pulmonary alveolar proteinosis and tuberculosis in a ...is a symmetrical, bilateral, alveolar...

188 BJID 2002; 6 (August)

Pulmonary Alveolar Proteinosis and Tuberculosis in a Diabetic Patient: A Rare ora Seldom Diagnosed Association?

Pereira-Silva J.L., Marinho M.M.M.A., Pulmonary Service, Professor Jorge ValenteVeloso T.V.B. and Coelho Filho J.C. Hospital, Salvador; Pathology Service, José

Silveira Foundation, Salvador, BA, Brazil

A case of Pulmonary Alveolar Proteinosis (PAP), in association with tuberculosis, is describedin a 35-year-old diabetic patient. Lung biopsy showed an intra-alveolar accumulation of PAS-positive material, and multifocal granulomas compatible with tuberculosis. The bronchoalveolarculture was positive for Mycobacterium tuberculosis. PAP results from an imbalance of themechanisms that regulate the homeostasis of the surfactant, where specific proteins are involved,especially SP-A and SP-D, the cytokines, IL-10 and GM-CSF, in addition to alveolar macrophagesand type-II pneumocytes. Chemotaxis and phagocytic capacity are reduced. PAP and diabetesshare several immunological disfunctions that may increase the risk for tuberculosis. Althoughthere are no controlled studies, the diagnosis of PAP in diabetic patients with tuberculosis mustbe considered.Key Words: Pulmonary Alveolar Proteinosis (PAP), tuberculosis, diabetic patient.

Received on 17 March 2002; revised 28 June 2002.Address for correspondence: Dr. Jorge L. Pereira-Silva. RuaConselheiro Corrêa de Menezes, 91 – Candeal. Salvador, Bahia,Brazil. Zip code: 40.295-030. Phone/Fax: (55 71) 334-7547. E-mail: [email protected] .

The Brazilian Journal of Infectious Diseases 2002;6(4):188-195© 2002 by The Brazilian Journal of Infectious Diseases andContexto Publishing. All rights reserved.1413-8670

Pulmonary Alveolar Proteinosis (PAP) was firstreported by Rosen, et al. [1] in 1958, in an attempt tocharacterize an abnormal accumulation of PAS-positive(periodic acid-Schiff) phospholipoprotein material in thealveoli. Two forms are described: primary or idiopathic,which occurs in the absence of another illness or a knownenvironmental exposure; and secondary, when associatedwith another morbid condition, especially infectious orneoplastic, in various states of immunosuppression [2],as well as in those resulting from the inhalation of chemicalagents and mineral particles (silica, aluminum, titanium, andsome insecticides) [3]. Several etiological agents have beenidentified in this population: Aspergillus sp. [4], Nocardiasp. [5-7], Mycobacterium sp. [8-13], Cryptococcusneoformans [14], Histoplasma capsulatum [15],

Pneumocystis carinii [16], and virus [17]. Rarely, casesof PAP may be associated with Mycobacteriumtuberculosis [10,13]. Witty, et al. [18] noted a highincidence (42%) of Mycobacterium avium-intracellularein systematic cultures of therapeutic lung lavage materialfrom PAP patients. Several recent studies [19-32] haverelated PAP’s pathogenesis and opportunistic infectionsto an imbalance of the mechanisms that regulate thehomeostasis of the surfactant, where specific proteins areinvolved, especially SP-A and SP-D, cytokines, especiallyIL-10 and GM-CSF, in addition to alveolar macrophagesand type-II pneumocytes.

The risk for tuberculosis in diabetic patients is greaterthan in the general population. Mycobacteria have beenisolated from BAL of PAP carriers. It is possible thatthe association between these clinical entities is morethan coincidental. PAP is usually a pathological diagnosisand diabetic patients with tuberculosis do not routinelyundergo biopsies.

Case Report

Thirty five-year-old African-Brazilian female nurseaid, an insulin-dependent diabetic, was admitted with

BJID 2002; 6 (August) 189

a history of persistent dry cough for 30 days, togetherwith left sided pleuritic chest pain, mild dyspnea andfever. In addition, she complained of weakness,anorexia and unmeasured weight loss. She had beenusing NPH insulin (24 UI in the morning and 8 UI atnight) for the previous 9 years. At the time of admission,she was in a fair general state, thin and slightly pale.BP: 130x80 mm Hg; HR: 120bpm; RR: 24bpm; T.:38.5°C. Crackles were present in the lower third ofthe left hemithorax.

Lab tests and image diagnosis exams:• WBC count: 12,200/mm3 (segs 68%, bands

8%, eos 1%, baso 1%, lymphs 21%,monocytes 2%).

• RBC count: 3.67 million/mm3. Hematocrit29.4%. Hemoglobin 10g%. Platelets545,000/mm3.

• Glucose: 223 mg/dL• Urea: 22mg/dL. Creatinine: 0.8mg/dL• Na: 136mEq/L; K: 4,7mEq/L; Ca: 9.7mg/

dL; Mg: 1.6mg/dL.• AFB’s (3 negative samples)• PPD: 15mm• AST: 44 UI/L. ALT: 13 UI/L• Total bilirubin: 0.4 (direct: 0.1)• Prothrombin time: 68% (13.3" INR: 1.24).

APTT: 32".• ABG’s (FI02=0,21): pH: 7.4;

PaO2:76.5mmHg; PaCO2: 40.4mmHg;HCO3: 25.1mEq/L; SatO2: 95.3%.

• Serology for HIV: negative.• Chest X-rays: non-homogeneous areas of

alveolar consolidation on the left lower lobe(Figure 1).

• High-resolution computed tomography(Figure 2): confluent alveolar nodules, areasof multifocal consolidation and a tree-in-bud pattern.

Evolution. Fiberoptic bronchoscopy withbronchoalveolar lavage (BAL) and trans-bronchialbiopsies (TBB) was performed on the left lower lobe.Direct exams for bacteria, fungi and AFB in the BALwere negative. The TBB showed non-specific

inflammatory changes. A left sided pneumothoraxdeveloped as a complication of bronchoscopy,requiring close chest tube drainage. AFB wasrecovered from the pleural fluid and the fourth sputumsample. Thoracoscopy was performed due to a lackof lung expansion and a persistent air leak. An openbiopsy was then obtained as well as a new sputumexam. AFB was again recovered from the pleuralsurface and from the sputum (5th sample). Isoniazid,rifampicin and pyrazinamide were instituted. Ahistopathological exam (Figure 3.) revealed lung tissuewith altered structure, multiple granulomatous reactionfoci and central caseous necrosis, epithelioid histiocytesand giant multinucleus cells, in addition to somelymphocytes. The direct exam for fungus was negative.The AFB smear was positive. In the remaining lungtissue, alveoli were filled with acidophilus material andmacrophages. This intra-alveolar substance stainedpositively with PAS (Figure 4.). The BAL culture showedMycobacterium tuberculosis. These findings supportedthe diagnosis of pulmonary tuberculosis and PAP (Figures4 and 5). She was discharged from the hospital, with arecommendation for ambulatory follow-up.

Discussion

The incidence of PAP in the general population is 1in 2 million people [26] with a 3 to 1 male-to-femalepredominance. Almost 80% of the patients are between20 and 50 years old, although it has also been describedin newborns [33,34], school age children [35,36], andin the elderly [37]. The main symptom is exertiondyspnea. Many patients present with dry cough or withopalescent and viscous sputum. Asthenia and weightloss may be present. Fever is more common in thesecondary form. Chest pain and hemoptysis are notfrequent in the primary form. The physical examinationis nonspecific, with predomination of crackles in theaffected areas [3,26]. The most common X-ray patternis a symmetrical, bilateral, alveolar infiltrate,predominantly in the lower lobes. In some cases, theinfiltrate is focal and asymmetric. There is usually nopleural effusion, mediastinal or pulmonary

Pulmonary Alveolar Proteinosis and Tuberculosis


Figure 1. Chest X-ray: non-homogeneous areas of alveolar consolidation on the left lower lobe

Figure 2. High-resolution computed tomography: confluent alveolar nodules, areas of multifocal consolidationand a tree-in-bud pattern



Figure 3. Histopathological exam (H.E.): lung tissue with an altered structure, with multiple granulomatous reactionfoci and central caseous necrosis, epithelioid histiocytes and giant multinucleus cells, in addition to some lymphocytes.In the remaining lung tissue, the alveoli were filled with acidophilus material and macrophages

Figure 4. Periodic acid-Schiff stain (PAS): the intra-alveolar substance stained positively with PAS



adenopathies. The high-resolution computedtomography usually shows coalescent alveolar nodules,sometimes evolving into areas of multifocalconsolidation, resulting from a complete filling of alveolarspaces and zones of increasing attenuation with theground-glass pattern, which results from partial fillingof alveolar structures with the proteinaceous material.At times, ground-glass areas are delimited by zonesof normal parenchyma that characterize the geographicdistribution. The presence of intra-alveolar and inter-lobular septa inside the ground-glass zonescharacterizes the crazy paving pattern that, althoughvery common in PAP, is not specific, and may beobserved in Pneumocystis carinii pneumonia and incytomegalovirus infections [38].

An elevated LDH is sometimes seen [3]. Thepredominant functional abnormality is a restrictiveventilatory disturbance, with a reduction of lung volumesand diffusion capacity [39]. Hypoxemia and an increaseof D(A-a)02, aggravated by exercise, are proportionalto the level of lung involvement. These alterations resultfrom a right-to-left shunt, where lung capillaries perfusepoorly ventilated alveolar units, filled with the lipoproteinmaterial [39]. Pulmonary function tests are useful toevaluate the illness’ severity, its progress and itsresponse to therapy. Fiberoptic bronchoscopy is aroutine procedure, due to its capacity for ruling outother etiologies and because it can demonstrate thecharacteristic granular, amorphous, PAS-positivelipoprotein material in the bronchoalveolar fluid [3].Although the histopathological exam of the lung tissue,obtained through thoracotomy or transbronchial biopsy,is the gold-standard, PAP diagnosis can be consistentlybased on clinical-radiological findings plusbronchoalveolar lavage, as long as other diagnoses canbe excluded [3]. The most effective treatment is awhole-lung lavage, although in up to 25% of the casesthere will be spontaneous resolution [40]. Thisprocedure is reserved for those whose daily activitiesare limited due to dyspnea, especially if Pa02<70mmHgor D(A-a)02>40mmHg, causing greater discomfort andsignificant probability of disease progress [41].

PAP pathogenesis seems to be associated with anexcessive secretion of surfactant and alteration of its

quality. Besides reducing the surface tension of the alveoli,the surfactant, composed of 90% lipids and 10%proteins, plays an important role in the immunologicalmechanisms of lung natural defense and possibly othermucous surfaces [22]. The homeostasis of the surfactantis a result of a complex, dynamic process, involvingalveolar macrophages and type-II pneumocytes, withactive participation in collection, degradation andrecycling. The lipoprotein material that results from lunglavage in PAP patients is made up of a phospholipidfraction – of which lecithin is the main component –plasmatic proteins and proteins specific to the surfactant.The hydrophobic proteins (SP-B and SP-C) andhydrophilic proteins (SP-A and SP-D), components ofthe surfactant, are synthesized and secreted mainly bythe type-II pneumocytes [22,26]. A recent analysisrelates SP-B deficiency to PAP’s pathogenesis, whichresults from mutations of the SP-B gene. The mutation121ins2 is present in almost 2/3 of individuals with thisdeficiency [42]. SP-A and SP-D play an important rolein the organism’s defense mechanism. They bind to thecellular wall lipopolysaccharides of various pathogens,modulating the phagocytic activity of the macrophages[23,27]. In addition, the lipoprotein material has thecapacity of neutralizing the oxidizing stress resulting fromthe phagocytic process of the macrophages. As wasdemonstrated, the incubation of Mycobacteriumtuberculosis with SP-D results in bacillus agglutination.On the other hand, SP-D binds itself minimally on non-virulent Mycobacterium smegmatis [19]. In the firststage of infection by Mycobacterium tuberculosis, thebacilli that reach the alveoli are phagocytized bymacrophages through the immunomodulation of the SP-A and SP-D [20,21]. In PAP, chemotaxis and thephagocytic capacity of the macrophages are affected.This defect seems to be acquired, because afterincubation with fluid obtained from lung lavage of PAPpatients normal macrophages present a diminishedphagocytic capacity [26]. Besides, therapeutic lunglavage usually reestablishes the macrophagic functionand decreases the incidence of opportunisticinfections [25]. On the other hand, in some cases,treatment for tuberculosis may cause the PAP topartially or totally subside [24].



In diabetic individuals, especially when poorlycontrolled, the functional damage to thepolymorphonuclear neutrophils (adherence,chemotaxis and bactericidal activity), together witha dysfunction of the monocytic-macrophagic systemand of cellular immunity, determine a greater risk ofinfections [43]. In these individuals the risk fortuberculosis is 2.0 to 3.6 times greater than in thegeneral population [43]. However, there are nocontrolled studies that show a higher tendency ofopportunistic infections in diabetic patients with PAP.A recent study [28], in which the concentration ofthe surfactant apoprotein (SP-A) was measured inthe amniotic liquid of pregnant diabetics (n=29) andnon-diabetic pregnant women (n=358), revealedthat its level is directly proportional to the time ofpregnancy (less than 3 mg/mL between the 30th andthe 31st week, and 24 mg/mL between the 40th andthe 41st week). In pregnant diabetic women, thisconcentration is reduced.

It has been shown that laboratory rats withdeficiency of the gene that codifies the GM-CSFproduce an abnormal accumulation of surfactant,similar to that seen in humans with PAP [29].Experimental models, designed primarily for the studyof hematopoiesis in rats, suggest that mutations of thegene that codifies GM-CSF [42] or of the beta subunitof its receptor (I13rb1) [44] may stimulate metabolicalterations in the surfactant, which are responsible forPAP [31,42]. There is incipient evidence that seems todemonstrate that daily replacement of GM-CSF (3-9µg/kg/day) during 12 weeks, in PAP patients,stimulates clinical, radiological and functionalimprovement, without repercussions in the WBC count[45]. In this study, the therapeutic response occurredbetween the 8th and the 12th week [45].

Kitamura, et al. [46] developed an agglutination teston latex for serological diagnosis of primary PAP, with100% sensitivity and 98% specificity, based on theidentification of antibodies against GM-CSF in the BALfluid of individuals with PAP.

These observations regarding PAP pathogenesisopen new horizons for diagnosis and future therapeuticresources. The systemic immunological disturbances

that take place in diabetic patients, along with focallung alterations that turn PAP carriers more vulnerableto respiratory infections – among them tuberculosis –point towards a possible association.

Conclusion

Pulmonary Alveolar Proteinosis results from anabnormal accumulation of a phospholipoproteinsubstance in the alveoli. It is called primary oridiopathic when no other morbid condition or knownenvironmental exposure is present. In its secondaryform, it is associated with respiratory infections byvarious etiologic agents, myeloproliferative illnesses,various states of immunosuppression, orenvironmental exposure to chemical agents orinorganic particles. Rarely, it may be associated withtuberculosis. The predominant functional alterationis restrictive ventilatory disturbance, with a reductionof lung volumes and diffusion capacity. Hypoxemiaand an increase of D(A-a)02, aggravated by exercise,result from perfusion of poorly ventilated areas.Although the histopathological exam is the gold-standard, the diagnosis can be based on suggestivefindings from high-resolution computed tomography,and on characteristic aspects of the bronchoalveolarlavage. Whole-lung lavage in selected cases is themost effective treatment. New concepts regardingits pathogenesis, where a disturbance is describedin the surfactant’s homeostasis, involving proteins(SP-A and SP-D), cellular elements (alveolarmacrophages and type-II pneumocytes) and animbalance of the activity of cytokines (IL-10 andGM-CSF), may offer new opportunities for thediagnosis and treatment of Pulmonary AlveolarProteinosis.

The role of diabetes, causing a greater susceptibilityto tuberculosis in PAP patients, is not well known.However, considering the various immunologicaldisturbances that are common to these entities, thepossibility of a diagnosis of PAP in diabetic patientssuffering from pulmonary tuberculosis must beconsidered.



Acknowledgement

We are indebted to Octavio H. C. Messeder, M.D.for reviewing this manuscript.

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