AND CRYPTOSPORIDIAL. DIARRHEA IN HIV INFECTED PATIENTS

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FACTORS ASSOCIATED WITH MICROSPORIDIAL

AND CRYPTOSPORIDIAL. DIARRHEA IN HIV INFECTED PATIENTS

CORNET M.*, ROMAND S.*, WARSZAWSKI J.** & B O U R É E P.*

Summary :

Cryptosporidium and microsporidia are increasingly recognized as important agents of chronic diarrhea in human immunodeficiency virus (HIV) infected patients. These protozoa present clinical and biological similarities but confection with these two parasites seems uncommon. In a population of diarrheic HIV infected patients in the Paris area (France], a comparison study was performed in order to clarify epidemiological differences between these protozoa. From November 1993 to December 1994, 26 microsporidial infected patients were compared to 28

Cryptosporidial patients for various factors. Results of a multivariate logistic tegression analysis showed that trips to tropical countries remained strongly associated with microsporidia compared with Cryptosporidium (adjusted odds ratio (OR) = 4.6, 95 % confidence interval (CI) 1 .1-19.5). Thus, as compared with cryptosporidiosis, specific epidemiological factors could be associated with microsporidial transmission in tropical countries.

KEYWORDS : AIDS, Cryptosporidium, microsporidia, diarrhea, epidemiology.

MOTS CLÉS : SIDA, Cryptosporidium, microsporidia, diarrhée, èpidémioiogie.

Résumé : FACTEURS ASSOCIÉS AUX MICROSPIDIES ET CRYPTOSPORIDIES CHEZ DES PATIENTS DIARRHÉIQUES INFECTÉS PAR LE VIH

Les microsporidies et les cryptosporidies sont les principales causes parasitaires de diarrhée chronique chez les patients infectés par le virus de l'immunodéficience humaine (VIH). Malgré les similitudes cliniques et biologiques de ces protozoaires, l'association des deux parasites chez un même malade semble rare. Dans une population de sujets infectés par le VIH, les auteurs ont comparé les cas de microsporidiose aux cas de cryptosporidiose

diagnostiqués de novembre 1993 à décembre 1994. Les résultats de l'analyse comparative de 26 patients porteurs de

microsporidies et 28 porteurs de cryptosporidies montrent que les voyages en zone tropicale constituent un facteur significativement associé aux microsporidies, indépendamment des autres facteurs (Odds Ratio (OR) ajusté = 4,6; Intervalle de Confiance (IC) à 95 % : 1,1-19,5). Les sujets originaires des pays tropicaux présentent également un risque augmenté de contamination par les microsporidies (OR ajusté = 4,5; IC à 95 % : 0,7-30). Ces résultats suggèrent, pour les microsporidies, l'existence de facteurs épidémiologiques distincts des cryptosporidies, pouvant favoriser leur transmission en milieu tropical.

INTRODUCTION

C

h r o n i c diarrhea is a c o m m o n c o m p l i c a t i o n during the course o f human immunodeficiency virus ( H I V ) infection. In this context, the t w o most frequently identified parasitic infections, microsporidiosis and cryptosporidiosis, present s o m e clinical and b i o l o g i c a l similarities. B o t h o f them are opportunistic protozoan parasites infecting the small b o w e l . Microsporidial and cryptosporidial diarrheal diseases o c c u r in HIV infected patients when severe cellular immunodeficiency d e v e l o p s ( C D 4 cell counts

< 1 0 0 / m m 3 ) , during t h e later s t a g e s o f a c q u i r e d immunodeficiency syndrome (AIDS) (Current, 1 9 9 1 ; W e b e r , 1994; Kotier, 1 9 9 5 ) . However, coinfection with these t w o parasites in the s a m e patient s e e m s to b e

u n c o m m o n a n d s o m e e p i d e m i o l o g i c a l differences could explain this fact (Houze-Savage, 1 9 9 3 ; Wuhib,

1 9 9 4 ) . Human transmission, p r e v a l e n c e in tropical countries and risk factors for human infection with these protozoa are still uncertain, especially for micro- s p o r i d i a (Case-more, 1 9 9 0 ; Current, 1 9 9 1 ; W e b e r , 1 9 9 4 ) . A « c a s e control » study w a s carried out a m o n g diarrheic HIV infected patients in order to c o m p a r e microsporidial infected patients to cryptosporidial infected o n e s with regard to various different factors. T h e aim o f this study w a s to highlight s o m e possible epidemiological differences b e t w e e n these t w o infections in HIV infected patients.

PATIENTS AND METHODS

* Département de Parasitologie et Médecine Tropicale, Hôpital du Kremlin-Bicêtre, 78, rue du Général-Leclerc, 94275 Le Kremlin- Bicêtre, France.

** Unité 1NSFRM U292 Santé Publique et Épidémioiogie, Hôpital du Kremlin-Bicêtre, 82, rue du Général-Leclerc, 94276 Le Kremlin- Bicêtre Cedex. France.

Correspondance : Dr S. Romand. Tél. : (1) 45 21 33 21 - Fax : (1) 45 21 33 19.

PATIENTS AND PRESENTATION O F T H E S T U D Y

W

e c o n d u c t e d a 13 m o n t h s study from N o v e m b e r 1 9 9 3 to D e c e m b e r 1994 in the department o f parasitology o f the Kremlin- Bicetre hospital near Paris (France). T h e laboratory sys- tematically performed all parasitic stool examinations, Parasite, 1996, 4, 397-401

Note de recherche 397

Article available athttp://www.parasite-journal.orgorhttp://dx.doi.org/10.1051/parasite/1996034397

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CORNET M., ROMANO S., WARSZAWSKI J . & BOURÉE P.

prescribed for abdominal pain or diarrhea, in HIV infected patients admitted to four hospitals in the Paris area. Patients w e r e included in this study w h e n Cryp

tosporidium o r microsporidia w e r e r e c o v e r e d from at least o n e stool sample. T h e group o f microsporidial patients was c o m p a r e d to the cryptosporidial group for:

country o f origin, country o f residence, trips to tropical areas, p r e s e n c e o f animals, HIV e x p o s u r e category, other opportunistic infections, CD4 T-cell counts before and at the m o m e n t o f diagnosis, duration o f diarrhea before diagnosis and coinfection with other intestinal p a t h o g e n s .

P A R A S I T O L O G I C M E T H O D S

Both parasitic intestinal infections w e r e d i a g n o s e d by stool examination.

For Cryptosporidium parvum, a c o n c e n t r a t e d stool s p e c i m e n smear was stained using the acid-fast tech

n i q u e (Henriksen, 1 9 8 1 ) .

For microsporidia, two c o m p l e m e n t a r y methods w e r e associated for e a c h s p e c i m e n b e c a u s e o f the difficulty in detecting s p o r e s o f these parasites. Stools w e r e e x a m i n e d using W e b e r ' s c h r o m o t r o p e - b a s e d staining t e c h n i q u e and the fluorescent t e c h n i q u e described by Van C o o l ( W e b e r , 1992; Van G o o l , 1 9 9 3 ) . A stool was c o n s i d e r e d positive if both stains revealed spores with typical morphology. Microsporidian s p e c i e s (Entero- cytozoon bieneusi or Septata intestinalis) w e r e not identified by electron microscopy.

STATISTICAL M E T H O D S

Univariate analysis, Chi-square tests and Fisher's exact test w e r e performed with the EPI INFO 5.0 software, p r o d u c e d by the Center o f D i s e a s e Control (Atlanta, Georgia, USA). Logistic regressions analysis w e r e per

formed using the Statistical Analysis System (SAS Ins

titute, Cary, N C ) .

RESULTS

D uring the 13 months-study period, 8 5 8 stool s p e c i m e n s w e r e c o l l e c t e d and analyzed from 383 diarrheic HIV infected patients. Crypto

sporidium parvum o o c y s t s w e r e i d e n t i f i e d in 31 patients ( 8 %, 9 5 % Confidence Interval (CI) 5.3- 10.7) and microsporidia spores in 29 patients (7.6 % , 9 5 % CI 4 . 9 - 1 0 . 2 ) . Four patients (1 %, 9 5 % CI 0.7-1.3) presented coinfection with the t w o parasites and w e r e e x c l u d e d from the c o m p a r i s o n study. T h r e e c a s e s o f cryptosporidiosis and three c a s e s o f microsporidiosis w e r e also e x c l u d e d b e c a u s e n o data could b e col

lected. Finally, 26 patients with microsporidial diarrhea w e r e c o m p a r e d to 2 8 patients with cryptosporidial diarrhea.

T h e characteristics o f the study population are sum

marized in table I. T h e ages ranged from four to 62 years ( m e a n age: 36 years).

Were considered as tropical countries: Sub-Saharan African coun

tries, Central and South America, South-east Asia, West Indies and Pacific Islands.

Table I. — Characteristics of the study population in 54 HIV infected patients with microsporidial or cryptosporidial diarrhea: Paris, France, 1993-1994.

Univariate analysis did not s h o w any significant diffe

r e n c e b e t w e e n the t w o groups o f infected patients for sex, age, CD4 T-cell counts, rank o f the protozoan infection a m o n g other opportunistic infections or for contacts with animals (table II). Microsporidiosis was m o r e associated with patients born in tropical c o u n tries than cryptosporidiosis (odds ratio ( O R ) = 5.8; 9 5 % CI 0.9-45.6). Similarly, patients w h o traveled at least o n c e or m o r e to tropical countries w e r e m o r e likely to b e infected with microsporidia ( O R = 6; 9 5 % CI 1.6-24.3). T h e two groups w e r e similar c o n c e r n i n g the length o f these trips, the date o f return from the last trip before diagnosis and the conditions o f stay abroad (comfortable or n o t ) . T h e o c c u r r e n c e o f c h r o n i c diar

rhea (over three m o n t h s ) was significantly higher for microsporidiosis than for cryptosporidiosis with m e a n s o f s e v e n and four m o n t h s respectively.

A logistic regression analysis was performed, adjusting for all the significant factors found b y univariate c o m parisons, also taking into a c c o u n t s e x and rank o f opportunistic infections w h i c h may reflect the stage o f HIV infection (table III). Duration o f diarrhea before

3 9 8

(%)

F e a t u r e M e n W o m e n

n = 4 6 n = 8

A g e ( y e a r s )

[0-17] 4 0

[18-24] 2 0

[ 2 5 - 4 4 ] 7 6 7 5

> 4 4 18 25

H I V e x p o s u r e c a t e g o r y

H o m o / b i s e x u a l m e n 6 7

H e t e r o s e x u a l 15 6 2 . 5

D r u g I V 9 2 5

H e m o p h i l i c 4

F e t o - m a t e r n a l 2.5 0

H o m o s e x u a l + drug I V 2.5

A c c i d e n t a l 1 2 . 5

C o u n t r y o f o r i g i n

T r o p i c a l c o u n t r i e s f 1 7 2 5

W e s t e r n c o u n t r i e s 8 3 " 5

N u m b e r o f trips t o t r o p i c a l c o u n t r i e s

> 1 5 6 5 0

0 4 4 5 0

Note de recherche Parasite, 1996, 4, 397-401

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MICROSPORIDIAL AND CRYPTOSPORIDIAL. DIARRHEA IN A I D S

* Kruskall-Wallis' test or Fisher's exact test or chi-square test, t Oclcls Ratio, 95 % confidence interval.

t Were considered as tropical countries: Sub-Saharan African countries. Central and South America, South-east Asia. West Indies and Pacific Islands.

Table II. — Univariate analysis for factors associated with microsporidial and Cryptosporidia) diarrhea in 54 HIV infected patients: Paris, France, 1993-1994.

diagnosis, although being a significant factor in the uni

variate analysis, was u n k n o w n for eight patients and was not included into the final model. Multivariate ana

lysis s h o w e d that trips to tropical countries remained independently associated with microsporidial diarrhea (adjusted OK = 4.6; 9 5 % CI 1.1-19-5). Patients born in tropical countries t e n d e d m o r e likely to have microsporidiosis than cryptosporidiosis (adjusted O R = 4 . 5 ; 9 5 % CI 0 . 7 - 3 0 ) . Men also t e n d e d to have an increased risk for microsporidiosis (adjusted O R = 7.7; 9 5 % CI 0 . 8 - 7 8 ) .

DISCUSSION

Our results clearly s h o w that, c o m p a r e d with HIV- infected patients with cryptosporidiosis, microsporidial infection was significantly m o r e associated with pre

vious travels to tropical areas a m o n g the s a m e cate

gory o f individuals. Moreover, this association remained significant e v e n after controlling for confounding fac

tors such as sex, country o f origin, HIV e x p o s u r e cate

gory and rank o f opportunistic infection. Consistently, patients born in tropical countries also s e e m e d to b e

Parasite, 1 9 9 6 , 4, 3 9 7 - 4 0 1

N o ( % )

M i c r o s p o r i d i a C r y p t o s p o r i d i a O R f

V a r i a b l e ( c a s e s ) ( c o n t r o l s ) 9 5 % C I P'

S e x

M e n 2 4 ( 9 2 ) 2 2 ( 7 9 ) 3 . 3

[ 0 . 5 - 2 6 . 8 ] 0 . 2 5

W o m e n 2 ( 8 ) 6 ( 2 1 ) 1

A g e ( y e a r s )

(0-17] ' I 2 ( 7 )

[18-241 0 1 ( 4 ) 0 . 7 4

[25-441 21 ( 8 1 ) 2 0 ( 7 1 )

> 4 4 5 ( 1 9 ) 5 ( 1 8 )

M e a n 3 6 . 7 3 5 . 1

C o u n t r y o f o r i g i n

T r o p i c a l c o u n t r i e s ^ 8 ( 3 1 ) 2 ( 7 ) 5 . 8

[0.9-45.61 0 . 0 4

W e s t e r n c o u n t r i e s 1 8 ( 6 9 ) 2 6 ( 9 3 ) 1

N u m b e r o f trips t o t r o p i c a l c o u n t r i e s

> 1 2 0 ( 7 7 ) i o ( 3 6 ) 6

[1.6-24.31 0 . 0 0 2

0 6 ( 2 3 ) 18 ( 6 4 ) 1

First o p p o r t u n i s t i c i n f e c t i o n

Y e s 7 ( 2 7 ) 12 ( 4 3 ) 0 . 4 9

[0.1-1.81 0 . 2 2

N o 19 ( 7 3 ) 16 ( 5 7 ) 1

D u r a t i o n o f d i a r r h e a b e f o r e d i a g n o s i s

> 3 m o n t h s 17 ( 7 4 ) 9 ( 3 9 ) 4.4

[ 1 . 1 - 1 9 . 2 ] 0 . 0 2

< 3 m o n t h s 6 ( 2 6 ) 14 ( 6 1 ) 1

C D 4 T c e l l s at t h e m o m e n t o f d i a g n o s i s

< 5 0 / m m3 2 0 ( 7 7 ) 2 0 ( 7 1 ) 1.33

[0.3-5.51 0.6

> 5 0 / m m³ 6 ( 2 3 ) 8 ( 2 9 ) 1

A n i m a l s

Y e s 7 ( 3 3 ) 5 ( 2 5 ) 0 . 6 7

[0.1-3.2] 0 . 5 6

N o 14 ( 6 7 ) 15 ( 7 5 ) 1

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C O R N E T M . , R O M A N D S., W A R S Z A W S K I J . & B O U R E E P .

* Odds Ratio (95 % confidence interval).

f Were considered as tropical countries: Suh-Saharan African coun

tries. Central and South America. South-east Asia. West Indies and Pacific Islands.

Table III. — Risk factors for microsporidial diarrhea comparatively to Cryptosporidia! diarrhea in a population of HIV diarrhcic patients.

Reduced models by multivariate logistic regression: Paris, France, 1993-1994.

m o r e at risk o f microsporidiosis rather than cryptosporidiosis, although this a s s o c i a t i o n did n o t remain significant in t h e multivariate analysis. In that respect, c o m p a r e d with patients infected with Cryptospori

dium, the higher proportion o f microsporidia infected patients having stayed at least o n c e in a tropical r e g i o n must b e o f value s i n c e cryptosporidiosis itself is generally c o n s i d e r e d m o r e frequent in d e v e l o p i n g tropical countries. T h u s , most studies h a v e r e p o r t e d strikingly high prevalences o f cryptosporidiosis a m o n g i m m u n o c o m p e t e n t and i m m u n o c o m p r o m i s e d s u b jects living in tropical countries, a n d this w a s related with p o o r h y g i e n e c o n d i t i o n s resulting in i n c r e a s e d fecal-oral c o n t a m i n a t i o n s ( M a l e b r a n c h e , 1 9 8 3 ; Henry, 1 9 8 6 : Crawford, 1 9 8 8 ; Ungar, 1 9 8 8 ) . In addition, during t h e last few years, cryptosporidiosis h a s b e e n repeatedly reported as a c a u s e o f traveler's diarrhea (Sterling. 1 9 8 6 ) . O n t h e cither hand, f e w data are cur

rently available about t h e frequency o f microsporidial related diarrhea in tropical countries. Y e t , recent stu

dies suggest that microsporidiosis c o u l d b e a frequent d i s e a s e in the d e v e l o p i n g world. T h u s , in Z i m b a b w e , 11 % o f HIV-positive patients with diarrhea w e r e found to b e infected with E. bieneusi, w h i c h w a s t h e most prevalent parasite isolated ( V a n G o o l . 1 9 9 5 ) , w h e r e a s p r e v a l e n c e o f microsporidiosis w a s estimated at 2 3 % a m o n g AIDS patients with c h r o n i c diarrhea in Zambia (Drobniewski, 1 9 9 5 ) . In another large study c o n d u c t e d in Niger, E. bieneusi spores w e r e recovered from stools o f 8 / 9 9 0 children w h o w e r e not c o n s i d e r e d HIV positive, t h e r e b y suggesting a high pre

v a l e n c e o f enteric carriage a m o n g i m m u n o c o m p e t e n t p e r s o n s in tropical c o u n t r i e s ( B r e t a g n e , 1 9 9 3 ) , In addition, microsporidiosis h a s a l s o b e e n r e c o g n i z e d as a c a u s e o f traveler's diarrhea in i m m u n o c o m p e t e n t individuals returning from t h e Middle-East (Sandfort, 1 9 9 4 ; S o b o t t k a , 1 9 9 5 ) . T h u s , o u r results are in a g r e e

ment with t h e hypothesis o f a high rate o f transmis

sion o f microsporidiosis in tropical a n d sub-tropical areas.

B y contrast, n o significant difference w a s s h o w n bet

w e e n Cryptosporidia! a n d m i c r o s p o r i d i a l i n f e c t e d patients with regard to other different epidemiological factors, although our small sample sizes m a y not have allowed lis to a c h i e v e statistical significance. Thus, opportunistic infections with these t w o p r o t o z o a n s may b e c o n s i d e r e d as highly c o m p a r a b l e , consistently with similar intestinal target and clinical spectrum o f both infections (Current, 1 9 9 1 ; W e b e r , 1 9 9 4 ) .

S o m e authors have suggested that Cryptosporidium may b e sexually transmitted similarly to other protozoa such as Giardia intestinalis. Entamoeba histolytica or Isospora belli (Phillips, 1 9 8 1 ; Soave, 1 9 8 4 ; Smith, 1 9 8 8 ; C a s e m o r e , 1 9 9 0 ; Sorvillo, 1 9 9 4 ) . In our study, the fre

q u e n c y o f microsporidiosis w a s higher than crypto

sporidiosis a m o n g sexually transmitted HIV patients, although the difference w a s not significant. In tropical c o u n t r i e s , H I V c o n t a m i n a t i o n is m a i n l y a c q u i r e d through sexual contacts, h e n c e tropical origin or trips may more probably explain the difference o b s e r v e d b e t w e e n microsporidial and Cryptosporidia! patients with regard to HIV sexual transmission.

T h e significant difference o b s e r v e d b e t w e e n the t w o p a t h o g e n s for duration o f diarrhea before diagnosis rather reflects the difficulty in detecting microsporidial spores. T h e r e was n o significant difference in the C D 4 lymphocyte COLINTS b e t w e e n the t w o groups to explain the longer duration o f microsporidial diarrhea.

Finally, although environmental s o u r c e s o f m i c r o s p o ridia are still unknown, this report raises the hypothesis o f an increased risk o f transmission o f microsporidia in tropical countries as c o m p a r e d with Cryptospori

dium, even though high prevalences o f cryptosoridiosis are found in these countries. Since fecal-oral route o f microsporidial transmission is most likely, poor hygiene c o n d i t i o n s a n d p o s s i b l e i n c r e a s e d e n v i r o n m e n t a l s o u r c e s o f infection in these countries could explain this finding. Therefore, in order to better define risk factors associated with microsporidiosis, carefully desi

g n e d prospective epidemiological studies are n e e d e d , c o m p a r i n g patients infected and n o n infected with microsporidia.

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AND CRYPTOSPORIDIAL. DIARRHEA IN HIV INFECTED PATIENTS

FACTORS ASSOCIATED WITH MICROSPORIDIAL