|Year : 2015 | Volume
| Issue : 3 | Page : 627-634
Assessment of different diagnostic methods for scabies with follow-up of cellular immune response
Nashaat E Nassef, Nadia S El-Nahas, Salwa A Shams El-Din, Amira M Matar
Department of Parasitology, Faculty of Medicine, Menoufia University, Menoufia, Egypt
|Date of Submission||03-Jul-2014|
|Date of Acceptance||30-Aug-2014|
|Date of Web Publication||22-Oct-2015|
Salwa A Shams El-Din
Shebin El-kom, 32511 Menoufia
Source of Support: None, Conflict of Interest: None
The aim of the study was to compare between clinical examination, skin scraping, and histopathological examinat ion in the diagnosis of scabies and assess the role of immune cells (CD4+ and CD8+) and transforming growth factor b (TGF-b) to differentiate between scabietic and nonscabietic patients.
Scabies is a contagious skin infection characterized clinically by nocturnal pruritus and visible burrows. Scabies can occur in epidemic or endemic form. Scabies is still a major public health problem in many resource-poor regions, with prevalence rates reaching up to 10% in the general population and 50% in children. The diagnosis of scabies is challenging, leading to the observation that scabies is at once the easiest and most difficult diagnosis in medicine.
Patients and methods
Physical examination, skin scraping, and histopathological analysis were carried out for diagnosing scabies. Biopsies were taken from untreated skin lesions of patients 35 with scabies, six with psoriasis, eight with lichen planus and eight normal individuals. T-cell subsets (CD4+ and CD8+) and anti-inflammatory cytokine (TGF-b) were evaluated by immunohistochemical analysis.
Skin scraping and histopathological examination were highly specific (100%) when compared with physical examination, but the sensitivity of histopathology (88%) was superior to scraping (23%) and clinical diagnosis (85.6%). The highest number of CD4+ T cells was found in scabies and lichen planus but not in psoriasis. In contrast, the highest number of CD8+ T cells was found in psoriasis but not in scabies or lichen planus. There was statistically significant difference between scabietic and nonscabietic patients with regard to CD4+, CD8+, and CD4+/CD8+ ratio. Mild expression of TGF-b was observed in patients with scabies compared with moderate to strong expression in lichen planus and psoriasis.
Histopathology is an accurate diagnostic method but recommended in suspicious cases only as it is an invasive technique. A high number of CD4+ cells and low expression of TGF-b are characteristic of scabietic lesions.
Keywords: CD4+, CD8+, histopathology, scabies, transforming growth factor b
|How to cite this article:|
Nassef NE, El-Nahas NS, Shams El-Din SA, Matar AM. Assessment of different diagnostic methods for scabies with follow-up of cellular immune response. Menoufia Med J 2015;28:627-34
|How to cite this URL:|
Nassef NE, El-Nahas NS, Shams El-Din SA, Matar AM. Assessment of different diagnostic methods for scabies with follow-up of cellular immune response. Menoufia Med J [serial online] 2015 [cited 2020 Feb 24];28:627-34. Available from: http://www.mmj.eg.net/text.asp?2015/28/3/627/165826
| Introduction|| |
Scabies is a worldwide skin disease caused by Sarcoptes scabiei mite . The diagnosis of scabies is always challenging, leading to the observation that scabies is at once the easiest and most difficult diagnosis in medicine . Scabies can occur in epidemic or endemic form . It is one of the six major epidermal parasitic skin diseases that are prevalent in resource-poor populations, as reported in WHO . Approximately 300 million cases of scabies are reported worldwide each year .
A spectrum of diseases have been described, ranging from the most commonly recognized ordinary scabies to a rare and severely debilitating form of the disease termed crusted (Norwegian) scabies . Ordinary scabies is typically described as an intense, intractable, generalized pruritus, worse at night. The pathognomonic lesions are skin burrows. The burrow is a short serpiginous grayish, reddish, or brownish elevated line measuring 1-10 mm .
On the other hand, lichen planus is a chronic mucocutaneous inflammatory disease that frequently affects the oral mucosa of white women over 40 years old . It is characterized by purple-colored lesions, or bumps, with flat tops mostly found on the wrist, inner forearm, or ankles, but can be anywhere, with itching at the site of the rash, blisters, and thin white lines over the rash . However, psoriasis is characterized by irritated, red patches of skin. Patches are most often seen on the elbows, knees, and middle of the body, but can appear anywhere including the scalp. The skin is itchy, dry, and covered with scales, raised and thick .
The different clinical manifestations result from the type and magnitude of the innate, cellular, and humoral responses to mite proteins . It is well established that Th1-biased immune response is dominated by CD4+ T-cell populations secreting interferon-g and IL-2. Th2-biased T cells are dominant effector cells in the pathogenesis of IgE-mediated hypersensitivity and are capable of attracting, activating, and prolonging the survival of nonspecific effector cells. The Th1/Th2 concept has also been extended to CD8+ cells. T-regulatory populations inhibit the inflammatory and immune responses to the mites  by expressing IL-10 and transforming growth factor b (TGF-b) .
In contrast, in psoriasis, the characteristic T-helper (Th)-1 cytokine production by activated T cells and keratinocytes largely contributes to the induction and maintenance of psoriatic lesions . In contrast to psoriasis, activated T cells and keratinocytes in lichenplanus (LP) elicit both a Th1 and Th2 response .
The present study was carried out to compare between clinical examination, skin scraping, and histopathological examination for diagnosing scabies and assessing the role of immune cells (CD4+ and CD8+) and TGF-b to differentiate between scabietic and nonscabietic patients.
| Patients and methods|| |
This study was carried out on 49 patients with different dermatological diseases:35 scabietic patients, eight with lichen planus, and six with psoriasis. They comprised 22 male and 27 female patients. Eight (five male and three female) normal individuals with no apparent skin disease (control group) were also included in the study.
All cases (patients and controls) were subjected to detailed history taking and dermatological examination. The diagnosis of scabies was made clinically using a case definition. Thereafter, skin scrapings and microscopic examinations were performed to confirm the clinical diagnosis of scabies, and biopsies were taken for histopathological and immunohistochemical investigations.
Clinical examination and case definition
The patients were examined in a room with good light and in which privacy was guaranteed. In this room, the whole body was thoroughly examined for the presence of skin lesions typical for scabies. An individual was defined to have scabies if at least two of the following three criteria were fulfilled: presence of one or more typical lesions for longer than 2 weeks, pruritus which is intensified at night, or at least one more family member with similar lesions .
Skin scraping and parasitological examination
Skin scrapings were obtained with the edge of a sterile scalpel. The scraped material was transferred to a slide and covered with a coverslip. Slides were kept in a refrigerator until examination. Reading was performed within 3 h by means of a light microscope at ×400 magnification to detect S. scabiei mite or its by-products .
Lesions were cleaned with spirit and infiltrated with 2% xylocaine. Skin punch biopsy was taken with the help of bakers punch . Biopsy specimens were fixed in 10% formalin solution, dehydrated in graded ethanol solution and xylene, and embedded in paraffin. Paraffin-embedded blocks were sliced into 4-mm-thick sections using a microtome and stained with hematoxylin and eosin. Stained slides were microscopically examined to determine the diagnosis .
The labeled streptavidin biotin method (LSAB+) was used for immunohistochemical analysis. Skin biopsy sections of 4 mm thickness were deparaffinized, rehydrated, and then incubated with mouse anti-human monoclonal antibodies against CD4+ cells (Abcam, Cambridge, Massachusetts, USA), mouse anti-human monoclonal antibodies against CD8+ cells (Abcam), or with mouse monoclonal anti-human antibodies against TGF-b (R&D Systems Inc., Minneapolis, Minnesota, USA). This step was followed by incubation with biotinylated goat anti-polyvalent secondary antibody. Enzyme conjugate streptavidin peroxidase was applied before enzyme substrate chromogen solution. Counterstaining was done using Mayer's hematoxylin .
All cell counts were taken without reference to clinical details. The entire section was scored by observing under a binocular Olympus light microscope with a wide angle (field size of 0.274 mm and field diameter of 0.59 mm) at ×400 magnification. Positivity was considered when any cell showed brown cytoplasmic and/or membranous staining. Positively stained cells were counted per 10 high-power fields and the mean was calculated .
Positive (TGF-b) staining was identified when the cytoplasm showed brown staining, whereas negativity was considered when no staining was noticed. The staining intensity of the anti-inflammatory cytokine (TGF-b) was graded into four groups: strong and intense staining (≥50% of the cells stained), moderate staining (20-50% of the cells stained), weak staining (<20% of the cells stained), or no staining .
Results were collected, tabulated, and statistically analyzed with an IBM compatible personal computer with SPSS statistical package for the Social Science program for Windows (version 20; SPSS Inc., Chicago, Illinois, USA). All values are expressed as means ± standard deviation. The sensitivity and specificity of the diagnostic procedures were calculated as: sensitivity = TP/TP+FN, specificity = TN/TN+FP, positive predictive value (PPV) = TP/TP+FP, negative predictive value (NPV) = TN/TN+FN, and accuracy = TN+TP/TN+TP+FN+FP, where TN is true negative, TP is true positive, FN is false negative, and FP is false positive.
Qualitative data were analyzed using the χ2-test and Fishers' exact test. Normally distributed quantitative data were analyzed with the Student t-test (between two groups) and ANOVA (for more than two groups). Non-normally distributed quantitative data were analyzed using the MannWhitney U-test (between two groups) and the KruskalWallis test (for more than two groups). Pearson's correlation (r) was used to detect the association between quantitative variables. A P value less than 0.05 was considered statistically significant .
All tissues were obtained after taking consent from the patients.
| Results|| |
The data received after completion of this study clarified the following
[Table 1] shows that the 35 suspected patients (100%) were clinically diagnosed [Figure 1]a with scabies. However, skin scraping and microscopic examination showed that only seven (20%) patients harbored the parasites in their skin [Figure 1]b and 28 (80%) were free. Histopathological examination of skin biopsies showed that 30 (85.7%) patients were positive for scabies infection and five (14.28%) were negative.
|Figure 1: (a) Pathognomic lesion of scabies, burrow at the dorsum of the hand (red arrow). (b) Microscopic examination of skin scraping showing: Sarcoptes scabiei mite (red arrow) an d fecal pellets (blue arrow).|
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|Table 1: Detection of scabies infection in 35 clinically scabietic patients by different diagnostic methods|
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The comparisons for each diagnostic characteristic are shown in [Table 2]. The sensitivity of histopathological examination was higher (88.0%) than that of skin scraping (23%). Histopathological examination and skin scraping had the same specificity and positive predictive values (100%), whereas the negative predictive value of skin scraping was 14% and that of histopathological examination was 57%. The mean accuracy was 91 and 30% for histopathological examination and skin scraping, respectively.
|Table 2: Sensitivity and specificity of skin scraping and histopathological examination against clinical diagnosis in scabietic patients|
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Histopathological findings are summarized in [Table 3]. Scabies was characterized histologically by hypergranulosis, spongiosis, epidermal tunnels (burrows), and perivascular dermal infiltrate [Figure 2]b. However, LP showed more hypergranulosis, irregular elongation of rete ridges, and band-like dermal infiltrate [Figure 2]c. Psoriasis was marked by hyperkeratosis, parakeratosis, Munro microabscess, regular elongation of rete ridges (saw-tooth appearance), and perivascular dermal infiltrates [Figure 2]d.
|Figure 2: Haematoxylin and eosin staining of: (a) Normal skin section. Low power view of the cornifi ed layer (CL), epidermis (E) and dermis (D) (H&E, ×100). (b) Scabies mite infested skin biopsy showing: (a) epidermal tunnels (burrow) (b), mites inside the burrow (black arrows), denuded epidermis (d), and spongiosis (S) (H&E, ×100). (c) LP skin biopsy showing: hyperkeratosis (HK), irregular elongation of rete ridges (I), hypergranulosis (HG) and infl ammatory infi ltrate (IN F) at dermoepidermal junction (band-like infi ltrate) (H&E, ×200). (d) Psoriasis plaque biopsy in which all key features are present: hyperkeratosis with parakeratosis (Hy+P), regular elongation of reteridges(R) (saw-tooth appearance), neutrophil accumulation in stratum corneum (Munro microabscess) (M), diminished granul ar cell layer|
(DG) (H&E, ×200).
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|Table 3: Differentiation between histopathological findings in scabies, lichen planus, and psoriasis|
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Immunohistochemical findings are shown in [Table 4]. The mean numbers of CD4+ cells in the scabies, LP, and psoriasis groups were 54.9 ± 16.4, 21.3 ± 17.9, and 21.7 ± 6.1, respectively ([Figure 3]a-c, respectively). There was significant difference among the three groups (P < 0.5). The mean numbers of CD8+ cells in the scabies, LP, and psoriasis groups were 10.7 ± 3.1, 16.5 ± 5.6, and 67.5 ± 18.4, respectively ([Figure 3]d-f, respectively). There were significantly more CD8+ cells in psoriasis and LP than in scabies (P < 0.05). The mean CD4+/CD8+ ratio in scabies, psoriasis, and LP was 5.2 ± 1.01, 0.3 ± 0.06, and 3.2 ± 0.8, respectively. The ratio in scabies and LP was significantly higher than that in psoriasis (P < 0.05). It was found that the levels of expression of TGF-b differed between all groups. The mean TGF-b expression in scabies, LP, and psoriasis was 10 ± 4.6, 46.2 ± 17.5, and 53.3 ± 21.6%, respectively ([Figure 4]b-d, respectively). The percentage in psoriasis and LP was significantly higher than in scabies (P < 0.05).
|Figure 3: Immunohistochemical staining of T-cell subsets (CD4+ and CD8+). After immunohistochemical staining the labeled molecules are seen in brown: (a) a scabies mite infected skin biopsy stained with anti-CD4+ monoclonal antibody showing high proportion of CD4+ stained immunoreactive cells (×200). (b) A scabies mite infected skin biopsy stained with anti-CD8+ monoclonal antibody showing lower proportion of CD8+ stained immunoreactive cells (×200). (c) LP skin biopsy stained with anti-CD4+ monoclonal antibody showing high proportion of CD4+ stained immunoreactive cells (×200). (d) LP skin biopsy stained with anti-CD8+ monoclonal antibody showing lower proportion of CD8+ stained immunoreactive cells (×400). (e) A psoriasis plaque skin biopsy stained with anti-CD4+ monoclonal antibody showing lower proportion of CD4+-stained immunoreactive cells (×400). (f) A psoriasis plaque skin biopsy stained with anti- CD8+ monoclonal antibody showing high proportion of CD8+-st ained immunoreactive cells (×200).|
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|Figure 4: Immunoperoxidase staining of transforming growth factor-¦Â of: (a) normal skin section (healthy skin) showing negative expression (immune reaction) (×200). (b) Scabies mite infected skin biopsy showing mild expression in dermal layer (×200). (c) LP skin section showing strong expression in dermal layer (immune reaction) (×400). (d) Psoriasis plaque skin biopsy showing strong expression in dermal layer (immune reaction) (×100).|
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|Table 4: Comparison between scabies infection, laichen planus, and psoriasis as regarding cellular immune response|
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[Table 5] shows that there was significant positive correlation between CD4+, CD8+, and percentage TGF-b expression and positivity of skin scraping in scabietic patients (P < 0.05). It also shows significant negative correlation between CD4+ and duration of itching (P < 0.05) and TGF-b expression and duration of itching (P ≤ 0.001) in scabietic patients. However, there was no significant correlation between CD8+ counts and duration of itching (P > 0.05).
|Table 5: Correlation between skin scraping, and duration of itching and immune response in scabietic patients|
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| Discussion|| |
Scabies is one of the most common skin disorders in resource-poor settings, particularly in the developing world. In these settings, pruritus, with typical nocturnal exacerbation, is the main symptom, and scratching may lead to secondary infection . Scabies can mimic a broad range of infectious and noninfectious diseases and the clinical picture is frequently masked by super-infection. Hence, the specificity of the diagnosis based on clinical findings alone is low .
The diagnosis of scabies infection is problematic because of many factors: first, the diversity of symptoms and presentations and a high index of suspicion needed to diagnose infections; second, failed microscopic examination of skin scrapings because of low number of mites present in classic scabies infection; finally, the possible confusion with other skin diseases .
An individual was diagnosed with scabies if at least two of the following three requirements were fulfilled: presence of one or more typical lesions for longer than 2 weeks, pruritus which is intensified at night, or at least one more family member with similar lesions . For decades, the microscopic examination of skin scrapings was considered the standard procedure. This method provides excellent specificity but has low sensitivity for ordinary scabies, because of the low numbers of parasites .
The sensitivity of clinical diagnosis in this study was 85.6%. These results are nearly similar to those obtained by Mahι et al.  (80-100%), Mounsey et al.  (90%), and Dupuy et al.  (73%), whereas Walton and Currie  showed that the sensitivity of clinical diagnosis is less than 50% as detecting visible lesions can be difficult, because they are often obscured by eczema, impetigo, or atypical lesions. However, the sensitivity of skin scraping was 23%, because of low mite burden together with burrow destruction by scratching, but the specificity was very high, going up to 100%. Palicka et al.  showed that only 18% of the samples from 151 patients contained mites. Bhutto et al.  made similar observations. Walter and Hengge  showed that the sensitivity of skin scraping was 46%, whereas in the study by Park et al.  the sensitivity of skin scraping was 35%. This difference may have been due to the oriented skin scraping technique followed; that is, scraping was obtained exactly from the site where a mite was identified by the dermoscopist, which is not available in the current study. Hence, skin scraping cannot be recommended as a diagnostic tool in this setting.
In the present study, the histopathological features of clinically diagnosed scabietic patients were studied. Histopathological observations such as epidermal tunnels, spongiosis, acanthosis, and perivascular dermal infiltrates reported in the current study were also reported by several studies ,,.
The sensitivity of histopathological examination was 88%, with a mean accuracy of 91% and specificity of 100%. Bhattacharjee and Glusac  in their histopathological examination showed that 14/16 patients (87.5%) had typical histopathological features of scabies infection, although only eight of them (50%) were clinically diagnosed with scabies. Burch et al.  reported six children with scabies who were misdiagnosed clinically, and on biopsy showed typical histopathological features of scabies infection. Thus, histopathological examination is an acceptable method of diagnosis in this setting.
Cellular infiltrates were studied immunohistochemically. Scabies showed increased numbers of CD4+ and CD8+ T cells and mild staining for the anti-inflammatory cytokine (TGF-b). These infiltrates contained mainly CD4+ helper T cells, whereas the CD4+\CD8+ ratio ranged from 3.64 to 7.08, with a mean of 5.2 ± 1.01. These findings were consistent with some other investigations ,. Investigators observed that CD4+ cells are the major component of the cell infiltrate in scabietic lesions, with a reported CD4+/CD8+ ratio of 4 : 1. Walton et al.  showed that CD8+ T cells dominated the lymphocytic infiltrate of inflammatory skin lesions. However, the ratio of CD8+ to CD4+ T cells was greater in skin infiltrates in crusted scabies lesions, indicating a selective movement of these cells into the dermis.
In contrast, in psoriasis, a disease characterized by erythematous scaly papules and plaque formation, the infiltrates contained mainly CD8+ helper T cells with the CD4+\CD8+ ratio ranging from 0.25 to 0.42, with a mean of 0.3 ± 0.06. These findings were in accordance with those of several other studies [12,36-38], which observed that in psoriatic lesions CD8+ T cells were more frequent and T cells expressing CD4+ were less frequent or virtually absent. Onuma  and Coimbra et al.  observed that the lymphocytic infiltrate contains predominantly CD4+ T cells with few CD8+ T cells. This discrepancy may be associated with the fact that disease severity (extent and phase of the disease) may be a critical factor for the absolute scores of the parameters investigated in the present study.
Lichen planus is an inflammatory mucocutaneous condition that usually exhibits a distinctive morphology. In our study the lymphocytic infiltrate contained predominately CD4+ T cells with a CD4+\CD8+ ratio of 3.2 ± 0.8. This finding is concordant with earlier studies ,, that declared that a higher proportion of CD4+ helper T lymphocytes compared with CD8+ cytotoxic T lymphocytes were detected in the infiltrate. In contrast, results from other studies ,, showed that the infiltrate was dominated by CD8+ cytotoxic T lymphocytes. Such differences in cellular immunophenotypes may be related to disease progression or different measurement methods.
TGF-b is a multipotent cytokine that regulates both cell growth and differentiation. TGF-b stimulates migration of monocytes, lymphocytes, neutrophils, and fibroblasts . TGF-b suppresses the function of inflammatory Th1 lymphocytes in addition to macrophage inhibition .
The current study identified TGF-b-expressing mononuclear cells in the infiltrate in scabies. The TGF-b percentage expression ranged from 5 to 20%, with a mean of 10 ± 4.6% (mild staining of TGF-b-secreting T cells). This finding was consistent with other previous in-vitro studies carried out on human skin equivalent models. Morgan and Arlian  declared that small amounts of TGF-b were detected in the cells after 48 h in response to the burrowing of live mites into the human skin-equivalent culture surfaces, whereas Walton et al.  showed that there was strong staining of TGF-b-secreting T cells in patients with crusted scabies.
In contrast, there was strong staining of TGF-b-secreting T cells in LP and psoriasis. Chen et al.  and Juan  declared that TGF-b stained markedly mainly in the basal lamina, spinous layer, and granular layer in LP lesions. Lavanya et al.  showed that there was weak expression of TGF-b in oral lichen planus. Flisiak et al.  similarly reported the marked expression of TGF-b-secreting cells in psoriasis lesions, whereas Doi et al.  demonstrated a tendency for decreased expression of TGF-b in psoriatic skin. This difference in the results could be due to differences in specimen preparation or different measurement methods. In addition, the anti-TGF-b antibody we used specifically recognizes the mature form of TGF-b only.
| Conclusion|| |
Histopathology is an accurate diagnostic method for scabies but recommended in suspicious cases only as it is an invasive technique. A high number of CD4+ cells and low expression of TGF-b are characteristic of scabietic lesions.
| Acknowledgements|| |
The authors thank Dr Dalia Mohammed Fawzy Abd-Allah, Lecturer of Dermatology and Andrology, Faculty of Medicine, Menoufia University, for her great effort in this work. They also thank Dr Islam Mohamed Meligy, Assistant lecturer of Pathology, Faculty of Medicine, Menoufia University, for her invaluable help in this work.
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]