Infections or Vaccines Associated with Finkelstein-Seidlmayer Vasculitis: Systematic Review

Finkelstein-Seidlmayer vasculitis, also referred to as acute hemorrhagic edema of young children, is a rare small-vessel leukocytoclastic vasculitis. This condition is skin-limited, mainly affects infants up to 2 years of age and spontaneously remits. It has been suggested that an infection or a vaccine precede (by ≤ 14 days) this vasculitis. To better understand the interplay between infections or vaccines and Finkelstein-Seidlmayer vasculitis, we utilized the data contained in the Acute Hemorrhagic Edema BIbliographic Database AHEBID. The database, initiated in 2019, is being regularly updated, encompasses the entire original literature on Finkelstein-Seidlmayer vasculitis published after the original description and is attainable on request. The possible existence of an infectious or a vaccine precursor was addressed in 447 cases. Most cases were preceded by an infection (N = 384; 86%), by a vaccination (N = 20; 4.4%), or both an infection and a vaccination (N = 17; 3.8%). No precursor was reported in the remaining cases (N = 26; 5.8%). Two distinct infections preceded the onset of the vasculitis in 11 of the 381 cases with infection-associated Finkelstein-Seidlmayer vasculitis. The following infectious precursors were reported: upper respiratory tract infection (N = 292); acute gastroenteritis (N = 40); a benign febrile infection (N = 36); lower respiratory tract infection (N = 22); further infections (N = 8). The temporal relationship between the infectious precursor and the onset of the skin eruption was detailed in 336 cases: 54 cases developed before resolution and 282 after resolution of the infection. In conclusion, most cases of Finkelstein-Seidlmayer vasculitis are preceded by an infection. In a minority of cases, this skin vasculitis develops before resolution of the infection. In most cases, however, this vasculitis develops after resolution of the infection. More rarely, this vasculitis is preceded by a vaccination. Supplementary Information The online version contains supplementary material available at 10.1007/s12016-022-08940-2.


Introduction
Finkelstein-Seidlmayer vasculitis, also referred to as acute hemorrhagic edema of young children, cockade purpura with edema, infantile erythema multiforme, or infantile Henoch-Schönlein purpura, is a rare immune-mediated small-vessel leukocytoclastic vasculitis [1][2][3][4]. This condition is skin-limited, mainly occurs in infants up to 2 years of age, spontaneously remits in a maximum of 3 weeks and does not tend to recur [1][2][3][4]. Affected patients are well-appearing and acutely present with widespread and symmetrically distributed annular or nummular eruptions and edema [1][2][3][4]. The annular or nummular eruptions are distributed over the legs, feet, face, arms, ears, trunk, and genitals in that order of frequency. The distribution is identical for edema except for feet, which are very often affected [1][2][3][4].
Textbooks and narrative reviews state that Finkelstein-Seidlmayer vasculitis is often preceded by a respiratory tract infection, a gastroenteritis, a urinary tract infection, a benign febrile disease with unknown source, or a vaccine [2,4]. To better understand the interplay between infections or vaccines and Finkelstein-Seidlmayer vasculitis, we utilized the data contained in the Acute Hemorrhagic Edema BIbliographic Database AHEBID.

Methods
AHEBID was initiated by some of us [3,5,6] in 2019, is being regularly updated and encompasses the entire original literature on Finkelstein-Seidlmayer vasculitis published after the original description in 1913 [7]. The database is attainable on request (email: finkelstein-seidlmayer@usi.ch). For this purpose, the bibliography search engines Excerpta Medica, the National Library of Medicine database and Google scholar are screened every second month for "acute hemorrhagic edema", "cockade purpura and edema", "Finkelstein-Seidlmayer" and "infantile Henoch-Schönlein purpura" without any language restriction. To increase the rigor of the literature search, we conduct the search in agreement with 2020 version of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. AHEBID also incorporates secondary references and the literature on Finkelstein-Seidlmayer vasculitis collected by one of us in the early eighties of the last century [8]. As of September 1, 2021, the database ( Fig. 1) included 314 (see: supplementary material) original reports (letters, case reports or full-length articles) published after 1969, which addressed 504 (349 boys and 155 girls) individually documented cases: 7 neonates less than 4 weeks of age, 252 infants less than 12 months of age, 181 infants 12 to 23 months of age and 63 children 24 months or more of age (this piece information was not available in one case). For all patients, the diagnosis of hemorrhagic edema made in the original reports was reviewed using three well established clinical criteria: raised annular or nummular eruptions and inflammatory skin edema (mostly non-pitting, tender and sometimes also warmth) in a well-appearing and playful child with stable vital signs [5]. The clinical diagnosis was supported by a skin biopsy [9] disclosing a non-granulomatous neutrophil infiltration into small-vessel walls with karyorrhexis in 248 (50%) cases.
For the present study, we meticulously extracted published cases of Finkelstein-Seidlmayer vasculitis where the existence of an associated infectious or vaccine precursor (by 14 days or less) was discussed [4,5]. The temporal relationship between infection and onset of Finkelstein-Seidlmayer vasculitis was employed to classify the condition as intra-(skin vasculitis starting before resolution of the infection) or post-infectious (skin disorder starting after resolution of the infection). The term latency was used to denote the time (in days) elapsed from onset of infectious symptoms to onset of skin eruption. The infectious precursors [10][11][12] were classified as depicted in Table 1.
Categorical variables are shown as counts and were analyzed using the Fisher's exact test. Numerical variables are presented as medians and interquartile ranges and were compared using the Mann-Whitney U test. Two-sided P-values of less than 0.05 were regarded as statistically significant.
The latency time was significantly lower in the 23 intrainfectious cases (P < 0.001) as compared with the 205 post-infectious cases.

• Acute lower respiratory tract infection (including pneumonia)
-Cough associated with one or more of the following signs: labored breathing; chest indrawing; rales; stridor; wheezing; cyanosis; respiratory rate > 50/min -The term was also employed for cases diagnosed with croup, bronchitis, bronchiolitis, or pneumonia in the original report • Acute lower respiratory tract infection (including pneumonia) -Cough associated with one or more of the following signs: labored breathing; chest indrawing; rales; stridor; wheezing; cyanosis; respiratory rate > 50/min -The term was also employed for cases diagnosed with croup, bronchitis, bronchiolitis, or pneumonia in the original report • Acute gastroenteritis -Three or more loose stools per day (or a number of bowel movements exceeding the child's usual number of daily bowel movements by two or more) with or without associated fever and vomiting -The term was also employed for cases diagnosed with acute gastroenteritis or acute infectious diarrhea in the original report • Urinary tract infection -Increased body temperature, failure to thrive, poor feeding or acute urinary symptoms associated with urinalysis disclosing a pathological pyuria and a significant positive urine culture (excluding lactobacilli, corynebacteria, and coagulase-negative staphylococci) -The term was also employed for cases diagnosed with urinary tract infection or pyelonephritis in the original report • Benign febrile infection without a source -Fever in a previously healthy, otherwise well-appearing child when a complete history and physical examination do not identify a specific source of infection. Occult infections such as urinary tract infection, bacteremia or pneumonia have also been reasonably excluded -The term was also employed for cases diagnosed with benign febrile infection, fever without localizing signs or fever without a focus in the original report

• Further infections
The diagnosis made in the original report was retained

Discussion
This systematic literature review documents that most cases of Finkelstein-Seidlmayer vasculitis are preceded by an infection. In a minority of cases, this skin vasculitis develops before resolution of the infection, i.e. intra-infectiously. In the vast majority of cases, however, this vasculitis develops after resolution of the infection, i.e., post-infectiously. More rarely, this vasculitis is preceded by a vaccination or both an infection and a vaccination, indicating that infections by far more frequently trigger immune-mediated diseases than vaccinations.
The reason for the unique distribution of skin lesions with predilection for face and ears remains unclear. The following possible explanations may be offered. In immunoglobulin A vasculitis, the location of skin lesions is notoriously gravitydependent. Since infants with Finkelstein-Seidlmayer vasculitis spend most of their time lying down, gravity cannot play a role. The main factor that may modulate the distribution of lesions is the blood supply: the proportionally large head and face with a corresponding increase in blood supply in infants predisposes them more to facial lesions. A predilection for the face is observed also in infants with strawberry hemangioma, where the subcutaneous arteries that nourish the hemangioma are mostly found in the head [4]. Finally, it is tempting to assume a role also for skin-resident cells.
Infectious causes have long been suspected for many vasculitis syndromes [13,14]. In most cases, the vascular injury has been ascribed to immune-mediated mechanisms rather than direct microbial invasion [13,14]. There is a recognized association between some vasculitides and infections: Mycobacterium tuberculosis is likely involved in Takayasu arteritis [15] and a Burkholderia in Horton giant cell arteritis [16]; Hepatitis B and C viruses have been associated to polyarteritis nodosa [17]; Staphylococcus aureus has been the focus of many studies on granulomatosis with polyangiitis [18]; finally, Hepatitis C virus is a cause of cryoglobulinemia vasculitis [19]. Immunoglobulin A-associated small-vessel leukocytoclastic vasculitis has been associated with bacteria such as group A Streptococci, atypical bacterial pathogens (including Mycoplasma), Helicobacter pylori, Staphylococcus aureus, Salmonella enteritidis or Campylobacter, and with viruses such as Parvovirus B19, Varicellazoster virus, Epstein-Barr virus and especially common respiratory viruses [20]. Very recently, immunoglobulin A vasculitis has also been associated with severe acute respiratory syndrome coronavirus 2 [21].
The precursors noted in Finkelstein-Seidlmayer vasculitis are concurrently similar and different from those observed in immunoglobulin A vasculitis. Both Finkelstein-Seidlmayer vasculitis and immunoglobulin A vasculitis are often preceded either by a vaccination or, more frequently, an infection. However, Streptococcus pyogenes and atypical bacterial pathogens including Mycoplasma very often precede immunoglobulin A vasculitis but rather rarely precede Finkelstein-Seidlmayer vasculitis [20,22,23]. This difference is likely related to the fact that Streptococcus pyogenes [24] and atypical bacterial pathogens [25] rarely affect subjects 4-5 years or less of age. Textbooks and reviews sometimes emphasize an unproven association between Mycoplasma and Finkelstein-Seidlmayer vasculitis. This misunderstanding likely reflects the fact that the clinical hallmarks of this vasculitis resemble erythema multiforme, a condition often caused by Mycoplasma [1][2][3][4]. Our data also demonstrate that, like with immunoglobulin A vasculitis, respiratory tract viruses including coronavirus disease 2019 [26] may be associated with Finkelstein-Seidlmayer vasculitis. Vaccination against severe acute respiratory syndrome coronavirus 2 has also been occasionally associated  with immunoglobulin A vasculitis [27]. On the contrary, no cases of Finkelstein-Seidlmayer vasculitis have been so far associated with this vaccination, likely because it is currently not recommended in young children. Finally, it is worth of mention that a temporal association between an infection (or a vaccination) and Finkelstein-Seidlmayer vasculitis does not inexorably and in every case imply causality. Immunoglobulin A vasculitis is obviously an immunoglobulin A dominant vasculitis [2,4]. Since immunoglobulin A is an early response to a pathogen, the clinical features of this vasculitis mostly occur before resolution of the infectious precursor, i.e., intra-infectiously [2,4]. Finkelstein-Seidlmayer vasculitis is a non-immunoglobulin A dominant immune-mediated vasculitis. Consequently, the features of this vasculitis mostly occur after resolution of the infection, i.e., post-infectiously.
The results of this systematic review must be viewed with an understanding of the inherent limitations of the analysis process, which integrated information from reports detailing on average one to two cases of Finkelstein-Seidlmayer vasculitis reported over a period of 50 years. For example, the diagnostic strategy was heterogeneous: it was often supported by a skin biopsy study in cases managed by dermatologists but was made clinically in those managed by pediatricians. The obvious strength of this analysis is that it includes the whole literature on this vasculitis over the period 1970-2021.

Conclusions
In Finkelstein-Seidlmayer vasculitis (like in immunoglobulin A vasculitis), it is typical that different infectious agents may trigger the same pathological damage. On the other hand, a specific microbe may produce more than one vasculitis syndrome. The mechanisms underlying the occurrence of an infection-associated immune-mediated vasculitis are still speculative. It is currently postulated that bystander activation, microbial persistence, or molecular mimicry [28] and genetic factors [29] concurrently play a crucial role.

Declarations
Ethics Approval and Consent to Participate This was a systematic review study that in our institutions does not require specific ethics approval.

Conflict of interest
The authors declare no competing interests.
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