British Journal of Dermatology (1976) 94, 155.
Skin lesions in human yersiniosis A HISTOPATHOLOGICAL AND IMMUNOHISTOLOGICAL STUDY KIRSTI-MARIA NIEMI, MATTI HANNUKSELA AND OSMO P.SALO Department of Dermatology, University Central Hospital, Snellmaninkatu 14, 00170 Helsinki 17, Finland Accepted for publication 2 June 1975
SUMMARY
Various types of skin manifestations of human yersiniosis were examined with routine histological and immunohistoiogical methods. The biopsy material consisted of sixteen cases of erythema nodosum, eight cases of erythema multiforme, and one case of erythema figuratum. The principal histopathological changes in erythema nodosum were septal or diffuse, mild panniculitis and in seven cases also necrotizing vasculitis in small, medium-sized or large arteries. Perivascular lymphocytic infiltration without vasculitis was the most prominent feature in erythema figuratum. By using a polyvalent conjugate, immunoglobulins in vessel walls in the dermis were foxmd in two cases of EM. The rapid course of the skin eruptions and the frequency of necrotizing vasculitis in arteries fit the changes seen in an experimental Arthus reaction, in which necrotizing vasculitis is followed by lymphocytic inflammation consistent with a delayed type of reaction.
Infections caused by Yersinia enterocolitica and Yersinia pseudotuberculosis are usually manifested by gastrointestinal symptoms often mimicking acute gastroenteritis, but also acute appendicitis atid mesenteric lymphadenitis (Ahvonen, 1972). Quite often, yersiniosis also produces skin rashes, such as erythema nodosum (EN), as is well known in the Scandinavian coimtries and in France (Ahvonen, 1972; Kerzoncuf, 1967; Mollaret, 1971; Nilehn et al, 1968; Winblad, 1969), and sometimes erythema multiforme (EM) (Hannuksela & Ahvonen, 1975), exanthemata (Delorme et al, 1974; Haiinuksela& Ahvonen, 1975), and erythema figuratxim (EF) (Hannuksela & Ahvonen, 1975). This study, using routine histological and immunohistoiogical methods, aims at shedding more light on the pathophysiology of the skin lesions induced by yersinia infections.
PATIENTS AND METHODS
Twenty-five biopsies were taken from various kinds of skin lesions of twenty patients with acute human yersiniosis. In five cases biopsies were taken of both EN and EM lesions from the same patients. 155
K.-M.Niemiy M.Hannuksela and O.P.Salo
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Skin lesions in human yersiniosis
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The biopsies were taken under local anaesthesia. One half of each specimen was fixed in formalin for histological study and the other half was snap-frozen for immunohistoiogical studies. The histological procedure consisted of embedding in paraffin, cutting, and staining with haematoxylin-eosin, methyl green-pyronin and resorcin-fuchsin. For the immunohistoiogical examination, the biopsies were cut, stained and examined as described earlier (Salo, 1970). The diagnosis of yersiniosis was based on a raised antibody titre (160 or more) or on demonstration of the bacteria from faeces. The clinical and some laboratory data are given in Table i. EN only was diagnosed in nine cases, both EN and EM in tea cases, and both EN and EF in one ease. RESULTS
Sixteen lesions of EN, eight of EM (Figs i and 2) and one of EF were examined. In the histological examination the inflammation was most prominent in the subcutis in seventeen lesions and in the dermis in eight lesions (Table 2). In ten cases the subcutaneous inflammation was characterized by
(I)
^
^
^
•
(2)
FIGURE I. Case no. 7. Cockade-tike erythema multiforme on the nock and shoulders. FIGURE 2. Seven days later the same patient as in Fig. i. developed a vesicular form of erythema multiforme on her upper arms. TABLE 2. Histopathological reaction patterns of skin eruptions in human yersiniosis Histological findings Lymphocytic inflammation in the dermis
Patiniculitis Clinical type of eruption Erythema nodosum
Erythema multiforme
Without vasculitis
With vasculitis
7
8 (2, 3> 4. 5. 9.
d, 7, 8, 12, 13, 18, 20)* 2
10, 14,
(11,20)*
Without oedema
With oedema
I
—
(17)'
15)*
2
4
C9> 16)*
(3, 6> 7> 18)*
I (19)*
Erythema figuratum • Case numbers.
—
158
K.-M.Niemi, M.Hannuksela and O.P.Salo
broad connective tissue septa with few adjacent inflammatory round cells. In seven cases the subcutaneous tissue showed only mild difFuse inflammation characterized by the proliferation of small capillaries between the fat cells. In both the septal and diffuse types of panniculitis small tight masses of lymphocytes and in some cases neutrophils could occasionally be found. Necrotizing vasculitis of large and medium-sized arteries was found in five lesions (Fig. 3), and of small vessels in two lesions (Fig. 4)- A vein was found to be inflamed in only one case. The dermal inflammation appeared in two slightly different forms (Table 2). In four cases there was a tight perivascular infiltration of small lymphocytes in the upper or middle dermis., and in four additional cases this was combined with dermal oedema in the papillary layer. In two of these the
FIGURE 3. Erythema nodosum on the leg with necrotizing arteritis (case no. 5) (Resorcin-Fuchsin X400).
FIGURE 4. Erythema nodosum on the thigh Cease no. 10). Necrotizing vasculitis of small vessels on the dermo-subcutaneous border (H & E, x 400).
Skin lesions in human yersiniosis
159
lymphocytic infiltrate was mixed with polymorphonuclear leukocytes. In no case were eosinophils or plasma cells (Methyl green-pyroninophils) found. Vasculitis was not found in the dermal inflammation. Perivascular lymphocytic infiltrations with or without subepidermal or perivascular oedema were typical features both in the vesicular form (five lesions) and in the cockade-like form (three lesions) of EM. In the only case of yersinia EF, perivascular lymphocytic infiltration but no oedema was found in the dermis (Fig. 5).
^^;;.V: • V:,';V,.;, y , .::
FIGURE 5. Erythema tiguratum i.casc no. ly). Sleeve-like infiltrate of lytnphocytes in the upper part of the dermis (H & E, x 100).
The immunohistological examination revealed precipitation of immunoglobulins in the walls of dermal vessels in two cases (Nos 6 and 7), which were clinically classified as EM. Histologically these were the cases with a mixed inflammatory infiltrate and oedema. The different histological or immunohistological findings did not correlate with the antibody titre or with the age of the skin lesion. DISCUSSION
The combination of EN and EM with yersiniosis is more usual than that with other causes underlying EN (Haimuksela & Ahvonen, 1975). According to the classical concept, the consistent histopathological feature in EN is septal panniculitis with accumulations of lymphocytes in the septa of the panniculus adiposus. Sometimes non-necrotizing vasculitis can also be seen in large veins (Lofgren & Wahlgren, 1949). The present results fit this concept only in part. In ten cases of EN septal panniculitis was present, but in seven cases the infiammation in the adipose tissue was diffuse and mild, and all were characterized by small discrete accumulations of lymphocytes. In addition, necrotizing arteritis in the subcutis was seen in seven of sixteen cases of EN. EM, figurate erythemas and exanthemata belong to the large group typified by a dermal perivascular lymphocytic infiltration without vasculitis. The histological picture of the lesions classified clinically as EM in the present study is very close to EM as described by others (Pinkus & Mehregan, 1969; Orfanos, Schaumburg-Lever & Lever, 1974; Reed & Clark, 1971). The fact that in two of our eight cases of EM the subcutis was inflamed (Table 2) demonstrates the overlapping of EM and EN.
i6o
K.-M.Niemi, M.Hannuksela and O.P.Salo
EN has been considered a manifestation of a delayed hypersensitivity reaction influenced by mixed infections and other provocative factors (Lofgren, 1946; Westergren, 1946). Damage caused by antigenantibody reactions is also said to be of pathogenetic significance (Borrie, 1970; Fine & Meltzer, 1968). Parish & Rhodes (1967) have demonstrated immunoglobulins and bacterial antigens in lesions of nodular vasculitis, and Scott & Rowell (1965) have demonstrated immunoglobulins in the lesions of EN. Whether the presence of immunoglobulins in two of our eight cases of EM is a sign of an Arthus reaction or not cannot be resolved. The simultaneous appearance of EN and EM after various intervals from the first clinical signs and symptoms of yersiniosis suggests that both types of reactions are only different manifestations of the same immunological host response to Yersinia bacteria. In the experimental Arthus reaction, necrotizing vasculitis is followed by lymphocytic inflammation consistent with a delayed type of reaction (Cream, Bryceson & Ryder, 1971). The skin rash in yersiniosis may be induced by antigen-antibody complexes which disappear very quickly, while the reaction then continues as a lymphocytic infiltration as in the experimental Arthus reaction.
REFERENCES AHVONEN, P. (1972) Human yersiniosis in Finland. II. Clinical features. Amujls of Clinical Research, 4, 39. BORRIE, P. (1970) Cutaneous vasculitis. Proceedings of the Royal Society of Medicine, 63, 815. CREAM, J.J., BRYCESON, A.D.M., & RYDER, G . (1971) Disappearance of immunogtobulin and complement from the Arthus reaction and its relevance to studies of vasculitis in man. British Journal of Dermatology, 84, 106. DELORME, J., LAVERDIERE, M . , MARTINEAU, B . & LAFLEUR, L . (1974) Yersiniosis in children. Canadian Medical
Association Journal, Iio, 281. FINE, R.M. & MELTZER, H.D. (1968) Erythema nodosum: a form of allergic cutaneous vasculitis. Southern Medical Journal, 61, 680. HANNUKSELA, M . & AHVONEN, P. (1975) Skin manifestations in human yersiniosis. Annals of Clinical Research^ in press. KERZONCUF, A . (1967) L'erytht;me noueux i bacille de Malassez et Vignal. Thesis. Copedith, Paris. LOFGREN, S. (1946) Erythema nodosum. Studies on etiology and pathogenesis of 185 adult cases. Acta Medica .Scandinavica, supplement 174. LOFGREN, S. & WAHLGREN, E. (1949) On the liistopathology of erythema nodosum. Acia dermato-venereologica, 29, I. MOLLARET, H.H. (1971) L'infection humaine k Yersinia enterocolitica en 1970, k la lumicre de 642 cas r^cents. Aspects cliniques et perspectives 6pid6miologiques. Pathologie-Biohgie (Paris), 19, 189. NiLEHN, B., SjosTROM, B., DAMGAARD, K . & KiNDMARK, C. C1968) Yersinia enterocolitica in patients with symptoms of infectious diseases. Acta Pathologica et Microbiologica Scandinavica, 74, loi. ORFANOS, C.E., SCHAUMBURG-LEVER, G . & LEVER, W.F. (1974) Dermal and epidermal types of erythema multiforme. A histologic study of 24 cases. Archives of Dermatology, 109, 682. PARISH, W.E. & RHODES, E.L. (1967) Bacterial antigens and aggregated gamma globulin in the lesions of nodular vasculitis. British Journal of Dermatology, 79, 131. PINKUS, H . & MEHREGAN, A.H. (1969) A Guide to Dermato-histopathology, pp. 130-137. Appleton-Century-Crofts, New York. REED, J.R. & CLARK, W . H . (1971) Basic pathologic reactions of the skin. In: Dermatology in general medicine (Ed. by T.B.Eitzpatrick, K.A.Arndt, W.H.Clark, A.Z.Eisen, EJ.van Scott and J.H.Vaughan), pp. 192-21 r. McGraw-Hill, New York. SALO, O.P. (1970) SLE-like deposition of immunoglobulins in the skin in rosacea. Annals of Clinical Research, 2, 28.
SCOTT, D.G. & ROWELL, N.R. (1965) Preliminary investigations of arteric lesions using fluorescent antibody techniques. British Journal of Dermatology, 77, 211.
WESTERGREN, A. (1946) On a complex etiology of erythema nodosum with reference to the results of an odontologic study. Acta dermato-venereologica, 26, 384.
WINBLAD, S. (1969) Erythema nodosum associated with infection with Yersinia enterocolitica. Scandinavian Journal of Infectious Diseases, i , 11.
Skin lesions in human yersiniosis A HISTOPATHOLOGICAL AND IMMUNOHISTOLOGICAL STUDY KIRSTI-MARIA NIEMI, MATTI HANNUKSELA AND OSMO P.SALO Department of Dermatology, University Central Hospital, Snellmaninkatu 14, 00170 Helsinki 17, Finland Accepted for publication 2 June 1975
SUMMARY
Various types of skin manifestations of human yersiniosis were examined with routine histological and immunohistoiogical methods. The biopsy material consisted of sixteen cases of erythema nodosum, eight cases of erythema multiforme, and one case of erythema figuratum. The principal histopathological changes in erythema nodosum were septal or diffuse, mild panniculitis and in seven cases also necrotizing vasculitis in small, medium-sized or large arteries. Perivascular lymphocytic infiltration without vasculitis was the most prominent feature in erythema figuratum. By using a polyvalent conjugate, immunoglobulins in vessel walls in the dermis were foxmd in two cases of EM. The rapid course of the skin eruptions and the frequency of necrotizing vasculitis in arteries fit the changes seen in an experimental Arthus reaction, in which necrotizing vasculitis is followed by lymphocytic inflammation consistent with a delayed type of reaction.
Infections caused by Yersinia enterocolitica and Yersinia pseudotuberculosis are usually manifested by gastrointestinal symptoms often mimicking acute gastroenteritis, but also acute appendicitis atid mesenteric lymphadenitis (Ahvonen, 1972). Quite often, yersiniosis also produces skin rashes, such as erythema nodosum (EN), as is well known in the Scandinavian coimtries and in France (Ahvonen, 1972; Kerzoncuf, 1967; Mollaret, 1971; Nilehn et al, 1968; Winblad, 1969), and sometimes erythema multiforme (EM) (Hannuksela & Ahvonen, 1975), exanthemata (Delorme et al, 1974; Haiinuksela& Ahvonen, 1975), and erythema figuratxim (EF) (Hannuksela & Ahvonen, 1975). This study, using routine histological and immunohistoiogical methods, aims at shedding more light on the pathophysiology of the skin lesions induced by yersinia infections.
PATIENTS AND METHODS
Twenty-five biopsies were taken from various kinds of skin lesions of twenty patients with acute human yersiniosis. In five cases biopsies were taken of both EN and EM lesions from the same patients. 155
K.-M.Niemiy M.Hannuksela and O.P.Salo
156
.s-s •3 ca
.2 S O tn
(S
M
M
M
N
^ 0
M M B
M-a
•-•
K
i •a -o TJ ^ XI X) < <
> d
O oo
Q >o
O oo
O
- OS
Skin lesions in human yersiniosis
157
The biopsies were taken under local anaesthesia. One half of each specimen was fixed in formalin for histological study and the other half was snap-frozen for immunohistoiogical studies. The histological procedure consisted of embedding in paraffin, cutting, and staining with haematoxylin-eosin, methyl green-pyronin and resorcin-fuchsin. For the immunohistoiogical examination, the biopsies were cut, stained and examined as described earlier (Salo, 1970). The diagnosis of yersiniosis was based on a raised antibody titre (160 or more) or on demonstration of the bacteria from faeces. The clinical and some laboratory data are given in Table i. EN only was diagnosed in nine cases, both EN and EM in tea cases, and both EN and EF in one ease. RESULTS
Sixteen lesions of EN, eight of EM (Figs i and 2) and one of EF were examined. In the histological examination the inflammation was most prominent in the subcutis in seventeen lesions and in the dermis in eight lesions (Table 2). In ten cases the subcutaneous inflammation was characterized by
(I)
^
^
^
•
(2)
FIGURE I. Case no. 7. Cockade-tike erythema multiforme on the nock and shoulders. FIGURE 2. Seven days later the same patient as in Fig. i. developed a vesicular form of erythema multiforme on her upper arms. TABLE 2. Histopathological reaction patterns of skin eruptions in human yersiniosis Histological findings Lymphocytic inflammation in the dermis
Patiniculitis Clinical type of eruption Erythema nodosum
Erythema multiforme
Without vasculitis
With vasculitis
7
8 (2, 3> 4. 5. 9.
d, 7, 8, 12, 13, 18, 20)* 2
10, 14,
(11,20)*
Without oedema
With oedema
I
—
(17)'
15)*
2
4
C9> 16)*
(3, 6> 7> 18)*
I (19)*
Erythema figuratum • Case numbers.
—
158
K.-M.Niemi, M.Hannuksela and O.P.Salo
broad connective tissue septa with few adjacent inflammatory round cells. In seven cases the subcutaneous tissue showed only mild difFuse inflammation characterized by the proliferation of small capillaries between the fat cells. In both the septal and diffuse types of panniculitis small tight masses of lymphocytes and in some cases neutrophils could occasionally be found. Necrotizing vasculitis of large and medium-sized arteries was found in five lesions (Fig. 3), and of small vessels in two lesions (Fig. 4)- A vein was found to be inflamed in only one case. The dermal inflammation appeared in two slightly different forms (Table 2). In four cases there was a tight perivascular infiltration of small lymphocytes in the upper or middle dermis., and in four additional cases this was combined with dermal oedema in the papillary layer. In two of these the
FIGURE 3. Erythema nodosum on the leg with necrotizing arteritis (case no. 5) (Resorcin-Fuchsin X400).
FIGURE 4. Erythema nodosum on the thigh Cease no. 10). Necrotizing vasculitis of small vessels on the dermo-subcutaneous border (H & E, x 400).
Skin lesions in human yersiniosis
159
lymphocytic infiltrate was mixed with polymorphonuclear leukocytes. In no case were eosinophils or plasma cells (Methyl green-pyroninophils) found. Vasculitis was not found in the dermal inflammation. Perivascular lymphocytic infiltrations with or without subepidermal or perivascular oedema were typical features both in the vesicular form (five lesions) and in the cockade-like form (three lesions) of EM. In the only case of yersinia EF, perivascular lymphocytic infiltration but no oedema was found in the dermis (Fig. 5).
^^;;.V: • V:,';V,.;, y , .::
FIGURE 5. Erythema tiguratum i.casc no. ly). Sleeve-like infiltrate of lytnphocytes in the upper part of the dermis (H & E, x 100).
The immunohistological examination revealed precipitation of immunoglobulins in the walls of dermal vessels in two cases (Nos 6 and 7), which were clinically classified as EM. Histologically these were the cases with a mixed inflammatory infiltrate and oedema. The different histological or immunohistological findings did not correlate with the antibody titre or with the age of the skin lesion. DISCUSSION
The combination of EN and EM with yersiniosis is more usual than that with other causes underlying EN (Haimuksela & Ahvonen, 1975). According to the classical concept, the consistent histopathological feature in EN is septal panniculitis with accumulations of lymphocytes in the septa of the panniculus adiposus. Sometimes non-necrotizing vasculitis can also be seen in large veins (Lofgren & Wahlgren, 1949). The present results fit this concept only in part. In ten cases of EN septal panniculitis was present, but in seven cases the infiammation in the adipose tissue was diffuse and mild, and all were characterized by small discrete accumulations of lymphocytes. In addition, necrotizing arteritis in the subcutis was seen in seven of sixteen cases of EN. EM, figurate erythemas and exanthemata belong to the large group typified by a dermal perivascular lymphocytic infiltration without vasculitis. The histological picture of the lesions classified clinically as EM in the present study is very close to EM as described by others (Pinkus & Mehregan, 1969; Orfanos, Schaumburg-Lever & Lever, 1974; Reed & Clark, 1971). The fact that in two of our eight cases of EM the subcutis was inflamed (Table 2) demonstrates the overlapping of EM and EN.
i6o
K.-M.Niemi, M.Hannuksela and O.P.Salo
EN has been considered a manifestation of a delayed hypersensitivity reaction influenced by mixed infections and other provocative factors (Lofgren, 1946; Westergren, 1946). Damage caused by antigenantibody reactions is also said to be of pathogenetic significance (Borrie, 1970; Fine & Meltzer, 1968). Parish & Rhodes (1967) have demonstrated immunoglobulins and bacterial antigens in lesions of nodular vasculitis, and Scott & Rowell (1965) have demonstrated immunoglobulins in the lesions of EN. Whether the presence of immunoglobulins in two of our eight cases of EM is a sign of an Arthus reaction or not cannot be resolved. The simultaneous appearance of EN and EM after various intervals from the first clinical signs and symptoms of yersiniosis suggests that both types of reactions are only different manifestations of the same immunological host response to Yersinia bacteria. In the experimental Arthus reaction, necrotizing vasculitis is followed by lymphocytic inflammation consistent with a delayed type of reaction (Cream, Bryceson & Ryder, 1971). The skin rash in yersiniosis may be induced by antigen-antibody complexes which disappear very quickly, while the reaction then continues as a lymphocytic infiltration as in the experimental Arthus reaction.
REFERENCES AHVONEN, P. (1972) Human yersiniosis in Finland. II. Clinical features. Amujls of Clinical Research, 4, 39. BORRIE, P. (1970) Cutaneous vasculitis. Proceedings of the Royal Society of Medicine, 63, 815. CREAM, J.J., BRYCESON, A.D.M., & RYDER, G . (1971) Disappearance of immunogtobulin and complement from the Arthus reaction and its relevance to studies of vasculitis in man. British Journal of Dermatology, 84, 106. DELORME, J., LAVERDIERE, M . , MARTINEAU, B . & LAFLEUR, L . (1974) Yersiniosis in children. Canadian Medical
Association Journal, Iio, 281. FINE, R.M. & MELTZER, H.D. (1968) Erythema nodosum: a form of allergic cutaneous vasculitis. Southern Medical Journal, 61, 680. HANNUKSELA, M . & AHVONEN, P. (1975) Skin manifestations in human yersiniosis. Annals of Clinical Research^ in press. KERZONCUF, A . (1967) L'erytht;me noueux i bacille de Malassez et Vignal. Thesis. Copedith, Paris. LOFGREN, S. (1946) Erythema nodosum. Studies on etiology and pathogenesis of 185 adult cases. Acta Medica .Scandinavica, supplement 174. LOFGREN, S. & WAHLGREN, E. (1949) On the liistopathology of erythema nodosum. Acia dermato-venereologica, 29, I. MOLLARET, H.H. (1971) L'infection humaine k Yersinia enterocolitica en 1970, k la lumicre de 642 cas r^cents. Aspects cliniques et perspectives 6pid6miologiques. Pathologie-Biohgie (Paris), 19, 189. NiLEHN, B., SjosTROM, B., DAMGAARD, K . & KiNDMARK, C. C1968) Yersinia enterocolitica in patients with symptoms of infectious diseases. Acta Pathologica et Microbiologica Scandinavica, 74, loi. ORFANOS, C.E., SCHAUMBURG-LEVER, G . & LEVER, W.F. (1974) Dermal and epidermal types of erythema multiforme. A histologic study of 24 cases. Archives of Dermatology, 109, 682. PARISH, W.E. & RHODES, E.L. (1967) Bacterial antigens and aggregated gamma globulin in the lesions of nodular vasculitis. British Journal of Dermatology, 79, 131. PINKUS, H . & MEHREGAN, A.H. (1969) A Guide to Dermato-histopathology, pp. 130-137. Appleton-Century-Crofts, New York. REED, J.R. & CLARK, W . H . (1971) Basic pathologic reactions of the skin. In: Dermatology in general medicine (Ed. by T.B.Eitzpatrick, K.A.Arndt, W.H.Clark, A.Z.Eisen, EJ.van Scott and J.H.Vaughan), pp. 192-21 r. McGraw-Hill, New York. SALO, O.P. (1970) SLE-like deposition of immunoglobulins in the skin in rosacea. Annals of Clinical Research, 2, 28.
SCOTT, D.G. & ROWELL, N.R. (1965) Preliminary investigations of arteric lesions using fluorescent antibody techniques. British Journal of Dermatology, 77, 211.
WESTERGREN, A. (1946) On a complex etiology of erythema nodosum with reference to the results of an odontologic study. Acta dermato-venereologica, 26, 384.
WINBLAD, S. (1969) Erythema nodosum associated with infection with Yersinia enterocolitica. Scandinavian Journal of Infectious Diseases, i , 11.
