Mycoplasma pneumoniae-related hepatitis in children

Journal Pre-proof Mycoplasma pneumoniae-related hepatitis in children Poddighe D PII:

S0882-4010(19)31526-8

DOI:

https://doi.org/10.1016/j.micpath.2019.103863

Reference:

YMPAT 103863

To appear in:

Microbial Pathogenesis

Received Date: 28 August 2019 Revised Date:

6 November 2019

Accepted Date: 8 November 2019

Please cite this article as: D P, Mycoplasma pneumoniae-related hepatitis in children, Microbial Pathogenesis (2019), doi: https://doi.org/10.1016/j.micpath.2019.103863. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Ltd.

Mycoplasma pneumoniae-related hepatitis in children Poddighe D.

-

Poddighe Dimitri, Department of Medicine, School of Medicine, Nazarbayev University (010000, Astana, Kazakhstan)

ORCID number: Dimitri Poddighe (0000-0001-6431-9334)

Author contributions: Dimitri Poddighe conceived and wrote the manuscript; Vitaliy Sazonov contributed in the literature research and data collection.

Funding: N/A Conflict of Interest statement: The authors have no conflict of interest to declare Correspondence: Dimitri Poddighe, M.D., Specialist in Pediatrics, Med. M.Sc.; Department of Medicine, School of Medicine, Nazarbayev University, Kerei-Zhanibek Str. 5/1, Nur-Sultan City 010000 (KZ), Astana 010000, Kazakhstan. [email protected]. Phone: 2679413.

+7 (700)

ABSTRACT Mycoplasma pneumoniae (M. pneumoniae) is a small bacterium characterized by the absence of cell wall. It is a human pathogen causing upper and lower respiratory infections, both in adults and children. However, it is also considered to be implicated in the pathogenesis of several types of extra-respiratory diseases, including gastrointestinal disorders. The liver involvement in children during or after M. pneumoniae infections is analyzed and discussed in this review. Through a systematic literature search, it is evidenced that M. pneumoniae is not infrequently associated with alteration of liver function, but rarely causes acute and severe hepatitis in children. M. pneumoniae should be considered among the unusual causes of acute hepatitis in children, whenever the most common hepatotropic viruses have been excluded. The pathogenesis of M. pneumoniae-related hepatitis is likely to be immune-mediated: both the innate and adaptive immune responses may play a fundamental role. However, the exact pathological mechanisms have to be elucidated yet. Further clinical studies are needed in order to understand the actual relevance of this microorganism in liver disease and its pathogenesis.

Key Words: Mycoplasma pneumoniae; extra-pulmonary manifestations; hepatitis; cholestasis; children; immune-mediated disorders.

INTRODUCTION Mycoplasma pneumoniae (M. pneumoniae) is taxonomically classified into Mollicutes class, which includes gram-negative bacteria characterized by the absence of cell wall outside the cell membrane. They are the smallest (in terms of cellular size and genome length) free-living and self-replicating bacteria. M. pneumoniae is well known as a cause of upper and lower respiratory infections in both children and adults. [1] In human infections, it acts as an intracellular pathogen, as it exploits the metabolic resources of the host cells to survive and replicate and, importantly, this localization into the cell may help it to evade the immune response. Actually, M. pneumoniae can adhere to the host cell membrane through a terminal tip structure (serving as cyto-adherence organelle) and eventually can penetrate intracellularly. Indeed, the available evidences suggested that the cell invasion by this microorganism is not necessary to produce cytotoxic effects in the host cells: the cellular adherence by itself seems to induce cilia deterioration and biochemical impairments in glucose metabolism, amino-acids uptake, and protein synthesis; moreover, oxygen radicals produced by M. pneumoniae and/or host cell upon its endocytosis, may cause cell damage and structural deterioration anyway. [2-3] Tracheobronchitis is considered the most common clinical manifestation of M. pneumoniae infection; however, several respiratory conditions have been associated with this infection, including pneumonia. In this regard, M. pneumoniae is estimated to be responsible of at least 4 to 8% of community-acquired bacterial pneumonias during periods of endemicity, but it may be implicated up to 20-40% of cases in the general population during epidemics. However, the clinical presentation of M. pneumoniae respiratory infections is often consistent with an undifferentiated respiratory infection (with a mild and self-limiting clinical course) and can be pauci-symptomatic. As a consequence, many isolated cases (and even small clusters and outbreaks) of M. pneumoniae infections are likely to be undetected and may be eventually diagnosed, because of the occurrence of extra-pulmonary manifestations. [4-6] M. pneumoniae-related extra-pulmonary diseases (MPEPDs) represent a heterogeneous group of diseases. Most MPEPDs are often characterized by skin (urticarial rashes, multiform erythema, Stevens-Johnson syndrome, nodular erythema, etc.) and articular (reactive arthritis/arthralgia) manifestations, but a wide range of neurological, cardiovascular, gastrointestinal, hematologic disorders have been correlated to M. pneumoniae. [7-8] Actually, the most common

gastrointestinal manifestations during M. pneumoniae infection are nausea, vomiting, diarrhea and abdominal pain, which could be often due to other concomitant viral agents and/or antibiotic therapy. [9] However, a number of different gastrointestinal diseases/manifestations have been described as MPEPDs. [7-9] Here, we performed a systematic literature research, in order to specifically discuss the occurrence of hepatitis as MPEPDs in children.

SEARCH STRATEGY A systematic search in MEDLINE/PubMed and Scopus databases was carried out, retrieving all original

English-language

publications

(case–control

studies,

cross-sectional

studies,

retrospective cohort studies, case-reports, case series) describing pediatric patients developing hepatitis related to M. pneumoniae infection. In detail, the search term “hepatitis” OR “liver” AND “Mycoplasma pneumoniae” OR “M. pneumoniae” were used, in order to lose as less related articles as possible: 157 and 181 items have been retrieved from MEDLINE/Pubmed and Scopus, respectively Thus, after the elimination of duplicated articles, the abstracts of 107 papers were analyzed and all articles describing pediatric cases have been extracted with full-text. Finally, these articles have been considered for discussion in this review and, in detail, the available case reports and small case series providing detailed clinical descriptions of patients younger than 18 years, have been specifically analyzed. In detail, the articles published since 2000 have been considered, whereby information about the specific serology for M. pneumoniae is provided in the materials and methods.

RESULTS This systematic (medical literature) research about M. pneumoniae-related hepatitis provided 6 pediatric case reports or small case series, accounting for 8 patients in total, as showed in Table 1. [10-15] Additionally, 3 original articles (1 retrospective study, 2 prospective studies) assessing liver function in children with M. pneumoniae infection, has been retrieved, discussed and schematically summarized in Table 2. [16-18] Even though this review focused on the pediatric population, the research output yielded also adult-related articles, which have been used in term of comparison, in a functional way to our discussion.

DISCUSSION

Liver involvement, often accompanied with cholestatic features, has been reported in association to several infectious diseases whereby the gastrointestinal disorder does not present as the main or initial clinical manifestation. [19-23] Clinically evident or subclinical hepatitis have been even reported as a consequence of M. pneumoniae infection, especially in adults. According to recent articles discussing this clinical issue, the number of case reports and original articles describingthe occurrence of acute hepatitis in adults during or after M. pneumoniae infections, is greater than those regarding the pediatric population. [24-25] Indeed, Romero-Gomez M et al. mentioned a significant frequency of liver abnormalities (5 out of 35 patients) in their case series of respiratory M. pneumoniae infection [26] and, more recently, Shin SR et al. described acute hepatitis associated with M. pneumoniae infection in around 21% of their retrospective cohort including 163 patients. [27] Again, Daxboeck F et al. detected elevated serum ALT levels in 36.4% of 33 adult patients with M. pneumoniae community acquired pneumonia (CAP), which was significantly higher than in their control group (10.5%), including 38 patients with Streptococcus pneumoniae CAP. [28] Even though M. pneumoniae-related diseases seem to be less frequent, the first description in children dated back to 1988: Squadrini F et al. reported that almost 50% of 61 children admitted with M. pneumoniae CAP showed evidence of “moderate or isolated cholestasis”. [29] However, since then, only 8 children were clearly described with acute hepatitis during M. pneumoniae infections in absence of other potential and probable causes (according to the authors of these case reports), and only 3 pediatric studies could be retrieved. [10-18] In this latter group of scientific contributions, the largest study was published by Kim KW et al. in 2015. These authors prospectively examined the clinical features of 1,044 pediatric patients (aged 1 to 16 years), hospitalized with a diagnosis of M. pneumoniae respiratory infection, in a Korean medical center and during a 6-year period. Among them, 80 children showed altered liver function tests, in presence of negative serology for other common infectious agents causing hepatitis (e.g. HAV, HBV, HCV, EBV, CMV) and, importantly, before starting the antibiotic therapy. According to this case series, the prevalence of hepatitis during M. pneumoniae infection in children, resulted to be 7.7%. Most patients normalized the liver function in 7-10 days and, anyway, all cases got the liver function completely restored within 4 weeks. In detail,

the liver function tests were mildly to moderately altered (AST: 100.65±20.34; ALT: 118.73±19.43) and only 4 patients were reported as having AST and/or ALT levels greater than 500 IU/L. Moreover, gastrointestinal symptoms resulted to be quite infrequent and, thus, the hepatic involvement was almost always asymptomatic. [16] Recently, Jujaray D et al. published a retrospective study, including 105 children with M. pneumoniae CAP (study group) and 55 children with CAP unrelated to this microorganism (control group). They reported a statistically significant difference between the groups, as regards the rate of liver enzymes abnormalities and their mean increase. As regards ALT specifically, they noticed an increase above the reference range in 57% children with M. pneumoniae infections (vs. 12% in children with etiologically different CAP); however, the retrospective nature of this study must be taken in account and, therefore, these conclusions should be carefully considered. [18] Before considering the third original article by Fan Q et al., which is more focused on the immunologic pathogenesis of hepatic MPEPDs, [17] it is appropriate to discuss all those papers describing individual patients whereby the liver involvement could be reasonably attributed to M. pneumoniae infection, as summarized in Table 1. However, the clinical background and context described in these pediatric cases seem to be quite different from the aforementioned studies, since most patients (5 out of 8 children) were specifically investigated for extrarespiratory manifestations, both gastrointestinal (e.g. abdominal pain) and/or non-gastrointestinal (e.g. lymphadenopathy, thrombocytopenia). Briefly, almost all patients showed a systemic inflammatory response/disease leading to persistent and/or high fever, but only one was diagnosed with a specific immune-mediated disorder, namely Kawasaki disease. Compared to the cohort of children described in the aforementioned original articles, all these case-report patients showed a much more significant liver dysfunction: six out of 8 patients having AST and/or ALT levels greater than 2,000 IU/L, along with a parallel alteration of the coagulative parameters (e.g. PT, aPTT). [10-15] Considering the small number of patients and the heterogeneity of the clinical manifestations of these children diagnosed with M. pneumoniae-related gastrointestinal diseases and, in detail, acute hepatitis, the pathogenesis of this extra-pulmonary complication is completely elusive, even though it is supposed to be immune-mediated. Some authors speculated that M. pneumoniae may directly infect epithelial cells in the liver, but such an occurrence has not been

demonstrated, yet; or the liver localization of M. pneumoniae might induce a local production of inflammatory cytokines and/or vascular occlusion-type damage. Others suggested the potential contribution of cross-reacting autoantibodies and immune complexes triggered by M. pneumoniae via molecular mimicry. [7-8,30-31] However, the immune-pathogenesis appears to be much more complex than this and could rely upon a combination of innate and adaptive immune responses. Recently, Fan Q et al. investigated some immunological and inflammatory molecules (including some TLRs, TIM proteins and cytokines) in 59 children with M. pneumoniae pneumonia. Tool-like receptors (TLRs) are key molecules for the recognition of pathogen associated molecular patterns (PAMPs) and, thus, play a fundamental role in the innate immunity, whereas TIMs (T cell immunoglobulin and mucin domain) proteins can regulate some aspects of the adaptive immune response. [17] In detail, TIM-3 is especially expressed on Th1 cells, even though it has also been found on CD8+ T, Th17, Treg cells, in addition to monocytes, dendritic cells, mast cells and microglia. Therefore, TIM-3 has been implicated in the mechanisms of immunological tolerance and, thus, in the pathogenesis of several immune-mediated diseases. Interestingly, TIM-3 can modulate the immune responses of T cells and was associated with immune exhaustion during (viral) infections: indeed, it may be an important determinant of effector versus memory T-cell differentiation, impacting on the clinical course and/or persistence of the infection. Actually, very recent studies suggested that TIM-3 may play a role also in the immunologic response to Mycobacterium tuberculosis and Listeria monocytogenes infections, which are both considered mainly intra-cellular pathogens, like M. pneumoniae. [32-33]Fan Q et al. investigated 59 patients with M. pneumoniae infection and, in detail, 21 of them developed alterations of liver function tests; moreover, they also considered 30 healthy children matched for sex and age. These authors showed a statistically significant increase of TLR2 mRNA blood titers in children with M. pneumoniae hepatitis, compared to children without any hepatic involvement and control group. Moreover, also TIM3 protein mRNA in blood was increased and correlated with ALT plasmatic levels. Therefore, both innate and adaptive immune mechanisms may play a specific role in M. pneumoniae-related hepatic damage. [17]

CONCLUSION

Acute hepatitis (with or without cholestatic features) can be included in the heterogeneous group of M. pneumoniae-related extra-pulmonary diseases. Even though most articles are related to adult patients, M. pneumoniae should be considered among the unusual causes of acute hepatitis in children, whenever the most common hepatotropic viruses have been excluded through a careful diagnostic work-up. The pathogenesis of M. pneumoniae-related hepatitis is likely to be immune-mediated: both the innate and adaptive immune responses may play a fundamental role. However, the exact pathological mechanisms have to be elucidated yet; further clinical studies are needed in order to understand the actual relevance of this microorganism in liver disease and its pathogenesis.

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7- Narita M. Classification of extrapulmonary manifestations due to Mycoplasma & pneumoniae infection on the basis of possible pathogenesis. Front Microbiol 2016; 7:23 [PMID: 26858701 DOI: 10.3389/fmicb.2016.00023] 8- Poddighe D. Extra-pulmonary diseases related to Mycoplasma pneumoniae in children: recent insights into the pathogenesis. Curr Opin Rheumatol 2018; 30(4):380-387. [PMID: 29432224 DOI: 10.1097/BOR.0000000000000494] 9- Søndergaard MJ, Friis MB, Hansen DS, Jørgensen IM. Clinical manifestations in infants and children with Mycoplasma pneumoniae infection. PLoS One 2018; 13(4):e0195288. [PMID: 29698412 DOI: 10.1371/journal.pone.0195288] 10- Narita M, Yamada S, Nakayama T, Sawada H, Nakajima M, Sageshima S. Two cases of lymphadenopathy with liver dysfunction due to Mycoplasma pneumoniae infection with mycoplasmal bacteraemia without pneumonia. J Infect 2001; 42(2):154-156. [PMID: 11531323 DOI: 10.1053/jinf.2000.0769] 11- Chen CJ, Juan CJ, Hsu ML, Lai YS, Lin SP, Cheng SN. Mycoplasma pneumoniae infection presenting as neutropenia, thrombocytopenia, and acute hepatitis in a child. J Microbiol Immunol Infect 2004; 37(2):128-130. [PMID: 15181497] 12- Chang JH, Kwon YS, Kim BK, Son BK, Lee JE, Lim DH, Kim SK, Kim JM, Kang SK. A case of acute hepatitis with Mycoplasma pneumoniae infection and transient depression of multiple coagulation factors. Yonsei Med J 2008; 49(6):1055-1059. [PMID: 19108034 DOI: 10.3349/ymj.2008.49.6.1055] 13- Murayama A, Abukawa D, Watanabe K, Umebayashi H, Inagaki T, Miura K, Takeyama J. Severe liver dysfunction in patients with Mycoplasma pneumoniae infection. Pediatr Int 2010; 52(2):e105-107. [PMID: 20500455 DOI: 10.1111/j.1442-200X.2010.03084.x] 14- Park SJ, Pai KS, Kim AR, Lee JH, Shin JI, Lee SY. Fulminant and Fatal Multiple Organ Failure in a 12-Year-Old Boy with Mycoplasma pneumoniae Infection. Allergy Asthma Immunol Res 2012; 4(1):55-57. [PMID: 22211173 DOI: 10.4168/aair.2012.4.1.55] 15- Song WJ, Kang B, Lee HP, Cho J, Lee HJ, Choe YH. Pediatric Mycoplasma pneumoniae Infection Presenting with Acute Cholestatic Hepatitis and Other Extrapulmonary Manifestations in the Absence of Pneumonia. Pediatr Gastroenterol Hepatol

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2017;

10.5223/pghn.2017.20.2.124]

20(2):124-129.

[PMID:

28730137

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26- Romero-Gómez M, Otero MA, Sánchez-Muñoz D, Ramírez-Arcos M, Larraona JL, Suárez García E, Vargas-Romero J. Acute hepatitis due to Mycoplasma pneumoniae infection without lung involvement in adult patients. J Hepatol 2006; 44(4):827-828. [PMID: 16483682 DOI: 10.1016/j.jhep.2005.12.014] 27- Shin SR, Park SH, Kim JH, Ha JW, Kim YJ, Jung SW, Kim JB, Lee MS, Park CK. Clinical characteristics of patients with Mycoplasma pneumoniae-related acute hepatitis. Digestion 2012; 86(4):302-8. [PMID: 23095373 DOI: 10.1159/000341401] 28- Daxboeck F, Gattringer R, Mustafa S, Bauer C, Assadian O. Elevated serum alanine aminotransferase (ALT) levels in patients with serologically verified Mycoplasma pneumoniae pneumonia. Clin Microbiol Infect 2005; 11(6):507-150. [PMID: 15882205 DOI: 10.1111/j.1469-0691.2005.01154.x] 29- Squadrini F, Lami G, Pellegrino F, Pinelli G, Bavieri M, Fontana A, Bisetti A. Acute hepatitis complicating Mycoplasma pneumoniae infection. J Infect 1988; 16(2):201-202. [PMID: 3127476] 30- Poddighe D, Brambilla I, Marseglia GL. Basophils activated via TLR signaling may contribute to pathophysiology of type I autoimmune pancreatitis. J Gastroenterol 2018; 53(6):791-792. [PMID: 29663078 DOI: 10.1007/s00535-018-1456-0] 31- Berg CP, Kannan TR, Klein R, Gregor M, Baseman JB, Wesselborg S, Lauber K, Stein GM. Mycoplasma antigens as a possible trigger for the induction of antimitochondrial antibodies in primary biliary cirrhosis. Liver Int 2009; 29(6):797-809. [PMID: 19638108 DOI: 10.1111/j.1478-3231.2008.01942.x] 32- He Y, Cao J, Zhao C, Li X, Zhou C, Hirsch FR. TIM-3, a promising target for cancer immunotherapy. Onco Targets Ther 2018; 11:7005-7009. [PMID: 30410357 DOI: 10.2147/OTT.S170385] 33- Banerjee H, Kane LP. Immune regulation by Tim-3. F1000Res 2018; 7:316. [PMID: 29560265 DOI: 10.12688/f1000research.13446.1]

Table II. Original articles describing case series of children with M. pneumoniae-related acute hepatitis in children.

Authors

Age

Sex

Number of cases of hepatitis

CRP

ALT

AST

Normalization

(M:F ratio)

Number of patients (affected with MP)

(year, type of study)

(mean, range)

(mg/l)

(U/l)

(U/l)

(Liver enzymes)

Kim KV et al.

5.5

1.7:1

1,044

80 (7.7%)

5.39±5.67

118.73±19.43

100.65±20.3 4

(2015, prospective)

0.8-16

Fan Q et al.

3.8

(2015, prospective)*

1-7

Jujaray D et al.

4.5

(2018, retrospective)

1-9

IgM (ELISA)

Antibiotic Treatment

Normalization

Ref.

(Liver enzymes)

Roxithromycin

7.51±4.57

[16]

(2 weeks) 1.2:1

59

21

n/a

> 40 U/l

n/a

IgM and IgG (complement fixation test)

n/a

n/a

[17]

1:1

105

66 (62.8%)

16.8±8.58

39.3±22.3**

32.3±12.9**

IgM (ELISA)

Macrolides

10-day follow-up:

[18]

(average: 5 days)

normal in 46 (out of 60)

Abbreviations: ALT, alanine transaminase; AST, aspartate aminotransferase; n/a, not available; CRP, C-reactive protein; ELISA, enzyme-linked immunosorbent assay; MP: Mycoplasma pneumoniae. *This study aimed to perform immunological analysis in children developing MPEPDs, rather than to describe clinical and epidemiological aspects. ** AST and ALT levels were measured by an enzyme-immunoassay method with upper limits of reference ranges of 23 U/l and 19 U/l, according to what reported by the authors in their materials and methods.

Table I. Case reports describing M. pneumoniae-related acute hepatitis in children. Authors

Age

(year, type of article)

(years)

Sex

Liver Function Tests (ALT, AST)

Narita M et al.

10

M

240, 129

(2001, case report)

5

M

1488, 2375

Chen CJ et al.

4

F

5

Murayama A et al.

Associated symptoms or diseases

GGT

Coagulative Panel

CRP

Test

Antibiotic Treatment

Outcome

Ref.

(Normal Liver Enzymes)

(PT, aPTT)

- fever, lymphadenopathy (the 2nd case was diagnosed with KD)

n/a

n/a

3

Minocycline

day: 20

83.8

Microparticle agglutination IgM-titer

n/a

n/a

Clarithromycin

day: 25

998,1131

- neutropenia, thrombocytopenia

172

normal

n/a

IgM (ELISA)

None

day: n/a

[11]

M

2725, 2985

- fever, cough, abdominal pain (pneumonia)

n/a

15.6, 82.1

1.32

IgM (ELISA)

Azithromycin

day: 14-15

[12]

8

F

3490, 6020

- fever, cough (pneumonia)

n/a

14.7, 32

2.78

Minocycline

day:24-26

[13]

12.2, 25.7

0.74

Micro-particle agglutination IgM titer

(2010, case report)

2

F

2126, 3849

Minocycline

day:19-21

Park SJ et al.

12

M

482,2023

24.9, 123

17.50

IgM and IgG

Clarithromycin

exitus

[14]

Clarithromycin

day: 22

[15]

[10]

(2004, case report) Chang JH et al. (2008, case report)

(2012, case report) Song WJ et al. (2017, case report)

9

M

1079, 2689

- fever, abdominal pain (multiple organ failure))

106

-thrombocytopenia fever, abdominal pain.

69

n/a 18.5, 95.5

2.21

IgM and IgG (ELISA)

Abbreviations: ALT, alanine transaminase [n.v. 15-55 U/l]; AST, aspartate aminotransferase [n.v. 10-45 U/l]; KD, Kawasaki disease; n/a, not available; GGT, gamma-glutamyl transferase [n.v. 5-35 U/l]; PT, prothrombin time [n.v. 12.6-14.9 sec.]; aPTT, activated partial thromboplastin time [n.v. 29.1-41.9 sec.]; CRP, C-reactive protein [n.v. 0-2 mg/l]; ELISA, enzyme-linked immunosorbent assay.

Highlights - M. pneumoniae has been implicated in a variety of extra-pulmonary diseases (MPEPDs). - A number of different gastrointestinal diseases/manifestations have been described as MPEPDs, including hepatitis. - Compared to adults, there are much fewer reports of M. pneumoniaerelated hepatitis. - The pathogenesis of M. pneumoniae-related hepatitis is supposed to involve both innate and adaptive immune mechanisms. - Further clinical studies are needed to better understand the actual relevance of M. pneumoniae in liver disease and its pathogenesis