What Is Lymphocytic Oesophagitis

The importance of eosinophils and neutrophils infiltrating oesophageal squamous epithelium as markers for reflux, eosinophilic oesophagitis, and infection are well entrenched, although traditionally less attention has been paid to lymphocytes.

Small numbers of lymphocytes are normally seen in oesophageal epithelium including CD4 helper and CD8 positive cytotoxic lymphocytes.

However, isolated increases in lymphocytes in the oesophageal epithelium, outside the context of entities such as lichen planus and graft versus host disease, have been less well recognised until recently.

The criteria for a diagnosis of lymphocytic oesophagitis, where lymphocyte numbers are markedly increased with few or no eosinophils, is not strictly defined since this is still a reaction pattern and not a specific diagnosis per se, and thresholds vary from study to study. The strictest definition requires at least 50 intraepithelial or peripapillary lymphocytes per HPF with few or no granulocytes.

The term lymphocytic oesophagitis was originally coined in 2005 by Rubio et al to describe a histological reaction pattern in the oesophagus of a series of 20 patients. The patients had a high number of peripapillary lymphocytes and a lack of neutrophils and eosinophils.

The papillae are projections of lamina propria, containing capillaries, which project a short distance into the epithelium of the normal oesophagus. The pattern of lymphocytic oesophagitis showed an association with Crohn’s disease, though not a completely specific one. Of the 20 patients, 11 were age 17 or younger and of these, eight (40%) had Crohn’s disease; 20% had manifestations of reflux and the remainder a mixture of conditions including coeliac, gastroduodenitis, and Hashimoto’s thyroiditis.

A similar study of 40 patients in 2008 was unable to confirm these findings.

Looking at it from a different angle, Ebach et al studied 60 paediatric patients with known Crohn’s disease and control groups and found an association. Lymphocytic oesophagitis  which was found in 28% of patients with Crohn’s disease (mean age 13.3) but in only 2/30 patients with ulcerative colitis.

A 2014 study of 580 paediatric patients confirms the association with Crohn’s disease, but also shows the non-specific nature of lymphocytic oesophagitis. This found 31 patients with lymphocytic oesophagitis and 49 with Crohn’s disease. Six of the 31 lymphocytic oesophagitis patients (19%) and 43 of the 514 non- lymphocytic oesophagitis patients (8.4%) had Crohn’s disease. The remaining lymphocytic oesophagitis patients had other diagnoses with no significant clinical correlates. Conversely, lymphocytic oesophagitis was identified in 12.2% of the patients with Crohn’s disease. Thus, there were still more lymphocytic oesophagitis patients without Crohn’s disease than with Crohn’s disease.

In adults, the association with Crohn’s disease is not seen but there appears to be an association with oesophageal dysmotility. A 2011 study of over 129,000 patients from a large outpatient private GI pathology lab service revealed lymphocytic oesophagitis in only 119 patients, 60% female.

Most patients had symptoms of oesophageal disease such as dysphagia or odynophagia, with dysphagia being the most common complaint, and around 20% complaining of reflux. Endoscopically, around a third of patients were suspected of having eosinophilic oesophagitis (including ‘feline oesophagus’ where the oesophagus has rings resembling that of a cat’s oesophagus), around 20% were normal, 18% had features suggestive of reflux, and 10% had stricture. However, none had Crohn’s disease or an association with Helicobacter gastritis. Although this study drew no firm conclusions as to the nature of lymphocytic oesophagitis in adults, the prevalence of dysphagia as a presenting complaint, and the number of patients with findings reminiscent of eosinophilic oesophagitis were noted.

The association with dysmotility is enhanced by the finding that in adult patients, a lymphocytic oesophagitis with a complete absence of granulocytes was mostly seen in older female patients who presented with dysphagia and had an oesophageal motility disorder.

CD4- and CD8-predominant lymphocytic oesophagitis occurs with roughly equal frequency. However, patients with CD4-predominant lymphocytic oesophagitis are more likely to be female (71%), and have a motility disorder (90% of those tested). This suggests a new entity of ‘dysmotility lymphocytic oesophagitis’.

In summary, the reaction pattern of lymphocytic oesophagitis appears to be real, however, the term cannot be used as a wastebasket and true increased numbers of intraepithelial lymphocytes must be seen.

Clinical and endoscopic correlations determine the significance of any pathologist comment on increased numbers of lymphocytes in the epithelium.


General Practice Pathology is a new regular column each authored by an Australian expert pathologist on a topic of particular relevance and interest to practising GPs.

The authors provide this editorial, free of charge as part of an educational initiative developed and coordinated by Sonic Pathology.

New Virus Putting Babies in Hospital

In the last few months of 2017, over 200 Australian infants were hospitalised due to infection with the little known human parechovirus, say Australian public health experts in the latest issue of the MJA.

The infected infants were admitted with conditions such as severe sepsis and meningoencephalitis. Less common presentations included acute abdomen from intussusception, pseudo-appendicitis and even bowel perforation.

According to the MJA review, parechovirus was originally included under the echovirus umbrella back in the 1960’s, but became an entity in its own right, in the 90’s. There are close to 20 genotypes of the virus, but to date only three (genotypes 1,3 and 6) are thought to cause human disease.

For the most part parechovirus causes mild gastro or respiratory tract infections. However, one of the genotypes – genotype 3  – has been found to be considerably more dangerous, especially in babies.

“It is now recognised as a leading cause of sepsis-like illness and central nervous system infection, particularly in young infants,” the review authors wrote.

The first ‘epidemic’ in Australia of this parechovirus genotype occurred in spring-summer of 2013-2014. Another outbreak occurred two years later – the spring-summer of 2015-2016. This most recent ‘epidemic’ appeared to start in Victoria last August and has now spread nationwide with over 200 infants hospitalised to December.

For GPs, the key presenting features to be on the lookout for are fever, irritability and sepsis-like illness – which aren’t very specific.

More helpfully – while not all infected children will have a rash, if the presenting infant is ‘red, hot and angry’ -think parechovirus, the authors recommend.

Infants younger than three months are most likely to be hospitalised and, of course, really young infants (less than a month old) are at greatest risk of complications so should be sent to hospital earlier rather than later.

To diagnose this infection, specific PCR testing needs to be requested of either stool or CSF. Just testing for enteroviruses will not be sufficient.

Unfortunately, as yet there is no specific treatment for parechovirus. Given the presentation is the same as that of bacterial sepsis, the review authors suggest antibiotics be commenced until cultures come back negative and bacterial infection is excluded. But other than that, the treatment is mainly supportive and close monitoring and perhaps hospitalisation is required.

Of particular concern are a number of studies that suggest infection that is severe enough to require the child be hospitalised is associated with high risk of neurological sequelae.

As a consequence, the authors recommend that all children hospitalised with parechovirus be followed up with a paediatrician – at least until they start school- ‘to monitor development and learning, and manage complications including seizures.’

In terms of a vaccine, there is not one yet developed against parechovirus. They suggest research efforts should focus on developing vaccines that target the most pathogenic genotypes of a virus rather than trying to eradicate the entire genus such as has occurred in China with the vaccine against EV71 – a specific enterovirus that causes a complicated hand, foot and mouth disease.

Regardless the need to find a vaccine is a priority.

“The high morbidity in young children provides a strong case for prevention,” they concluded.

Ref:

MJA doi: 10.5694/mja18.00149

Focus on dermatophytes

Diagnosing and treating fungal nail, scalp and skin infections

The Process:

Once specimens are received in the laboratory, microscopy is performed.

An interim report is then released. Specimens are then set up on specialised agar containing antibiotics and cycloheximide to inhibit the growth of bacteria and saprophytic fungi. Cultures are incubated at 28°C for three weeks.

If microscopy is positive (M+) and no pathogen (C-) has grown in the interim, specimens are held an extra week. Infrequently, where microscopy and culture of nail scrapings is negative and the diagnosis is still suspected, nails can be examined for fungal elements using special stains.

Results:

Specimen types have been subdivided into three anatomical categories (nails, hair and skin) based broadly on the three clinical presentations of onychomycosis, tinea capitis, and tinea corporis/ cruris/pedis.

Onychomycosis refers to fungal infections of the nails and includes tinea unguium caused by dermatophytes but also non-dermatophyte fungi and yeasts, predominantly Candida spp.

Negative laboratory report:

A common reason for negative microscopy and /or culture is an incorrect clinical diagnosis. More than 50% of dystrophic nails do not have a fungal cause, so it is important to establish a correct laboratory diagnosis before treating a patient with an antifungal agent.

Other reasons for false negative results include sampling variation associated with an inadequate specimen and/or splitting the sample to perform microscopy and culture; the presence of nonviable hyphae in the distal portion of the nail; uneven colonisation of the nail by fungus; and overgrowth by contaminant saprophytic fungi.

Careful re-collection to obtain sufficient material may be necessary to confirm negative results.

Nails:

The analysis of nail specimens from the hands and feet.
Fingernails:
Of 1202 specimens processed, 59% were negative by both microscopy and culture; 11% had hyphae seen on microscopy but were negative by culture; 27% of all finger and thumbnail cultures grew a yeast, predominantly Candida albicans (88% of all positive nail/hand cultures).

Only 3% of all fingernail specimens grew a dermatophyte.

Toenails:

57% of 5097 toenail cultures were negative by both microscopy and culture. 22% were positive by microscopy but culture negative for reasons stated previously.

As the literature would suggest, yeast infection of toenails is rare.

Dermatophytes (20%) predominate as the main cause of onychomycosis of the lower limbs.

Transmission of these dermatophytes is usually via the feet and toe web spaces, which are the major reservoir on the human body. Onychomycosis can be regarded as the end stage of tinea pedis. Desquamated skin scales containing hyphae are shed and survive for months to years on floors and carpets.

Infrequently non-dermatophyte moulds are implicated in toenail infections such as Aspergillus. There is some uncertainty as to the significance of these cultures, and repeat culture may be indicated.

Treatment options:

With tinea unguium, topical treatment is successful only with surgical removal of the nail combined with oral therapy.

First-line treatment for all types of nail tinea consists of:

1. terbinafine (child < 20 kg: 62.5 mg; 20 to 40 kg: 125 mg) 250 mg orally, daily for six weeks for fingernails and 12 weeks for toenails or (if terbinafine is not tolerated)

2. itraconazole 200 mg orally, twice daily for seven days every month for 2-4 months or

3. fluconazole 150 to 450 mg orally, once weekly for 12 to 52 weeks.

Successful management of candidiasis of the nail requires removal of risk factors e.g. water immersion.

Tinea capitis:

Of 414 hair samples submitted over this period, 329 (80%) were negative by both microscopy and culture.

Dermatophytes isolated include M. canis (46%); T. tonsurans (42%); M. gypseum (5%); T. mentagrophytes (5%) and T. rubrum (2.5%). This condition afflicts predominantly prepubertal children.

Clinically it can present as alopecia or a more inflammatory lesion (kerion). It is noteworthy that T. tonsurans, an anthropophilic fungus, is emerging as a common cause of tinea capitis in children and spreads easily from child to child.

Treatment options:

Tinea capitis often requires oral therapy to eradicate the infection. Treatment options include

1. griseofulvin fine particle (child: 20 mg/kg up to) 500 mg orally, daily for 4-8 weeks, or

2. terbinafine (child< 20 kg: 62.5 mg; 20 to 40 kg: 125 mg) 250 mg orally, daily for four weeks.

Tinea corporis/cruris/pedis:

Of the 7406 specimens received from skin sites, 73% were both microscopy and culture negative; 5% were positive only by microscopy.

Of the 22% culture positive specimens, 19% grew a dermatophyte and 3% a yeast.

Treatment options:

When topical treatments have failed, recommended oral therapy includes:

1. griseofulvin fine particle (child: 10 to 20 mg/kg up to) 500 mg orally, daily for at least four weeks or

2. terbinafine (child <20 kg: 62.5 mg; 20 to 40 kg: 125mg) 250 mg orally, daily for at least two weeks, depending on the response or

3. itraconazole capsules 200 mg orally, twice daily for one week for tinea of the feet or hands or

4. itraconazole capsules 200 mg orally, once daily for one week for tinea elsewhere.


General Practice Pathology is a new regular column each authored by an Australian expert pathologist on a topic of particular relevance and interest to practising GPs.

The authors provide this editorial, free of charge as part of an educational initiative developed and coordinated by Sonic Pathology.