some causal factors of pulmonary-renal syndromes [4,7]

ANCA- associated vasculitis Non-ANCA associated systemicvasculitis

WG MPA CSS GP SLE

Clinical presentation Conductiondeafness with

Eustachian tubedamage, collapseof nasal bridgecartilage, orbitalscleritis, proptosis

GN reported in 90%,Pulmonary in 50%,

DAH in 33% of cases,Pleurisy & pl. effusion.

Asthma, fibrosis,Hemoptysis &occasionally

pulmonary edema. Theupper airway is much

less prominentlyaffected by MPA.

Other organs affection:[MSK 60%, Skin -

40%, CNS 30%, GIT50%].

Late onset asthma,Sinusitis, rhinitis.

Eosinophilia> 10%,GIT disturbance with

mesentericeosinophilic infiltration,

Myositis, (Cardiacfailure) mono orpolyneuropathy,

migratory pulmonaryopacities on PCX-R.

50% present withRPGN, 50%present with

PRS

Photosensitivity ,Malar rash, Discoidrash, polyserositis,Oral ulcers, non-erosive arthritis

polyserositis (pleural,pericardial)

General symptoms ofvasculitis

+ + + − +

Granuloma formation + − + − −

Possibility of PRS + + ++ + ++

Laboratory investigations

ANCA 80–90% 80–90% 50–70% Absent Absent

Pr3-antibody ∼70% ∼30% ∼10% 30%) if DAH

RBCs andsiderophages (>30%)

if DAH

Eosinophilia

Renal biopsy

Light microscopy Necrotizinggranulomatous

vasculitis,capillaritis

Necrotising vasculitiswith few or no immunedeposits on immuno-flourescence (pauci-

immune)

Eosinophil-richgranulomatous

infiltration. Vasculitishistologically

indistinguishablefromWG and MPA.

Segmental toglobal fibrinoidnecrosis with

crescentformation in 90%progressing to

fibrous crescents

Lupus nephritis

Immuno-histopathology

Pauci-immune GN without immune-complex deposits Linear IgGdeposits in the

GBM

Granular deposits ofIgG, IgM, IgA &complement

ANCA, antineutrophil cytoplasmic antibodies; CSS, Churg–Strauss syndrome; DAH, diffuse alveolar hemorrhage; GBM, glomerularbasement membrane; GP, Goodpasture’s syndrome; IC, immune complex; MPA, microscopic polyangiitis; MPO, myeloperoxidase; Pr3,proteinase 3; PRS, pulmonary–renal syndrome; RPGN, rapid progressive glomerulonephritis; SLE, systemic lupus erythematosus; WG,Wegener’s granulomatosis; MSK, musculoskeletal; ∼, nearly , +, common; ++, more common; -, uncommon or absent.

What does PRS stand for? Farag and Farag 3

patients with generalized WG and in 60% ofpatients with the limited form of the disease.P-ANCA is nonspecific, frequently observed inother vasculitic syndromesor isolatednecrotizingglomerulonephritis [3].

(c) MPA is a systemic small-vessel vasculitis that isconfined to the microvessels and is alwaysassociated with a focal segmental necrotizingglomerulonephritis (80–100% of patients),pulmonary capillaritis (10–30%), skin lesions,and arthralgias [19]. It is differentiated fromWG by the absence of upper airway

involvement; also, ∼40–80% of patientswith MPA have P-ANCA directed againstneutrophil myeloperoxidase (MPO-ANCA).Positive P-ANCA/MPO-ANCA and anegative serological test for hepatitis B are, ingeneral, suggestive of MPA [3]. UnlikeANCA-associated granulomatous vasculitis,the level of MPO-ANCA titers is notassociated with disease activity [17].

(d) CSS is a rare systemic and pulmonaryvasculitis, with an incidence of fewer thanthree cases/million. A higher incidence was

4 Egyptian Journal of Bronchology, Vol. 12 No. 1, January-March 2018

estimated in asthmatic patients (64 cases/million), with a male-to-female ratio of 2 :1. CSS typically presents with an initialasthma/sinusitis phase, followed by amarked blood and tissue eosinophilia; thefinal stage is a vasculitic phase, which canprogress to severe respiratory and renalfailure [19]. Roughly 35–70% of patientswith CSS have positive P-ANCA/MPO-ANCA, whereas only 10% have positive Pr3ANCA [3]. Renal disorders are milder inCSS compared with WG, MPA, andGoodpasture’s syndrome [20].

(e) PRS in ANCA-negative systemic vasculitis:PRS in ANCA-negative systemic vasculitis isextremely uncommon [3] and has beendescribed only infrequently in Behçet’sdisease, in Henoch–Schönlein purpura, inimmunoglobulin (Ig) A nephropathy, and inmixed cryoglobulinemia (Table 1) [4]. InHenoch–Schönlein purpura, acute capillaritisand DAH involve the deposition of IgAimmunocomplexes along the pulmonaryalveoli [3].

(f) ANCA-positive PRS without systemicvasculitis: idiopathic PRS:This group includes patients presenting withDAH, RPGN, and positive ANCA (eitherPr3 or MPO), but without othermanifestations of systemic vasculitis. Fever,malaise, weight loss, generalized body ache,and arthralgias may coexist. Mortalityduring the first episode of the syndromeexceeds 50%. It is not clear whether thesyndrome represents either a limited type ofMPA or a variant of Wegener’s syndrome [3].

associated with anti-GBM antibodies:

PRS

(2)

Goodpasture’s syndrome:Goodpasture’s syndrome is extremely rare (onecase/million). The disease principally influencesWhites of any age, with a slight malepredominance. Despite its rarity, this syndromeis accountable in nearly 20% of acute renal failurecases because of RPGN [21]. Genetic andenvironmental factors have been implicated inthe pathogenesis of Goodpasture’s syndrome.The disease has been found in brothers and inidentical twins. 80% and more of patients carry theHLA alleles DR15 or DR4, whereas the allelesDR7 and DR1 are rarely established, signifyingthat the latter may play a defensive role [22]. As themajority of patients present infrequently, theremay be an etiology other than geneticpredilection. Environmental factors for example

smoking-related lung injury, infections orinhalation injuries, such as cocaine inhalation, orpast hydrocarbon exposure are triggering factorsfor pulmonary capillaritis causing DAH or ‘full-blown’ Goodpasture’s syndrome [4].

In Goodpasture’s disease the production ofantibodies occurs against an intrinsic antigen tothe GBM (etiology unknown). Antibodies mayprecede clinical signs by weeks or months. Anti-GBM antibodies, mainly to IgG1 or IgG3,interact with small numbers of epitopes (EA andEB) on the noncollageneous domain of the α3chain of type IV collagen, a particle released inthe BM of renal tubule, renal glomeruli, alveoli,retinal capillaries, and chorioid plexus [16,17].Renal injury in RPGN occurs mainly because ofbinding of anti-GBM antibodies to GBM, whichtrigger complement and protease activations,causing damage of the capillaries, basalmembranes, impairment of the Bowman’scapsule filtration barrier, with flooding of RBCs,followed by an invasion of fibrinogen andmacrophages, inducing proteinuria and crescentdevelopment [3,4].

Anti-GBM antibodies recognized utilizingdifferent immunoassays have a sensitivity of95–100% and a specificity of 90–100% forGoodpasture’s syndrome. In patients withnegative anti-GBM antibodies, a lung or a renalbiopsy with IF showing linear antibody depositionwithin the alveolar or the GBM establishes thediagnosis. However, in up to 10% of patients withGoodpasture syndrome, DAH is present withoutrenal affections and is similar to isolatedpulmonary capillaritis. Lung biopsies with IFstudies can differentiate both [15].

Immune-complex-mediated disease: systemic

(3)

lupus erythmatoses (SLE) is the most widelyrecognized underlying factor of PRS mediatedby immune-complex. This is an autoimmunedisease that involves pathological autoantibodyproduction to double-stranded DNA throughoutreactions involving T helper cells as well as B cells[23]. DNA–anti-DNA immune complexes arereleased within the glomeruli and triggerglomerular complement, causing the release ofchemoattractants together with inflammatorycytokines. A continual inflammatory processresults in extracellular matrix deposition withinthe renal mesangium [24]. Immune-complex-mediated vasculitis results in an isolated necroticpulmonary capillaritis with extravasations ofdamaged erythrocyte directly into alveolar

What does PRS stand for? Farag and Farag 5

spaces, causing alveolar hemorrhage [23].Essential mixed cryoglobulinemia (type II) isanother uncommon reason for PRS caused byimmune-complex deposition. It is considered tobe initiated in the majority of cases by chronicinfectivity by hepatitis C virus [24].

(4)

Drug-induced vasculitides are generally initiatedby tiny particles forming immune-complexdeposition within the pulmonary and renalcapillaries. They are frequently ANCA positive(prevalently MPO). Some drugs may possiblyconsider as haptens denote that they can causeimmune reactions just while coupled to a carrierprotein. Propylthiouracil and hydralazine arefrequent causal drug induced vasculitides [3,25],and commonly showing dosage dependent hazard[3,26].

Pathology and pathophysiology of pulmonary–renalsyndromeSmall-vessel vasculitis, necrotic pulmonary capillaritis,as well as focal proliferative glomerulo-nephritis are thecharacteristic pathological features of PRS [27].

Among the histopathologies of DAH (pulmonarycapillaritis, pulmonary hemorrhage, diffuse alveolardamage, and various histologies), pulmonary capillaritisis the most common. Pulmonary capillaritis differs frompulmonary vasculitis. Pulmonary vasculitis refers toinflammation of lung vessels of any size, whereaspulmonary capillaritis is restricted to the micro-circulation of the lung (destructive inflammationaffecting arterioles, venules, and alveolar capillaries).Despite this, both may be encountered in systemicvasculitides and in connective tissue disorders [15,27].Pulmonary capillaritis has an exclusive histopathologicappearance consisting of an interstitial mainlyneutrophilic infiltration, fibrinoid necrosis of thealveolar capillary walls, and leukocytoclasis. Theinfiltrating neutrophils undergo cytoclasis; nucleardebris accumulates within the interstitium, causinginterstitial and alveolar edema with hyaline membraneformation [15]. After recurrent attacks or episodes ofDAH, interstitial fibrosis may develop [28]. Theseinjuries disrupt perfusion and increase pulmonarycapillary permeability [3], causing flooding of bloodinto the alveoli, resulting in hypoxemia and hypocapniawith impairment of oxygen transfer [4].

Extensive glomerular crescent formation (crescenticglomerulonephritis) is the fundamental pathologicfinding of RPGN that is observed by light microscopyand electron microscopy. The pathological aspect ofcrescentic glomerulonephritis is a focal rupture of

glomerular capillaries, basement membranes, andblood extravasations, followed by an invasionof macrophages and fibrinogen with the developmentof extracapillary cellular proliferation (crescentsformation). Fibrinoid necrosis is commonly en-countered, in addition to microvascular thrombi [29].

There are numerous pathological varieties relying onthe correct etiology. Necrotizing granulomata withWG is infrequently observed on renal biopsy, anddirect proof of small-vessel vasculitis is alsoinfrequent [30]. The three major pathologic featureson WG lung biopsy include granuloma, inflammationof the vascular wall (arteriolar, venular, or capillary),and areas of geographic necrosis [31]. The histologiccriteria of CSS include necrotizing vasculitis,eosinophilic tissue infiltration, and extravasculargranulomas [32]. Extensive crescent formations areusually found in glomerular tuft disease. Theoccurrence of interstitial infiltration, with or withoutfibrosis or tubular atrophy, has a poor prognosis.

Electron microscopy and IF examinations of pauci-immune glomerulonephritis biopsy sample indicate alack of immune-complex deposits, as well ascomplement or Igs. These profiles of necrotizingvasculitis are observed in MPA [4].

In an IF examination, the type and deposition pattern ofIgs differ (either linear, capillary, granular, or mesangial,allwithin theGBM).Only inGoodpasture syndromecanthe anti-GBM antibody be detected as linear depositsalong the glomerular and/or the alveolar basementmembrane. However, the granular pattern depositof complement and Ig is observed in Lupusand postinfectious glomerulonephritis, and also innecrotizing vasculitis (pauci-immune glomerulo-nephritis) [3]. Interestingly, in immune-complexvaculitis, an alternate profile may be detected, typicallywith a granular pattern of IgA, IgM, IgG, or complement[3].

Diagnostic workup of pulmonary–renal syndrome

(1)

The diagnosis of PRS in the ICU is challenging.There is no single specific test, andthe symptoms and signs are usually vague.There is an overlap with other common ICUpresentations such as sepsis and cardio-respiratory morbidity.

(2)

The clinical presentation of PRS is variable, andcould be related to acute respiratory and/or renalfailure, a common symptom of systemic vasculitis,as well as the underlying pathology.

6 Egyptian Journal of Bronchology, Vol. 12 No. 1, January-March 2018

(3)

Acute exacerbation of the underlying pathologyor infectious complications secondary to severeimmunosuppressive therapy of the underlying causeare the most common triggering factors of PRS [15].

The three basic steps for the diagnosis of PRS as withany systemic vasculitis involve the following:

(1)

Carful clinical evaluation of present and pastillnesses.

(2)

Confirmation of the diagnosis by laboratoryinvestigations and examinations of biopsy samples.

(3)

Exclusion of an alternative diagnosis for vasculitis.

Clinical manifestations

(1)

Breathlessness is a frequent clinical presentation ofPRS [4].

(2)

Presentation of patients withDAH can range fromfever and cough, often acute or sub acute (

What does PRS stand for? Farag and Farag 7

most of them reveal p-ANCA with MPOspecificity [19]. On the other hand, ANCAtype and specificity is not specific for thesedisorders, as few cases of WG are p-ANCA-positive, as well as c-ANCA-positivewere observed in few patients with MPA[33–36]. According to the InternationalConsensus Statement on Testing andReporting of ANCA, combining indirect IFessays and ELISAs for Pr3 and MPO is moreaccurate than the use of either assay alone [18].It is important to note, however, that not allpatients with ANCA-associated vasculitiswill test positive for ANCA, and therefore,ANCA are not considered a diagnosticcriterion [3]. However, ANCA have alsobeen observed in numerous other auto-immune nonvasculitic disorders, that is,inflammatory bowel disease, rheumatoidarthritis, and autoimmune hepatitis as wellas in infectious and neoplastic diseases [10].

(d) Cryoglobulin titer results should be negative inpatients with ANCA-related diseases assymptoms of cryoglobulinemia are similar tothose in ANCA-related disease [33–36].

(e) Hepatitis markers: hepatitis C is linked tomixed cryoglobulinemia, whereas hepatitis Bis linked to polyarteritis nodosa [33].

(f) Tests for antiphospholipid antibodies, anti-double strand-DNA, and complementfractions C3 and C4 must be requested ifthere is any suspicion of SLE orantiphospholipid syndrome [35].

Urine analysis with microscopic examination:

(7)

proteinuria is almost constantly present, but isseldom more than 2–3 g/24 h. Also, microscopichematuria is always detected and might be directevidence for glomerular membrane damagebecause of glomerulonephritis. Microscopichematuria with proteinuria are most commonlydetected early in WG and MPA [31]. Nephriticurinary sediments (dysmorphic red blood cell and/or red blood cell casts), if crescents more than 50%,indicate a poor prognosis [31].

(8)

Urine and serum protein electrophoresis: thismay be considered a key investigation inpatients with RPGN with the aim ofconfirming or excluding the light-chain diseaseor overt multiple myeloma as a reason for thepresenting symptoms [3,4].

Imaging studiesThere are benefits of imaging to determine the severityof pneumonic capillaritis causing DAH:

(1)

Plain chest radiography or computed tomography:(a) There are abnormal radiographic pictures even

without clinically significant manifestations.Normal chest radiography is recorded in25% of cases, and in such cases, pulmonaryembolic disease should be excluded [4].

(b) The most common findings include bilateraldiffuse alveolar infiltrates, mainly perihilarinfiltrates, toward the lower zones or areasof consolidations with air bronchogram withpreserved normal areas; up to diffuseconsolidation mimic an adult respiratorydistress syndrome picture; rarely DAHradiographic pictures appear as ground glassopacities. These changes are usuallynonspecific and often frequently difficult todifferentiate form infection or acutepulmonary edema [3,4,32].

(c) Vasculitis as a cause of DAH is highlysuggested by multiple cavities, diffuseground glass infiltrations, and nodules. WGis commonly associated with cavitations;diagnostic workup should be performed forexclusion of alternative diagnoses, that is,cavitating pneumonia, mycobacterial, ormalignant disease [4].

(d) Lymphadenopathy is usually not present inDAH, but usually add suspicious of infectivityor malignancy [5].

(e) Radiographic resolution in general takes 3–4days (or sometimes even 1 day) only if thesource of bleeding has stopped. The presenceof interstitial opacities might be a result of anunderlying cause or may indicate the presenceof primary pulmonary hemosiderosis, causedby chronic or repeated episodes of DAH[37,38].

(f) The finding of Kerley A, B, or C shadowswith diffuse alveolar infiltrate indicates analternative diagnosis, that is, veno-occlusivedisease of the lung, cardiogenic pulmonaryedema, or mitral valve stenosis [39].

Nowadays, nuclear imaging, for example, gallium

(2)

or tagged red blood cell studies, are rarelyperformed in the evaluation of DAH. Othernuclear studies, which may reveal breakdownof the microcirculatory integrity and RBCsextravasations out of the vessels, haveadditionally not been shown to be useful [32].

(3)

Renal ultrasound is definitely performed to excludeobstructive uropathy in any patient with acuterenal failure [6] and also to establish thepresence of two functioning kidneys before apercutaneous renal biopsy [6].

8 Egyptian Journal of Bronchology, Vol. 12 No. 1, January-March 2018

Pulmonary function tests in stable patients

(1)

Diffusion lung capacity for carbon monoxide(DLCO) can be measured; this is significant ifthere is an increase of greater than 30%. Recentalveolar hemorrhage increases DLCO, whereasDAH that occurs more than 2 days before thetest is unlikely to cause a significant increase inDLCO. Continuous increase in DLCO may besuggestive of progressive alveolar hemorrhage.DLCO measurement maneuvers require breath-holding on an air, carbon monoxide, and heliummixture for around 10 sec. The major disadvantageof this maneuver is that it is difficult and notpractical in patients with marked dyspnea orhemoptysis [4]. In contrast, decreased exhalednitric oxide of exhaled breath condensate mayplay a role in the diagnosis of DAH [32].

(2)

Restrictive changes, that is ↓total lung capacity and↓forced vital capacity (FVC), with a preserved ratioof forced expiratory volume in 1 s (FEV1)/FVC,may characterize DAH. Frequent attacks of DAHcan cause interstitial fibrosis [32].

(3)

Obstructive changes, that is, ↓FEV1 and ↓ratio ofFEV1/FVC are less commonly observed in patientswith DAH, but if present, may indicate airflowobstruction. Many authors attributed this possiblyto flooding of alveolar spaces by blood, which causesneutrophilic infiltration that sequentially releasesproteolytic enzymes and reactive oxygen species,which in turn may result in parenchymaldestruction and small airway disease, for example,emphysema and bronchiolitis [32].(a) A mixed pattern of obstructive and restrictive

lung disease associated with DAH is suggestiveof a differential diagnosis causing airflowobstruction and parenchymal destruction,that is, commonly, sarcoidosis, MPA, orWG, occasionally idiopathic pulmonaryhemosiderosis, or, less frequently, pulmonarycapillaritis, lymphangioleiomyomatosis, orhistiocytosis X [32].

BronchoscopyBronchoscopic examination, serves three purposes:visual inspection of airway sources of bleeding,exclusion of infection, and obtain lavage samples forvarious laboratory investigations that is, bacterial, viral,mycobacterial, and fungal cultures, in addition topneumocystis stains. Evidence supporting DAH iscontinual or increase blood quantity on threesequential lavage aliquots from a single affected area;Prussian blue staining for bronchioloalveolar lavageshows hemosiderin-laden macrophages (siderophages)

[4].Thediagnostic yield is enhanced if thebronchoscopyis carried out within the first 2 days of manifestationsinstead of later [3,32].

Tissue biopsyThe gold standard for the diagnosis of PRS is renaland/or pulmonary biopsy when the lung is involved.Transbronchial biopsy specimens are small andunlikely to help establish a diagnosis. Thoracoscopiclung biopsy or open lung biopsy, although invasive andinvolving considerable risk, is more definitive [3,32].In general, lung biopsy should only be used as a lastoption if the diagnosis cannot be confirmed in adifferent way [4].

In difficult cases with vague symptoms or once there isa suspicion of systemic vasculitis, collagen vasculardisease, or Goodpasture’s syndrome, renal biopsy isfavored and should be performed as soon as possibleKeeping in mind the end goal of assessment of a renalbiopsy, the pathologist should correlate completeclinical and laboratory research facility data withLight microscope and IF, and the electronmicroscopic examinations should be carried out assoon as appropriate [6,35].

In those patients whom can’t tolerate or at high-riskoperative interference for lung or renal biopsy [3],biopsies from other organs (i.e. skin, sinuses ornerves) can be replaced. Proper treatment shouldbe initiated rapidly even in the absence ofhistopathological proof to reduce morbidity andmortality in patients with a high clinical suspicion ofANCA-associated or anti-GBM-associated vasculitisand with a positive ANCA or anti-GBM antibodyresult, respectively [1,3].

When initial treatment is started, patients should beclosely monitored for response to treatment.Radiological clearance, and improvements inarterial blood gases, renal function, neurologicsigns, and other signs (such as purpura) can beexpected within a few days of initiation of therapy[3] (Fig. 1).

If this diagnostic workup is not conclusive or if is thepatient’s condition worsens, refractory PRS with adifferential diagnosis should be considered, forexample, Papiris and colleagues [3,7,40]:

(1)

Drug reactions, sepsis syndrome, or septicemia orexacerbation of the underlying cause.

(2)

Antiphospholipid syndrome with vasculitis

Figure 1

Diagnostic workup of pulmonary–renal syndrome. ANA, anti-nuclearantibody; ANCA, anti-neutrophil cytoplasmic antibodies; anti-ds, antidouble strand; APL, anti-phospholipid; BAL, bronchioloalveolar la-vage; C3 and C4, complement fractions; DAH: diffuse alveolarhemorrhage; FOB, fiberoptic bronchoscopy; GBM, glomerular base-ment membrane; RF, rheumatic factor; U/A, urinalysis

What does PRS stand for? Farag and Farag 9

(3)

Mixed connective tissue diseases, that is, systemicsclerosis, polymyositis.

(4)

Thrombocytopenic purpura.

(5)

Infectious complications of the lung and kidney

(e.g. sepsis, tuberculosis, mycoplasma, legionella,cytomegalie-virus, hantavirus, leptospirosis).

Furthermore, a primary renal disorder results in lungdisease and resembles the profile of PRS:

(1)

Acute renal failure with pulmonary edema anduremic hemoptysis.

(2)

Thromboembolism in nephrotic syndrome: renalvein thrombosis and/or pulmonary embolism.

(3)

Immunosuppression in renal disease andpneumonia.

In addition, a primary lung disease results in renaldisease and resembles the profile of PRS:

(1)

Pulmonary infectionwith prerenal renal failure and/or postinfectious glomerulonephritis or hematuriain IgA nephropathy.

(2)

Lung cancer with immune-complex nephritis.

Treatment of pulmonary–renal syndrome in critically illpatients

(1)

The primary goal of therapy for patients with PRSis to induce remission as fast as possible tominimize irreversible organ damage as well asto prevent further antibody formations. Inaddition, treatment plans should be focused oncausal factors with the prevention of treatment-related toxicity.

(2)

Once the induction–remission phase has occurred,the secondary goal of therapy is to maintainremission with as few side effects as possible.

(3)

Supportive therapies and care should be providedthroughout the duration of illness.

Therapy is subdivided into the induction–remissionphase and the maintenance phase [41,42].

Anti-neutrophilic-cytoplasmic antibodies-associatedpulmonary–renal syndromeInduction–remission phaseImmunosuppressive therapy is the basis of treatment ofANCA-associated PRS. Standard remission inductiontherapy forpatientswith severediseasegenerally involvesa pulsed intravenous dose of methylprednisolone (500mg–1 g/day) for 3–5 days; this is coupled with pulsedintravenous cyclophosphamide, which is the preferabledrug in severely ill patients with systemic disorders.Intravenous cyclophosphamide is administered every2–3 weeks at a dose of (15mg/kg/pulse) on 6–9occasions or as a daily oral regimen (1–2mg/kg/day)[3,4,15,43],witha lowerdose in thoseolder than60yearsand those with renal impairment. The dose interval andduration of treatment are dependent on the nature of theunderlying inflammatory disease and the response[43,44]. Intravenous cyclophosphamide therapy isincreasingly favored over oral therapy because ofsignificantly fewer side effects. Optimal dosing withcyclophosphamide is achieved when the lymphocyticcount is reduced, but the total white blood count ismaintained above 3500. Its undesired effect related tocumulative dose. Hemorrhagic cystitis, bladder cancer,and gonadal toxicity are uncommon but serious sideeffects of cyclophosphamide therapy [4]. Bonemarrow suppression is the most common serious side-effect and regular full blood count monitoring ismandatory [44].

In case of severe renal impairment defined as a serumcreatinine (>500mmol/l) [4] or (serum creatinine>5.7mg/dl) [3], plasmapheresis may be beneficial atleast for the first week, with the possibility ofrestoration of renal function [41,42]. Plasmapheresis isa blood-purification procedure used to treat severalautoimmune diseases. It is also known as therapeuticplasma exchange (PE). Debates still exist on thebeneficial effect of PE in the acute phase. Themechanism of action of PE is largely unknown. PEdoes not directly influence the ability of the immunesystem to generate more antibodies, but can be used todilute and remove antibodies from circulation as well asto eliminate a large fraction of proinflammatorycytokine complement and coagulation factors from the

10 Egyptian Journal of Bronchology, Vol. 12 No. 1, January-March 2018

bloodstream. PE may therefore only offer temporarybenefits. It almost certainly decreases progression toend-stage renal disease in those with severe renalfailure at attendance [3,4], There is no establishedlong-standing survival advantage from its applicationand, in addition, little evidence for its role in thetreatment of cases with moderate renal impairment [3].

There are data showing that extracorporealmembrane oxygenation and activated humanrecombinant factor can be used to treat severeDAH in MPA with unremitting respiratory failure[3]. The mechanism of factor VIIa treatmentinvolves increased thrombin generation onthe surface of activated platelets at the sitesof hemorrhage [3]. Alternative agents are notcommonly used for induction of remission, that is,methotrexate and mycophenolate mofetil (MMF)[Suppressor for B lymphocytes and T celllymphocytes]. Although methotrexate is contra-indicated in severe renal disease, MMF is superiorto cyclophosphamide in preservation of normal renalfunction at 6 months from diagnosis [45]. Treatmentwith rituximab [Anti-CD20 monoclonal antibody]results in of B cells depletion. B cells producepathogenic autoantibodies and inhibit thecellular interaction, by reduction of both cytokinesproduction and immune complex formationsthat maintain mononuclear cells and help tosustain the disease [15,46]. A recent trial onrituximab for induction of remission in ANCA-associated disease did not find superior results tothe use of standard intravenous cyclophosphamide.With this therapy, nearly 85% of patients achieveremission [[41,42]. Transition to maintenancetherapy may occur 6–12 months after the initiationof induction therapy or after clinical remission[47].

Table 3 Current biological therapies for the treatment of pulmonar

Biologicaltherapy

Mood of action Indication

Mycofenolatemofetil

Suppressor for both Blymphocytes and Tlymphocytes

ANCA-associated vamaintenance)

Rituximab Anti-CD20 monoclonalantibody (B-cell depletion)

ANCA-associated vato or as a contraindic

Etanercept Tumor necrosis factor-αinhibitor

WG (maintenance th

Infliximab Tumor necrosis factor-αinhibitor

ANCA-associated va

Leflunomide Suppressor for T cells WG (remission, main

Antithymocyteglobulin

Suppressor for T cells Severe refractory WG

ANCA, antineutrophil cytoplasmic antibodies; WG, Wegener’s granulom

Maintenance phase therapyIf the patient continues to remain stable or improves,methylprednisolone is switched to prednisone at a doseof 1mg/kg/day for the first month and tapered over 5–6months with the aim of complete stoppage. Currently,glucocorticoids are sustained at a low dose for at least 18months together with steroid-sparing drugs. This isfrequently extended to 2 years in total in those withPr3-positive ANCA with a high incidence of relapse[42].Formaintenanceof remission,patients treatedwithcyclophosphamide have to be switched to eitherazathioprine or methotrexate. Azathioprine is favoredin patients with any degree of renal impairment. TheEuropean Practice is to switch from cyclophosphamideto azathioprine within 3- to 6-month intervals fromdiagnosis.MMFis an alternative for eithermethotrexateor azathioprine. Remission maintenance therapy iscontinued for at least 1 year after remission and longerin patients who have suffered relapses. Early stoppage ofimmune-suppressive therapy is associated with anexcessively high relapse rate [4].

Treatment of patients refractory to standard therapyAbout 10% of patients do not respond adequately tostandard therapy and fail to achieve remission. Relapsewill occur in 11–57% of patients in remission. Somerelapses are severe, resulting in end-organ damage [42];in such cases, alternative agents have to be used. Recentresearches have focused on newbiological agents, that is,tumor necrosis factor-α inhibitors (etanercept,infliximab), B-cell depletion agents (MMF), andsuppressor of T cells agents (leflunomide andantithymocyte globulin) (Table 3) [48–59]. Thesenew biological agents have been found to be efficientin certain patients, but result in high relapse andcomplication rates. The majority of data arepreliminary and additional investigations are requiredfor accurate conclusions [3,4].

y–renal syndrome [48–59]

General comments

sculitis (remission and Well-tolerated, high relapse rate

sculitis (remission, refractoryation to treatment)

Effective, preliminary data

erapy) Ineffective, higher frequency ofinfection and malignancies

sculitis Effective, high infectioncomplication rates, high relapserate

tenance) Well-tolerated, high relapse rate

Partial or complete remission,high complication rate

atosis.

What does PRS stand for? Farag and Farag 11

Supportive therapyCareful monitoring of PRS patients is a mustbecause of high rates of fluid and electrolyte imbalance,cardiovascular disorders, neurological and hematologicalabnormalities, bone marrow suppression, in addition toopportunistic infection [3,60].

Pneumocystis jiroveci pneumonia still carries amortality of up to 35%. Therefore, prophylacticcotrimoxazole therapy to prevent Pneumocystisjiroveci pneumonia supplemented by folic acid1mg/day has been shown to be cost effectivein patients with WG; also, it is recommendedin patients receiving methotrexate for remissioninduction or maintenance [44]. Prophylactic anti-fungal therapy is suggested for patients receivingimmunosuppressive drugs during the induction–remission phase. Finally, osteoporosis prophylaxiswith calcium and vitamin D supplements andpossibly bisphosphonates is advised for every patienttreated with glucocorticoids.

Small endotracheal or tracheostomy tubes may berequired in patients with WG with thecomplication of subglottic stenosis resulting indifficult intubation [1,4]. In the management ofARDS, a lung-protective ventilation strategy withsmall tidal volumes of 6ml/kg and inspiratoryplateau pressures lower than 30 cmH2O withpermissive hypercapnia may decrease lung injury[1,4]. Inotropic supports are required in hypotensivePRS patients, which may result from dehydration,hemorrhage, and systemic inflammation [4].

The majority of patients develop severe acute renalfailure and require hemodialysis in ICU. Irrespectiveof meticulous treatment, nearly 66% of cases withPRS-related small-vessel vasculitis will require renaltransplantation within a maximum of 4 years ofattendance [3,60].

Goodpasture’s syndromeOnce a diagnosis of Goodpasture’s syndrome issuspected, immunosuppressant drugs coupled withurgent daily PE must be immediately initiated.There are data showing that an earlier andaggressive PE decreases plasma anti-GBMantibodies, which may result in a higher likelihoodof long-term renal restoration [4,15,46]. Nearly 14days of complete courses of plasmapheresis arerequired for the anti-GBM to revert to normaltiter [3,46]. If tests for anti-GBM antibodies arefound to be negative, plasmapheresis is thendiscontinued [46].

Systemic lupus erythematosusDAH secondary to SLE has a poor prognosis, andlupus nephritis requires prompt immunosuppressivetherapy with high-dose methylprednisolone andcyclophosphamide to prevent end-stage renaldamage [3,15]. To avoid the severe side effects ofSLE treatment, that is, bone marrow depression,opportunistic infections, hemorrhagic cystitis, mali-gnant transformations, and premature gonadalfailure, current biological therapies such as rituximaband MMF are still being researched. Both drugs resultin efficient disease remission in 80% of patients withlow toxicity, but with a high relapse rate [3,4,61,62].New studies have reported that the addition ofrituximab to SLE therapies failed to show asignificant advantage, although this may be becauseof poor trial designs [3,4,15].

Acute catastrophic antiphospholipid syndromeAnticoagulation is the cornerstone of treatment PRSrelated to acute catastrophic antiphospholipid syndrome[3,63].

Thrombotic thrombocytopenic purpuraIn cases of PRS and thrombotic thrombocytopenicpurpura, mortality exceeded 90% before the use ofPE. Currently, 80% of cases show a good responseto treatment with PE. While awaiting PE treatment,plasma transfusions are recommended to make up forthe inadequate von Willebrand factor cleavage protein[3,64].

Diagnostic barriers

(1)

Many pulmonologists do not have extensivetraining or experience in examining the extra-thoracic manifestations of systemic autoimmunediseases, especially in the absence of classic clinicalpresentations such as the skin exam, joint exam, orneurological exam. In addition, there is noconsensus on proper screening laboratory tests.

(2)

The majority of the current trials on biologicaltherapies are preliminary and more researches andinvestigations are required in the future to ensureavoidance of side effects of systemic steroids as wellas to obtain accurate conclusions.

Conclusion

(1)

PRS is an urgent clinical situation whichnecessitates a high index of suggestion.

(2)

A systematic approach focused on earlyrecognition, confirmation of diagnosis, and

12 Egyptian Journal of Bronchology, Vol. 12 No. 1, January-March 2018

aggressive treatment likely decreases the morbidityand mortality associated with untreated orunrecognized PRS.

(3)

The risks of a PRS and vasculitis have to be kept inmind, particularly in those presenting withbilateral pulmonary infiltration, with one ormore of the following: decreased hemoglobinlevels, renal failure requiring dialysis, orsymptoms and signs suggestive of vasculitis.

(4)

Pneumonia like pictures may be the presentingfeatures, or may be the precipitating factors ofPRS. Management of all patients should includeempirical broad-spectrum antimicrobial drugsuntil advanced workup is completed.

(5)

Pulse dose steroids and cyclophosphamide is lifethreatening drugs for renal and pulmonaryinvolvement.

(6)

Early use of PE, followed by intravenous Ig is lifethreatening and represents treatment for resistantcases.

(7)

PE has been useful in situations with aconcomitant need for anticoagulation.

(8)

Renal transplantation is the only alternative inend-stage renal disease.

(9)

Newer immunomodulatory agents such as thosecausing tumor necrosis factor blockade, B-celldepletion, and MMF could be used in patientswith refractory disease.

Financial support and sponsorshipNil.

Conflicts of interestThere are no conflicts of interest.

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http://www.brit-thoracic.org.ukhttp://www.brit-thoracic.org.uk

14 Original article

Magnetic resonance spectroscopy in evaluating cerebralmetabolite imbalance in chronic obstructive pulmonary diseaseOlfat M. El-Shinnawya, Eman M. Khedrb, Mohamed M. Metwallya,Alaa EL-din Thabiet Hassana, Ahmad M. Shaddada, Radwa Kamel Solimanc

Rationale Magnetic resonance spectroscopy (MRS) is apowerful research tool and has been proved to provideadditional clinically relevant information for several diseasessuch as brain tumors, metabolic disorders, and systemicdiseases.

Aim The aims of this study were to evaluate cerebralmetabolic imbalance in chronic obstructive pulmonarydisease (COPD) and to correlate the abnormalities withspirometric and gasometric parameters.

Patients and methods In a case–control study, eight COPDpatients and eight age-matched and sex-matched healthycontrol individuals were compared. 1H-MRS was performedusing 1.5-T MRI/MRS scanner. Using 1H-MRS single-voxeltechnique, N-acetyl aspartate/choline (NAA/Cho), choline/creatine (Cho/Cr), and N-acetyl aspartate/creatine (NAA/Cr)ratios were estimated and compared in both groups.

Results There were significant differences regarding thedistribution of neurotransmitters in the temporal lobe onlybetween COPD and control groups; there were significantpositive correlations between the NAA/Cho ratio at thethalamus with both partial pressure of arterial carbon dioxideand base excess or base deficit. However, there was asignificant positive correlation between the Cho/Cr ratio at thethalamus and forced vital capacity (l), and a significant positive

© 2018 Egyptian Journal of Bronchology | Published by Wolters Kluwer - Medknow

correlation between theNAA/Cr ratio at the thalamus and BMI,and a negative correlation between the NAA/Cr ratio at thethalamus and partial pressure of arterial oxygen. There was asignificant negative correlation between theNAA/Cr ratio at thetemporal lobe and partial pressure of arterial carbon dioxide.

Conclusion MRS provided an insight to study theneurochemical changes that occur in COPD patients. Chronichypoxemia and hypercapnia seem to play a key role in thepathophysiology of neurochemical changes in COPD.Egypt J Bronchol 2018 12:14–19© 2018 Egyptian Journal of Bronchology

Egyptian Journal of Bronchology 2018 12:14–19

Keywords: cerebral bioenergetics in chronic obstructive pulmonary disease,cerebral metabolite imbalance in chronic obstructive pulmonary disease,magnetic resonance spectroscopy in chronic obstructive pulmonary disease

aChest Diseases and Tuberculosis, bNeurology and Psychiatry and,,cDiagnostic Radiology Departments, Faculty of Medicine, Assuit University,

Assuit, Egypt

Correspondence to Ahmad M. Shaddad, MSc, Department of Chest

Diseases and Tuberculosis, Faculty of Medicine, Assuit University, Assuit,

71515, Egypt. Tel: +20 111 117 1930;

e-mail: shaddad_ahmad@yahoo.com

Received 22 March 2017 Accepted 24 May 2017

This is an open access article distributed under the terms of the Creative

Commons Attribution-NonCommercial-ShareAlike 3.0 License, which

allows others to remix, tweak, and build upon the work

noncommercially, as long as the author is credited and the new

creations are licensed under the identical terms.

IntroductionMagnetic resonance spectroscopy (MRS) is a modalitythat is available on most state-of-the-art clinicalmagnetic resonance (MR) scanners. For the brain inparticular; MRS has been a powerful research tool andhas also been proven to provide additional clinicallyrelevant information for several diseases such as braintumors; metabolic disorders; and systemic diseases.the most widely available MRS method; proton(1H; hydrogen) spectroscopy; is an FDA-approvedprocedure that can be ordered by clinicians for theirpatients if indicated. other methods such asphosphorous-31; carbon-13; or fluorine-19 MRS havebeen successfully applied to humans. however; with theever-increasing importance of clinicalMRI; these exoticand time-consuming applications have been pushed tothe side and are only available at a few academic centers.in addition; 1H MRS does not require any additionalhardwarebeyondwhat is already beingused forMRI [1].

Single-voxel MRS measures the MR signal of a singleselected region of interest, whereas signal outside this areais suppressed. For single-voxel MRS, the magnetic fieldandotherparametersareoptimizedtoget thebestpossiblespectrum from a relatively small region of the brain [2].

Each metabolite appears at a specific frequency(ppm), and each reflects specific cellular andbiochemical processes. N-acetyl aspartate (NAA) isa neuronal marker and decreases with any disease thatadversely affects neuronal integrity. Creatineprovides a measure of energy stores. Choline isa measure of increased cellular turnover and iselevated in tumors and inflammatory processes.The observable MR metabolites provide powerfulinformation, but unfortunately many notablemetabolites are not represented in brain MRspectra [3].

In the present study, we aimed to demonstrate thedifference in the cerebral metabolic profile of chronicobstructive pulmonary disease (COPD) patientsin comparison with age-matched and sex-matchedhealthy controls.

DOI: 10.4103/ejb.ejb_28_17

mailto:shaddad_ahmad@yahoo.com

MRS in COPD El-Shinnawy et al. 15

Patients and methodsEthical considerationThe present study was approved by the InstitutionalEthics Committee of Assiut University. In addition,written informed consentwas obtained from all patients.

PatientsThis study was conducted in Assiut University Hospitalat theChestDiseases andTuberculosisDepartment andthe Neurology and Psychiatry Department during theperiod between May 2013 and October 2015. Weenrolled eight stable COPD patients and eight adultage-matched and sex-matched healthy controls.

Inclusion and exclusion criteriaStable COPD patients aged 45–75 years who wereadmitted to the Chest Diseases and TuberculosisDepartment in Assiut University Hospital andCOPD patients who attended outpatient clinics aswell as healthy voluntaries of the same age, area ofresidence, smoking habits, and educational level wereeligible to participate in the present study.

Exclusion criteriaCOPDpatientswith anyof the following comorbidities:

(1)

Left-sided heart failure, renal insufficiency, or liverimpairment.

(2)

COPD patients with exacerbation.

(3)

Electrolyte disturbance or diabetic patients.

(4)

Chronic use of systemic steroids or any other drug

affecting the results.

(5)

Severedecompensated respiratory failure interfering

with the study protocol.

(6)

Previous cerebral stroke or any neuropsychiatric

condition.

All patients were subjected to careful history taking.Height, body weight, and BMI were recorded, and fullchest and neurological examinations were performed.All routine investigations related to exclusion criteriawere performed.

All patients eligible to participate were subjected to thefollowing:

(1)

Spirometric evaluation: conventional spirometryusing Zan 300 (Company nSpire HealthTM,Sensor Medics MGA USB, Oberthulba,Germany) was performed for COPD and controlgroups. The reference values used were those ofthe American Thoracic Society standards. Thefollowing parameters were observed and recorded

for the study − forced expiratory volume in the firstsecond percentage predicted and volume in liters,forced expiratory volume in the first second/forcedvital capacity (FVC) ratio, and FVC percentagepredicted and volume in liters.

(2)

Gasometric evaluation: arterial blood gases sampleswere analyzed by Radiometer blood gas analyzer(Radiometer Medical ApS Company, Åkandevej,Demark). Arterial blood acidity (pH), partialpressure of arterial oxygen, partial pressure ofarterial carbon dioxide (PaCO2), arterial oxygensaturation (SaO2), arterial bicarbonate level(HCO3

−), and base excess or deficit were recorded.

(3)

MRS: 1H-MRSwas carriedoutusinga1.5-TMRI/

MRSscanner (Siemens,Erlangen,Germany).Afterscout images in three orthogonal planes, multisliceT2-weighted axial images of the whole brain wereacquired. The single-voxel technique was used fortwoareas−namely, theparietotemporal lobe and thethalamus. The metabolic ratios N-acetyl aspartate/creatine (NAA/Cr), N-acetyl aspartate/choline(NAA/Cho), and choline/creatine (Cho/Cr) werecalculated by integrating area under each peak.

Statistical analysisSamplingSampling was performed using nonprobabilityconvenient sampling technique. Patients were selectedfrom those consecutively attending the Chest Diseasesand Tuberculosis Department and those attending theoutpatient clinic.

Sample sizeThe estimated sample size was eight COPD patientsand eight controls because of financial issues.

Data were recorded and analyzed using statisticalpackage for social science software computerprogram version 20 (SPSS; SPSS Inc., Chicago,Illinois, USA), Medcalc v.11.6 (MedCalc SoftwareCompany, Ostend, Belgium), and Open Epi V.3.01(Open Source Programe, Atlanta, USA). Quantitativedata are described using mean±SD, and qualitative dataare described using frequencies. Nonparametric testswere used in the present study as follows:

(1)

The Mann–Whitney U-test was used to compareresults between the COPD group and the controlgroup.

(2)

Spearman’s correlation coefficient was used todetermine the correlation between cognitivedysfunction and spirometric and gasometricparameters of COPD patients.

(3)

P-value below 0.05 was accepted as significant.

16 Egyptian Journal of Bronchology, Vol. 12 No. 1, January-March 2018

ResultsWe enrolled eight stable COPD patients andcompared them with eight age-matched and sex-matched healthy controls. Distribution of age andsex in both groups were as follows: 60.62±6.75 yearsand six males in the COPD group and 56.12±7.35years and seven males in the control group. Detaileddemographic data of both groups are represented inTable 1.

Spirometric and gasometric evaluation showed thatthere was a significant difference between the COPDgroup and the control group in all parameters exceptblood acidity. Detailed spirometric and gasometricevaluation are represented in Table 2.

MRI spectroscopy measurements in the COPD groupand the control group showed that there was nosignificant difference in the distribution ofneurotransmitters in the thalamus, but there was asignificant difference regarding the distribution ofneurotransmitters in the temporal lobe. Table 3shows the detailed results of the MRS.

There were significant negative correlations betweenNAA/Cho at the thalamus and both PaCO2 and baseexcess or base deficit, whereas there was a significantpositive correlation between Cho/Cr at the thalamusand FVC (l). Moreover, there was a significant positivecorrelation between NAA/Cr at the thalamus andBMI, and a negative correlation between NAA/Crat the thalamus and SaO2 as shown in Table 4.

Table 1 Demographic data of chronic obstructive pulmonary disea

COPD group (N=8) [N (%)]

Sex

Male 6 (75.0)

Female 2 (25.0)

Age (years)

Mean±SD 60.62±6.75

Smoking

Smoker 2 (25.0)

Ex-smoker 6 (75.0)

Residence

Urban 2 (25.0)

Rural 6 (75.0)

Dominant hand

Right handed 7 (88.0)

Left handed 1 (12.0)

Education

Literate 2 (25.0)

Illiterate 6 (75.0)

Duration of illness (years)

Mean

Range

COPD, chronic obstructive pulmonary disease.

The level of neurotransmitters in the temporal lobe andspirometric and gasometric parameters showed thatthere was a significant negative correlation betweenNAA/Cr and PaCO2 as shown in Fig. 1.

DiscussionThe study of specific patterns of cerebral metabolites inCOPD is still novel, andmost of the few studies carriedout thus far have shown three landmarks of cerebralmetabolite imbalance in COPD.

Elevation of cholineThe most pronounced neurochemical changes inCOPD is the elevation of choline [4,5]. We proposethat frequent oxygen desaturation during everydayactivity of COPD patients may be a key mechanismunderlying the damage of brain tissue reflected inelevated brain choline. Similar choline elevationsobserved in systemic diseases were associated withbrain tissue breakdown and cognitive impairment[6,7] and appeared to reflect damage to myelin andincreased turnover of neuronal membrane precursors[8]. These results are consistent with the finding of ourresults in the pariototemboral lobe.

Decrease in N-acetyl aspartateThe second landmark in neurochemical changes inCOPD was a decrease in NAA. Neuronal cell deathis generally considered an irreversible processaccompanying aging, and decreased levels of NAAare reported frequently in healthy aged persons.

se patients and controls undergoing spectroscopy

Control group (N=8) [N (%)] P-value

7 (87.5) 0.32

1 (12.5)

56.12±7.35 0.61

3 (37.5) 0.51

5 (62.5)

3 (37.5) 0.93

5 (62.5)

6 (75.0) 0.87

2 (25.0)

3 (37.5) 0.92

5 (62.5)

16±6.6

7–26

Table 3 Magnetic resonance spectroscopy measurements in chronic obstructive pulmonary disease and control groups at thethalamus and the parietotemporal area

COPD group (n=8) (mean±SD) Control group (n=8) (mean±SD) P-value

NAA/Cho at thalamus 0.41±0.14 0.38±0.11 0.562

Cho/Cr at thalamus 0.75±0.22 0.76±0.19 0.916

NAA/Cr at thalamus 1.57±0.38 2.09±0.66 0.059

NAA/Cho at parietotemporal area 0.64±0.32 1.72±0.41 0.001*

Cho/Cr at parietotemporal area 0.71±0.24 1.22±0.38 0.002*

NAA/Cr at parietotemporal area 2.31±0.45 1.65±0.39 0.009*

Cho/Cr, choline/creatine ratio; COPD, chronic obstructive pulmonary disease; NAA/Cho, N-acetyl aspartate/choline ratio; NAA/Cr, N-acetylaspartate/creatine ratio. *Significant difference.

Table 2 Gasometric and spirometric data of chronic obstructive pulmonary disease and control groups undergoingspectroscopy

COPD group (n=8) (mean±SD) Control group (n=8) (mean±SD) P-value

FEV1 (l) 1.4±0.84 2.93±0.92

Figure 1

Shows there was a significant negative correlation between N-acetylaspartate/creatine, at parietotemporal lobe, and partial pressure ofarterial carbon dioxide

18 Egyptian Journal of Bronchology, Vol. 12 No. 1, January-March 2018

Increase in cerebral neurochemical markers ofoxidative stress and anaerobic respirationThe third landmark was the unique study performed byMathur et al. [9], which correlates chronic hypoxemiato the increase in cerebral neurochemical markers ofoxidative stress and anerobic respiration − namely,inorganic phosphate and phosphomonoesters −evaluated using the 31P-MRS technique. In ourstudy, we did not use the 31P-MRS technique.

In agreement with our results, a study by Shim et al. [10]evaluated the clinical significance of cerebral metabolicabnormalities in COPD patients usingMRS, including17 symptomatic COPD patients and 21 age-matchedhealthy volunteers. NAA, Cr, and Cho levels in theparietal white matter were all significantly lower inCOPD patients than in control subjects (P

MRS in COPD El-Shinnawy et al. 19

(CPAP). Before CPAP treatment, cortical NAA inOSAS was significantly lower than in controls andpositively correlated with minimum SaO2 during sleep.Cortical NAA reduction persisted after CPAP therapy.

In conclusion, MRS provides insight into theneurochemical changes that occur in COPD patients.Chronic hypoxemia and hypercapnia seem to play a keyrole in the pathophysiology of neurochemical changes inCOPD. A limitation of the present study was thatMRI spectroscopy was only applied to small numberof patients and controls because of financial issues. Werecommend future studies to combine functional MRIand perfusion MRI together with MRI spectroscopy toobtain a greater understanding of the cerebral metabolicchanges in COPD.

Financial support and sponsorshipNil.

Conflicts of interestThere are no conflicts of interest.

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