Drug-Induced vs. Viral Maculopapular Exanthem—Resolving the Dilemma
Round 1
Reviewer 1 Report
This is a nice review about clinical and histopathological comparison between drug and viral maculopapular exanthem. The contents are well-organized and provide useful information.
There are some typesetting errors, for example, maculopapularexanthem (several pages), withspongiosisbeing (page 4), commonesthistopathological (page 5), maculopapularexanthems (page 6), and many spaces are lacking before left parenthesis.
Author Response
Response to Reviewer 1
This is a nice review about clinical and histopathological comparison between drug and viral maculopapular exanthem. The contents are well-organized and provide useful information.
There are some typesetting errors, for example, maculopapularexanthem (several pages), withspongiosisbeing (page 4), commonesthistopathological (page 5), maculopapularexanthems (page 6), and many spaces are lacking before left parenthesis.
Thank you sir, we appreciate your suggestions. We have made the necessary typesetting corrections in the entire manuscript. These changes have been highlighted in the manuscript.
Author Response File: 
Author Response.docx
Reviewer 2 Report
The paragraph on IHC findings was a bit confusing .
Try to convey the relevant points in a more simplified, short sentences.
Author Response
Response to Reviewer 2
The paragraph on IHC findings was a bit confusing .
Try to convey the relevant points in a more simplified, short sentences.
Thank you sir, we appreciate your suggestions. We have tried to modify the section on Immunohistochemical techniques as per your suggestions. These changes have been highlighted in the manuscript. Please find below the modified section.
Immunohistochemical techniques
Attempts have been made to histologically diagnose drug-induced exanthem and differentiate from viral exanthem using immunohistochemical techniques. Using CD4, CD8, FAS ligand, IL-5 and Eotaxin markers, differentiation between the two entities have been made. Serum and tissue FAS–ligand is elevated in most cases of maculopapular drug exanthem, but it is normal in viral exanthem (18,19).
IL-5 and eotaxin cause activation and recruitment of eosinophils and thereby contribute to the development of skin inflammation in drug-induced maculopapular exanthems. Yawalkar et al performed IHC analysis of the dermal mononuclear infiltrate in drug exanthem biopsies and compared it with normal skin of control subjects. IL-5 expression was mainly found among mononuclear cells of the inflammatory infiltrate. Immunoreactivity for eotaxin, RANTES (Regulated on Activation, Normal T Cell Expressed and Secreted), IL-8 and to a lesser extent, monocyte chemotactic protein-3 was also seen in the mononuclear cells. In addition, resident cells (i.e, endothelial cells and keratinocytes) also demonstrated positivity for eotaxin, RANTES and IL-8 (6).
The chronic dermal inflammatory infiltrate in a drug exanthem is primarily composed of CD3+ T cells. Within T-lymphocytes, CD4+T cells are noted predominantly in perivascular location, whereas equal proportions of CD4+ and CD8+ T cells are located at the dermoepidermal junction and in the epidermis (20). Upto 20% of the infiltrating T cells in drug-induced maculopapular exanthem express perforin and granzyme B which are important mediators of cell mediated cytotoxic reaction. In addition to T cells, eosinophils are also present within the dermal infiltrate. These may also contribute to the generation of tissue damage by the release of various toxic granule proteins, such as eosinophilic cationic protein, major basic protein and eosinophil peroxidase.
Bellini et al performed IHC evaluation of the cutaneous cytokine expression in maculopapular eruptions (36 patients- drug exanthem, 30 patients- viral or bacterial exanthem). They also noted a higher number of IL-5-, perforin- and granzyme B positive cells in drug- induced exanthem. The distribution of cytokine positivity gradually decreased with increase in the duration between the onset of the exanthem and timing of the biopsy. In contrast, FAS-L, IL-10, and INF-ɣ were expressed in biopsies from both groups (~40%), so their levels were non-discriminatory. However, FAS-L levels were disproportionately raised (~90%) in those patients with amoxicillin- induced exanthem, so it may represent a differentiating tool only for amoxicillin-induced rash (21).
Besides drug exanthem, IHC may help confirm a suspicion of viral exanthem. eg. staining of skin biopsies with anti-measles virus (MeV) nucleoprotein and anti-MeV phosphoprotein can be of great value in confirming the diagnosis of this exanthem (15).
Author Response File: Author Response.docx
