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Table of Contents
Year : 2018  |  Volume : 55  |  Issue : 4  |  Page : 310-314

The relationship between skin rash and outcome in dengue

1 Department of General Medicine, Christian Medical College, Vellore, Tamil Nadu, India
2 Department of Dermatology, Christian Medical College, Vellore, Tamil Nadu, India

Date of Submission14-Nov-2017
Date of Acceptance03-May-2018
Date of Web Publication18-Apr-2019

Correspondence Address:
Anu Anna George
Department of Dermatology, Hospital Campus, Christian Medical College, Vellore–632 004, Tamil Nadu
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0972-9062.256567

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Background & objectives: Dengue fever (DF) is a common cause of acute febrile illness. Skin involvement is seen in more than half of the patients. This study was aimed to compare the clinical profile and outcome in DF patients with or without skin involvement.
Methods: This study included all the patients with DF from the acute febrile illness database of a tertiary care health centre in south India. These patients were further subgrouped into SP and SN (skin involvement positive and negative) based on the presence and absence of skin rash. Differences in clinical presentation, laboratory parameters, disease course, morbidity and outcome among patients with DF with or without skin rash were recorded and analysed statistically.
Results: In total 387 patients (>16 yr) with DF were enrolled into the study. Among these 55 patients had evidence of skin rash. Presence of history of overt bleeding (OR = 4.96, p = 0.027) including gum bleeding (OR = 1.17, p = 0.23), epistaxis (OR = 5.52, p = 0.04), and haematuria (OR = 6.41, p = 0.01) were more among patients with SP as compared to SN. The SP patients were found to have lower levels of platelets during the disease course. Patients with SP had a higher percentage of platelet transfusion which was statistically significant. There was no difference in organ dysfunction and mortality among both the groups.
Interpretation & conclusion: Cutaneous involvement, though common, is not pathognomonic and can help in dengue diagnosis. Adult patients with skin rash can develop worsening thrombocytopenia requiring platelet transfusion. However, there are limited data to suggest that such patients have a worse outcome and higher mortality.

Keywords: Dengue; outcome; skin rash; thrombocytopenia

How to cite this article:
Mishra AK, George AA, Abhilash K. The relationship between skin rash and outcome in dengue. J Vector Borne Dis 2018;55:310-4

How to cite this URL:
Mishra AK, George AA, Abhilash K. The relationship between skin rash and outcome in dengue. J Vector Borne Dis [serial online] 2018 [cited 2023 Mar 27];55:310-4. Available from: http://www.jvbd.org//text.asp?2018/55/4/310/256567

  Introduction Top

Dengue fever (DF) is a common cause of acute febrile illness and is caused by dengue virus[1]. Dengue virus is a single-stranded, positive-sense RNA virus of family Flaviviridae. It has four serotypes. Aedes aegypti mosquito is the principal vector responsible for its transmission[2]. With the doubling of cases of DF in 2015, in the Indian subcontinent, it continues to be a significant public health problem. All over the world, millions of people get infected with dengue virus annually[3]. Most DF infections are asymptomatic. However, it is known for its diverse clinical presentation, from mild acute febrile illness to dengue haemorrhagic fever (DHF) and dengue shock syndrome (DSS)[1],[3]. One of the differential diagnosis for patients presenting with acute febrile illness in an endemic region or patients with the history of travel to an endemic region is DF[3]. In the past patients were diagnosed to have DF or a DHF based on various parameters, however recently WHO has simplified it as DF and severe DF based on the absence or presence of major organ involvement[2],[3].

Skin involvement is common in DF. It can vary from confluent erythematous rash to generalized morbilliform rash[4]. Presence of skin rash initially in the setting of acute febrile illness can assist with making the diagnosis of DF[5]. The implications of the presence of skin rash to disease severity, its prognosis and outcome are still not clear. This study, was aimed to compare the differences in clinical presentation, laboratory parameters, disease course, morbidity and outcome among patients with DF with or without skin rash.

  Material & Methods Top

Study design and sampling

The present study is a sub-analysis of a large prospective observational study conducted in the Emergency Department and the Department of General Medicine of Christian Medical College, Vellore (Tamil Nadu), a 2700 bedded tertiary health care centre in south India[6]. All the patients were older than 16 yr; and had clinical features and laboratory evidences supporting dengue infection. These patients were recruited into Microsoft Excel database between October 2012 and September 2013.

The patients with clinical presentations of acute febrile illness, progressive thrombocytopenia, elevated hepatic transaminase and presence of detectable dengue IgM and detectable virus-expressed soluble non-structural protein 1 (NS1) by means of enzyme-linked immunosorbent assay (ELISA) (Panbio®; Dengue Duo Cassette), with other serologies being negative and blood cultures sterile OR seroconversion of convalescent sera, were diagnosed to have DF. Such patients were enrolled into the study. Patients were excluded if they had laboratory evidence of coinfection.

At the time of presentation to the hospital, based on the presence of skin rash, all patients were divided into skin rash positive (SP) and skin rash negative (SN). Patients with petechial and/or morbilliform skin lesions were classified as SP. Details of clinical features, laboratory investigations, major organ involvement, treatment, and the outcome were also recorded. Outcomes on the need of hospitalization, oxygen supplementation, and requirement of platelet transfusion, non-invasive ventilation, inotropes, dialysis, and mortality were compared across both the groups.

Data analysis

Data were entered into Microsoft's Excel programme and statistical analysis was done using SPSS software version 16; unpaired students t-test was used to compare the categorical variables. Analysis of variance (ANOVA) was used for variables between the two groups with significant difference. A p-value of <0.05 was considered as significant.

Ethical clearance

This study was approved by the Institutional Review Board of Christian Medical College, Vellore (IRB Min. No. 8007 dated 19/09/2012). In order to ensure patient confidentiality, each patient was given a unique identifier in a password protected data sheet.

  Results Top

A total of 387 patients with DF were included in the study. The details of demographic parameters, clinical features and disease outcome among both the groups are shown in [Table 1]a and [Table 1]b. Total patients with the presence of skin rash (SP) were 55 as compared to 331 without skin rash (SN). The mean age of patients with SP was 29 as compared to 31 in SN. There was a slight male preponderance, but male to female ratio was equal among both the groups. The mean duration of fever was 5–6 days in both the groups. Clinical features of fever; chills, myalgia, headache, vomiting, and arthralgia were similar among both the groups as shown in [Table 1]. Symptoms of cough, breathlessness, diarrhoea and low sensorium was similar in both the groups. Presence of history of abdominal pain (OR = 2.15, p = 0.12), overt bleeding (OR = 4.96, p = 0.027) including gum bleeding (OR = 1.17, p = 0.23), gastrointestinal bleeding (OR = 1.77, p = 0.15), epistaxis (OR = 5.52, p = 0.04), and haematuria (OR = 6.41, p = 0.01) were more among SP patients as compared to SN. Among these symptoms, presence of overt bleeding, epistaxis and haematuria were statistically significant. There was no reported CNS bleed in either group. There was no significant difference in vital signs and haemogram between both the groups except heart rate at the time of admission. However, patient with SP were found to have lower levels of platelets during the disease course. SGPT levels were abnormal in both the groups though its levels were higher among SP patients. Other biochemical parameters were similar across both the groups. Among these only heart rate (p = 0.009) and SGPT (p = 0.043) were statistically significant, but admission platelet (p = 0.237) and lowest platelet during the course of the disease (p = 0.102) were not significant. There was no difference in the sequential organ failure assessment score among both the groups.
Table 1:

Click here to view

[Table 2] shows the various outcomes studied between both the groups. More patients with SN required inpatients admission. Patients with SP had a higher percentage of platelet transfusion, requirement of O2, non-invasive ventilation (NIV), inotropes, and dialysis. However, only the requirement of platelet transfusion was statistically significant. Mortality was noted only among SN patients, but it was not statistically significant.
Table 2: The outcome in patients with dengue fever based on presence or absence of skin rash

Click here to view

  Discussion Top

Skin involvement is common in DF and seen in almost 50–82% patients. In the first 24–48 h of infection, capillary dilatation can lead to transient erythema of face[4]. Asymptomatic maculopapular rash and morbilliform eruptions sparing palms and soles are usually noted 3 to 6 days after fever[4],[5]. The skin rash can either resolve completely or become generalized and involve dorsum of hands and feet. It can also involve arms, legs, torso and last several days[5]. An area of normal skin ‘Island of white’ surrounded by erythema can also be seen while the patient is febrile[7]. Haemorrhagic manifestations like petechial, purpura and ecchymosis of skin usually occur after Day 4 of fever onset. Skin rash in DF is postulated to be because of virus-induced injury of smaller blood vessels[4]. Flavivirus replication in vascular endothelium results in endothelial swelling, perivascular oedema, and mononuclear cell infiltration[4],[8] which leads to release of various pro-inflammatory cytokines and further immunological reactions thus precipitating the injury[8].

Furthermore, activation of cutaneous dendritic cells and T-cells have been attributed to dengue shock syndrome[9]. These skin manifestations tend to vary and are nonspecific[10]. Though, in earlier studies skin involvement has been reported in >50% of patients, in this study it was seen in only 14.2% of the patients, which could be attributed to absence of skin rash at the time of initial assessment by the physician, larger number of patients with non-severe DF, outpatient management of most patients [n = 251 (75%)], cutaneous assessment by different clinicians, and variations secondary to darker complexion in patients. Skin histopathology though possible has not been found to have diagnostic or prognostic value and hence is not necessary[11]. Dengue virus NS1 is known to disrupt endothelium causing vascular injury and hyper-meability[12]. A positive NS1 ELISA is highly sensitive and specific for DF, and hence is recommended in the diagnostic evaluation[13].

This study aimed at evaluating the clinical significance of the patients with skin rash in terms of prognosis and mortality. An earlier study by Huang et al[5] comparing the same had included 45 patients in total. Their study had shown that patients in the SN group were older than in the present study. The mean age of patients with SP or SN were however similar to this study. Huang et al[5] had found that SN patients had severe thrombocytopenia and required more transfusion, contrasting our findings of patients with SP having the lowest level of platelet and requiring more platelet transfusion. In that study only 5 (11%) patients received a transfusion while in this study 28 (7.2%) patients received a transfusion. The numbers of platelet transfusion across both the groups were statistically significant; the pattern changed with the decrease in the overall percentage of transfusion which might be due to decline in transfusion rate owing to a larger sample size[14]. In this study, percentage of overt bleeding (23%), including, epistaxis, gum bleeding, gastrointestinal bleeding and haematuria were higher in the SP group compared to the SN group (12%), which is contrary to that study[5]. In the present study, only 14% of all the patients developed overt bleeding as compared to 51% in the earlier study. An adequately designed and randomized study might modify these factors further.

The study also analysed the various outcome details of the DF. Patients with SP had a higher percentage of platelet transfusion, requirement of O2, NIV, inotropes and dialysis; however, only the requirement of platelet transfusion was statistically significant. More patients with SN required inpatients admission, which was also statistically significant. Mortality was noted only among SN patients, but it was not statistically significant. Other than the requirement of platelet transfusion, all the other outcomes were observed only in few patients and were non-significant. Various clinical, viral, immunological and endothelial biomarkers have been studied and found to have prognostic relevance in smaller studies[15]. With the present results, authors are unable to attribute presence or absence of skin rash as one of the strong predictors of increased complications and worst outcome. In view of very low mortality (<1%) even in the patients with DSS, identification of a single and accurate prognostic marker continues to be a challenge for the future[16].

The limitations of the study were lack of data on the disease onset; the pattern, types and extent of skin lesions; presence of mucosal lesions, details of progression or regression of lesions, details of associated pruritus, presence of hand and leg oedema, availability of DNA RT-PCR, details of dengue virus serotype, and cutaneous biopsy. Availability of these would make the description of skin lesion more robust, however, it might not change the outcome that has been interpreted in the study. The study did not included children with dengue, in whom the complications of the infection are known to be higher[17]. Also, this study did not have long-term follow up data on the patients.

  Conclusion Top

In conclusion, DF continues to be one of the commonest causes of acute febrile illness in developing countries. Though, cutaneous involvement can facilitate clinical diagnosis, it is not present in all patients. The present study also confirms that there is no statistically significant difference in complications and mortality in patients with DF with or without skin rash. However, future prospective studies might facilitate in classifying the extent of cutaneous involvement and its association with organ involvement and mortality. Future studies with larger sample size, more details of skin and mucosal involvement and longer duration of follow up can give us a clearer and better picture about the association between skin rash and dengue complications.

Conflict of interest

The authors declare that they do not have any conflict of interest.

  References Top

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Simmons CP, Farrar JJ, Nguyen VV, Wills B. Dengue. N Engl J Med 2012; 366(15): 1423–32.  Back to cited text no. 3
Thomas EA, John M, Kanish B. Mucocutaneous manifestations of dengue fever. Indian J Dermatol 2010; 55(1): 79.  Back to cited text no. 4
Huang H-W, Tseng H-C, Lee C-H, Chuang H-Y, Lin S-H. Clinical significance of skin rash in dengue fever: A focus on discomfort, complications, and disease outcome. Asian Pac J Trop Med 2016; 9(7): 713–8.  Back to cited text no. 5
Abhilash KPP, Jeevan JA, Mitra S, Paul N, Murugan TP, Rangaraj A, et al. Acute undifferentiated febrile illness in patients presenting to a tertiary care hospital in south India: Clinical spectrum and outcome. J Glob Infect Dis 2016; 8(4): 147–54.  Back to cited text no. 6
Kenzaka T, Kumabe A. Skin rash from dengue fever. BMJ Case Rep 2013; 2013: bcr2013201598.  Back to cited text no. 7
Eapen CE, Nair SC. Potential danger of isolated platelet transfusion in patients with dengue infection. Indian J Med Res 2017; 145(2): 158.  Back to cited text no. 8
Duyen HTL, Cerny D, Trung DT, Pang J, Velumani S, Toh YX, et al. Skin dendritic cell and T-cell activation associated with dengue shock syndrome. Sci Rep 2017; 7(1): 14224.  Back to cited text no. 9
Bolivar-Mejia A, Alarcón-Olave C, Rodriguez-Morales AJ. Skin manifestations of arthropod-borne infection in Latin America. Curr Opin Infect Dis 2014; 27(3): 288–94.  Back to cited text no. 10
Saadiah S, Sharifah BI, Robson A, Greaves MW. Skin histopathology and immunopathology are not of prognostic value in dengue haemorrhagic fever. Br J Dermatol 2008; 158(4): 836–7.  Back to cited text no. 11
Puerta-Guardo H, Glasner DR, Harris E. Dengue virus NS1 disrupts the endothelial glycocalyx, leading to hyperpermeability. PLoS Pathog 2016; 12(7): e1005738.  Back to cited text no. 12
Hang VT, Nguyet NM, Trung DT, Tricou V, Yoksan S, Dung NM, et al. Diagnostic accuracy of NS1 ELISA and lateral flow rapid tests for dengue sensitivity, specificity and relationship to viraemia and antibody responses. PLoS Negl Trop Dis 2009; 3(1): e360.  Back to cited text no. 13
Noordzij M, Tripepi G, Dekker FW, Zoccali C, Tanck MW, Jager KJ. Sample size calculations: Basic principles and common pitfalls. Nephrol Dial Transplant 2010; 25(5): 1388–93.  Back to cited text no. 14
Yacoub S, Wills B. Predicting outcome from dengue. BMC Med 2014; 12(1): 147.  Back to cited text no. 15
Lam PK, Tam DTH, Diet TV, Tam CT, Tien NTH, Kieu NTT, et al. Clinical characteristics of dengue shock syndrome in Vietnamese children: A 10-year prospective study in a single hospital. Clin Infect Dis 2013; 57(11): 1577–86.  Back to cited text no. 16
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