Syndrome resembling tropical pulmonary eosinophilia but of non-filarial aetiology: serological findings with filarial antigens

573

TRANSACWINS OFTBE ROYALSOCIETY OFTROPICALMEDICWEANI) HYGIENE (1995) 89,573-575

Syndrome resembling tropical pulmonary eosinophilia aetiology: serological findings with filarial antigens

but of non-filarial

Abraham Roehal, Gerusa Dreyer l, Robert W. Poindexteg and Eric A. Ottesen2 ‘Cmtro de PesquisusAggeu MagalhaesiFIOCRiJZ, Caixa Postal 7472, Recife, PE, Brazil 50670-420; 2Laborutory of Parasitic Diseases,National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA Abstract Although the tropical pulmonary eosinophilia (TPE) syndrome of fiarial aetiology has very distinctive chnical and immunological features. its clinical urofile is not uniaue: other h&ninths sometimes induce similar presentations. Wevcarefully e&luated 7 individuals with non-f-&trial TPE-like syndromes and found that serological tests basedon detection of ‘antifilarial’ immunoglobulin (Ig) G, IgG4, and IgE antibodies that are usually considered diagnostic for f&trial TPE were equally elevated in patients with non-filarial, TPE-like syndromes and were therefore unhelpful diagnostically. The apparent reasons were immunological hyperresponsiveness of such individuals and the shared (i.e., cross-reactive) antigenicity found in the filarial antigen preparations used routinely for diagnosis. Because appropriate treatment for those different pulmonary eosinophilia conditions requires different drugs and management, and because delay in effective treatment results in significant morbidity in such patients, diagnostic capabilities must be improved by identifying and obtaining unique antigens that can serologically discriminate between filarial TPE and other similar, but non-filarial, pulmonary eosinophilia syndromes. tropicalpulmonaryeosinophilia,non-filarial pulmonaryeosinophilia,serology

Keywords:

Introduction In tropical countries, infections with helminths are the most common causes of pulmonary eosinophilia syndromes. Most of these PIE syndromes (pulmonary intiltrates with peripheral blood eosinophilia [CROFTON er al., 19521) are transient and self-limited, reflecting migration of larval parasites through the lung during the maturational phases of their life cycles as originally described by LBFFLER (1932). Somehehninth-induced PIE syndromes, however, are more persistent and require specific antiparasite treatment before they will resolve. The best described of these is tropical pulmonary eosinophilia (TPE), a syndrome of lilarial aetiology defined by (i) severe cough and wheezing, especially at night; (ii) frequent weight loss and fatigue but with minimal or no fever; (iii) restrictive and/or obstructive lung abnormalities; (iv) generally abnormal chest radiographs that frequently show diffuse, mottled pulmonary interstitial

cific antifilarial chemotherapy with diethylcarbamazine (DEC). Extensive studies of the pathogenesis of the TPE syndrome have defined the clinical hyper-responsiveness as reflecting an underlying immunological hyper-responsiveness to filarial parasites (OTTESEN & NUTMAN, 1992); however, for other (non-filarial) heIrninth-induced PIE syndromes, very little effort has gone into studying either the pathogenesis or even the specific aetiologies. It is clear from both earlier findings (e.g. BEAVER & DANARAJ, 1958) and recent clinical observations (UDWADIA, 1993) that infection with certain other (often undefined) helminths does lead to clinical presentations that are essentially indistinguishable from those of TPE except that they do not respond to DEC treatment. Although no study has attempted to use antifiarial antibody responses to distinguish such patients from those with TPE, because of the highly characteristic

Table 1. Clinical and laboratory features of study patients P;~ulc~o;,t Duration of Patient !%G s mptoms anti- mAC no. and (units/mL) diagnosisa (y%s) Sex abnormalitiesb Pmonths) 1 PIE 38 Male 23 145 :iE

:i%

;: 2

6 PIE

z

Male

i

78 PIE TPE 9 TPE

2:

Male Male

E 0

FEt

iii!:

*;P ok

9: : 1;

6 8

;: Tii

:: E

Total IgG4 anti-BmAC W (ng/mL) (ng/mL)d 431 500

10s 750

530 550 4 ii: 268 2:: 000

E 59 12 363 125

70 000

374 840

24 27 670 020 23 850

1 280 87 000 610 81 780

Stool parasites

NA 628 300 125 %Z 19 525 Schistosomamansoni

aPIE=pulmonary infiltrates with peripheral blood eosinophilia; TPE= tropical pulmonary eosinophilia. bO=obstructive; R=restrictive. All patients had wheezin an&or cou h. pmA=saline extract of adult Bnrgia malayi (see LAL & CBTTESEN, 19 P8). NA = not available. eStron&oides found by Baermann stool concentration technique, at the 21st examination with patient no. 1 and the 10th exammation with atient no. 3. fStrongyloides foun f only by duodenal fluid examination (9 stool examinations were negative). infiltrates; (v) peripheral blood eosinophilia >2500 cellsiyl; (vi) extreme elevation of immunoglobulin (Ig) E; (vii) extreme elevation of antifilarial antibodies; and (viii) dramatic clinical improvement in response to speAddressfar correspondence:AbrahamRocha,Centra de Pesquisas Aggeu Magalhaes/FrOCRuz,Caixa Postal 7472, Recife, PE, Brazil 50670-420; or Eric A. Octesen, Laboratory of Parasitic Diseases, National Institute of Aller and Infectious Diseases,Building 4, Room 126, NationalY nstitutes . of Health, Bethesda, MD 20892, USA.

serological profile of patients with frlarial-induced TPE syndrome (OTTESEN & NUTMAN, 1992) one might expect such serological assessment to be helpful in discriminating between filarial and non-tilarial PIE syndromes. The present report, however, describes 7 patients with TPE-like PIE syndromes that appear not to be tilarial in aetiology and for whom serological responsesto filarial antigen were diagnostically confusing, or at least not helpful, in distinguishing filarial TPE from non-filarial, TPE-like syndromes.

574 Materials and Methods Study population and clinical evaluation

Nine patients were evaluated, 8 males and 1 female, ranging in age from 24 to 62 years (Table 1). All had clinical presentations compatible with TPE syndrome including pulmonary symptoms of wheezing and nocturnal cough that had persisted for %12 months, abnormal pulmonary function tests (restrictive abnormalities defined as vital capacity <80% of predicted; obstructive abnormalities defined as forced expiratory volume in the first second <70% of forced expiratory vital capacity), and generally abnormal chest radiographs. Serum chemistry was evaluated in each individual, together with at leasr 6 absolute eosinophil counts (PILOT, 1950)during the 3 weeks before treatment. Eosinophil counts were also made twice weekly during treatment and for 4 weeks following treatment. Treatment consisted of 1-3 courses of DEC (12 mglkgidx30 d), thiabendazole (500 mg three times daily ~7 d), mebendazole (200 mg twice dailyx7 d), or ivermectin (200 pgikgld x 2 d) . Parasitological evaluation

Stool examinations were carried out before treatment at least 6 times over a period of 4 weeks for each individual, both by direct examination and after Baermann concentration. Duodenal aspiration was performed to look for Strongyloides in one patient whose stool remained parasite-free in 9 examinations. Nocturnal blood filtration (WELLERet al., 1982) to look for microfilariae was also carried out for each individual. Serological assays

Serum total IgE levels were measured by enzymelinked immunosorbent assa (ELBA) as described by ?uzantifilarial antibody levels NUTMANet al. (1989). Specs of complete IgG and of the IgG4 subclass were also measured by ELBAas described previously (LAL & OTTESEN,1988). The filarial antigen (BmA) used in these assayswas a saline extract of Srugia malayi adult worms (male and female), described elsewhere (LAL & OTTESEN,

over a period of 3 weeks) ranged from 7800 to 23 750 cells/yL (Table 2). Serological findings. Total serum IgE levels ranged between 8300 and 105 750 ng/mL in the 6 patients so studied (Table I). IgG and IgG4 antibody levels to filarial antigens were extremely elevated in all 9 patients (Table l), and the levels did not differ between those patients who ultimately responded to DEC treatment (i.e., filarial TPE; patients no. 8 and 9 in Table 1) and those who did not (PIE; patients no l-7 in Table 1). Post-treatment Chical changes. After a single course of DEC, 2 patients (nos. 8 and 9) responded rapidly, with resolutron of their pulmonary symptoms which became essentially normal by week 4 of therapy. With the remaining patients, however, there was either a very transient improvement in symptoms (3 patients) or none (4 patients). These patients were treated with one or more additional coursesof DEC (Table 2) but still failed to respond clinically. Only after administration of other anthelmintics (thiabendazole, mebendazole, or ivermectin) did these 7 patients show clinical improvement with resolution of their symptoms. Eosinaphil responses. Changesin blood eosinophil levels reflected quite accurately the clinical changes following treatment. Specifically, in those individuals whose clinical responses to DEC were good, the eosinophilia fell dramatically within 8 weeks of initiating treatment (Table 2). For those not responding to DEC, however, there was no such resolution of the peripheral eosinophilia. In those patients not responsive to DEC, the therapy with other anthelmintics that induced clinical remission also resulted in decreasedblood eosinophil levels within 2 months of successful treatment (Table 2). Serological respo?lses. Specific ‘antifilarial’ antibody levels (IgG and IgG4) fell in those patients whose sera were available for testing, but only following successful treatment (with either DEC or the other anthelmintics); they did not, however, return to completely norma levels during 4-12 months of follow-up (data nor shown).

1988). Discussion

Results Pre-treatment ClinicaE findings. All patients were clinically sympto-

matic, with abnormal pulmonary function tests and chest radiographs (Table 1). Serum chemistry evaluations were normal in all patients (data not shown), but stool examinations were variably positive for helminth parasites (Table 1). Intensive efforts were made to identify Srrongyiuides in the stool of these patients, and in one individual this parasite was found only after examination of 21 different stool specimens. The peripheral blood eosinophi1 counts were raised in all individuals. Pre-treatment eosinophil levels (the mean of 6 pre-treatment evaluations

Patients presenting with filaria-induced TPE syndrome have a very characteristic serological response that includes extremely high levels of specific antifilarial antibody of all isotypes and subclasses.Indeed, the very high levels of their responsesare distinctive enough for these patients to be easily distinguished from patients with other manifestations of filarial infection (OTTESEN & NUTMAN, 1992). In essentially all assessmentsof these serological responses, however, the antigen preparations used have been complex mixtures of antigens obtained either by solubilizing filarial worms (usually B. malayi or Dirofilaria immitis) or by collecting their excretoryisecretory products, and it is well known that such prepara-

Table 2. Response to treatment

Patient no. and diagnosis”

Pre+reatmet# eosmophlha 10075 19950

Et: 23750

12125

Number of DEC courses’

Post-DEC eosinophiliad

Other anthelmintic treatmente Ivermectin Thiabendazole Thiabendazole Thiabendazole Thiabendazole Mebendazole Mebendazole -

Post-treatmegt eosinophilia 550 ‘E 435 940 325 200 -

iPIE= ulmonaq infi!trates pith peripheral blood eosinophilia; TPE= tropical pulmonary eosinophilia. Num i er of eosmophllsimm~; mean of 6 pre-treatment assessments. path course of treatment; dFthylcarbamazine 12mglkgidx 30 d. Number of eosino hilsimm one month after final treatment. ‘Thiabendazole (5B0 mg thrice daily) x 7 d; mebendazole (200 mg twice daily) x 7 d; ivermectin (200 W/kg/d x 2 d).

-

575 tions contain many ‘cross-reactive’ antigens shared with other helminths (LAL & OTTESEN, 1938). In patients with helminth-induced PIE syndromes not of filarial origins, there has been no formal study to look for immunological hyper-responsiveness to homologous or heterologous parasite antigens similar to that defined in patients with filaria-induced TPE. Their very similar clinical presentations and, indeed, the findings from the present study, suggest that such immunological hyperresponsivenessdaesexist in these patients aswell. Therefore, given that many epitopes in the frlarial antigen preparations used in diagnostic tests are shared with other helminths, it is perhaps not surprising that an apparent ‘nonspecificity’ of the serological responses to ‘f&trial’ antigens was seen in our aetiologically heterogeneous grou of clinically similar patients. Even with the IgG 4 subcPassof antibodies, which in lesshyper-responsive patients has much reater diagnostic specificity than antibodies of other Ig E subclasses (LAL & OTTESEN, 198X), significant ‘cross-reactivity’ was still seen. Thus, even these usually helpful, ‘specific’ IgG4 antibodies were diagnostically unhelpful for hy er-responsive patients with these other (non-filarial s helmrnth-induced., hyper-responsive PIE syndromes. Which specific parasites caused the PIE syndromes seen in our 7 ‘undiagnosed’ TPE-like patients remains uncertain; however, since the drugs used for these 7 ‘DE&-e&ant patients are most effective against nematodes, it is likely that some nematode parasite(s) of humans or animals was (were) responsible for initiating the disease. Indeed, both Snongyloides and Ascuris are good candidates, as they were isolated from 4 of the 7 patients with the non-filarial TPE-like syndrome. Efforts to discriminate among the various aetiologies serolo ically, however, have not been successful using ELISAS f or IgE and IgG4 directed against saline extracts of both Srrongy,,,,,p vd Ascarrsadult worms (unpubhsked daya). uahtatlve analyses of the anubodles usmg Western b9ot techniques will prove more helpful. Regardless of this uncertainty about specific aetiology, however, since the long-term pulmonary damage induced by TPE and other persistent PIE syndromes can be severe and even life-threatening (UDWADIA, 1993), it is important to recognize that all canditions that look hke filaria-induced TPE (both clinically and in laboratory studies) may not be, and astute therapeutic management is required. Indeed, in our filariasis clinic in Recife, such patients constitute about 30% (10133)of those presenting

the clinical picture of TPE. Thus, it is a matter of some urgency to improve our diagnostic capabilities by identifying and obtaining more specific, purified antigen preparations. The development of recombinant antigens unique for each s cific parasite is likely to be the most effective strategy F” or future research to create these better diagnostic tools. With such tools will come the improved care and managementnecessaryfor patients like those reported here, who present in endemic areas with helminth-induced PIE syndromes that resemble, but are not, TPE of filarial aetiology. Acknowledgements

This study wasfundedin part by the U!%Brtil Co-operative Program in Science and Technology administeredby the Fogarty International Center, National Institutes of Health, FACEPE (01572.13194) and FIOCRUZ (Pa es no. 02). We thank . assistance. CrystalTalley and Brenda Rae Marshall Por editorial

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eosinophilia.Annual Review of Medicine, 43,417-424.

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atoy Uedkne, 87, 17-Z 1. Weller, P. F., Ottesen, E. A., Heck, L., Tere, T. & Neva, F. A. (1982). Endemic filariasis an a Pacific island, I. Clirucal, epidemiologic, and parasitologic aspects. Anrericat~ Journal of Tropical Medicine and Hygiene, 31,942-952. Received February

6 Februav 1995

1995;

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