Viral exanthems in childhood. Part 3: Parainfectious exanthems and those associated with virus‐drug interactions

Viruses cause not only direct infectious exanthems, but also parainfectious exanthems, which provoke skin alterations via interactions with the immune system. These distinct exanthems, for instance Gianotti‐Crosti syndrome and pityriasis lichenoides group, do not reflect a specific pathogen but can occur in the course of many viral infections. In addition, some exanthems result from the interaction between viruses and drugs.     

Viral exanthems in childhood – infectious (direct) exanthems. Part 1: Classic exanthems

Exanthems during childhood occur quite often and are mostly harmless in nature. Among different trigger factors, viruses are of prime importance. Viral exanthems may manifest as a macular, maculopapular, papular, urticarial or vesicular rash. Exanthems with other causes (bacterial toxins, drugs, autoimmune diseases) as well as those with unclear etiology such as unilateral lat‐erothoracic exanthem or Kawasaki disease must be differentiated from viral exanthems. This review focuses on the classic viral exanthems.     

Atypical exanthems: morphology and laboratory investigations may lead to an aetiological diagnosis in about 70% of cases

BACKGROUND: Besides the six classical exanthems, other exanthems may occur, differing in morphology and causative agent (atypical exanthems). Their aetiological diagnosis is difficult but crucial for both the patient and community concerning issues such as time off school, immunizations, and risks for pregnant women and immunocompromised patients. OBJECTIVES: To investigate whether morphology, associated symptoms and laboratory results can help to determine the aetiology of atypical exanthems. METHODS: We studied 112 consecutive out-patients attending two university dermatology departments. Peripheral blood mononuclear cells (PBMC) and throat, rectal and vaginal swabs were studied to identify viral and bacterial growth. Nested polymerase chain reaction was performed on PBMC and plasma using specific primers for herpesviruses. Serology for common viruses was investigated. RESULTS: We classified the exanthems into seven morphological patterns: macular erythema (32 patients), papular erythema (eight), maculopapular erythema (42), maculopapular erythema with petechiae (seven), erythema with vesiculation (11), erythema with pustules (five) and urticaria (seven). On the basis of morphology, in concert with the associated symptoms and laboratory results, we found a causal relationship in 76 patients (68%): 25 cases due to drugs, 32 to viruses, 16 to bacteria and three to parasites. A good correspondence between morphology and aetiology was found. The erythematous-vesicular pattern was exclusive to viral infections and was often accompanied by enanthema. The erythemato-pustular and papular patterns were found only in drug-related cases and in some undiagnosed cases. In contrast, the macular and maculopapular patterns were almost evenly distributed among the various aetiologies, although their colour was duskier in the drug-related exanthems. Severe pruritus was associated with drug-related exanthems. CONCLUSIONS: This is the largest series of consecutive patients with atypical exanthems reported. Their morphology and their association with pruritus or constitutional symptoms proved to be important diagnostic clues.     

Viral exanthems in children: A great imitator

Viral exanthems are frequent in children and are mostly self-limited. Early recognition and differentiation from other childhood illnesses are important to direct further investigations and treatment initiation. The clinical presentation of viral exanthems in children includes a polymorphic spectrum of skin eruptions ranging from classic viral exanthems to “atypical” presentations that can mimic nonviral diseases; thus, viral exanthems of childhood can be readily diagnosed on clinical grounds, but not rarely do they represent a diagnostic challenge. In this review, we focus on viral diseases in children that may be difficult to diagnose due to their clinical similarities with nonviral diseases, and we offer clues for the differential diagnosis and proper diagnostic testing in such cases.     

Viral exanthems in the tropics

Viral exanthems are a common problem in tropical regions, particularly affecting children. Most exanthems are transient and harmless, but some are potentially very dangerous. Pregnant women and malnourished or immunocompromised infants carry the greatest risk of adverse outcome. In this article, parvovirus B19; dengue and yellow fever; West Nile, Barmah Forest, Marburg, and Ebola viruses, and human herpesviruses; asymmetric periflexural exanthema of childhood; measles; rubella; enteroviruses; Lassa fever; and South American hemorrhagic fevers will be discussed.     

Accentuated varicella exanthems due to cast application

Abstract:  We report a case of 14-year-old male with local augmentation of varicella zoster exanthems on the forearm on which cast application was performed. After 1 week, the first varicella zoster exanthems began to appear on the left forearm under the cast and trunk, while lesions on the other forearm and extremities were very rare. We postulated that the local pressure and heat increased the number of exanthems.     

Eosinophilic pustular folliculitis: A published work‐based comprehensive analysis of therapeutic responsiveness

Eosinophilic pustular folliculitis (EPF) is a non‐infectious inflammatory dermatosis of unknown etiology that principally affects the hair follicles. There are three variants of EPF: (i) classic EPF; (ii) immunosuppression‐associated EPF, which is subdivided into HIV‐associated (IS/HIV) and non‐HIV‐associated (IS/non‐HIV); and (iii) infancy‐associated EPF. Oral indomethacin is efficacious, especially for classic EPF. No comprehensive information on the efficacies of other medical management regimens is currently available. In this study, we surveyed regimens for EPF that were described in articles published between 1965 and 2013. In total, there were 1171 regimens; 874, 137, 45 and 115 of which were applied to classic, IS/HIV, IS/non‐HIV and infancy‐associated EPF, respectively. Classic EPF was preferentially treated with oral indomethacin with efficacy of 84% whereas topical steroids were preferred for IS/HIV, IS/non‐HIV and infancy‐associated EPF with efficacy of 47%, 73% and 82%, respectively. Other regimens such as oral Sairei‐to (a Chinese–Japanese herbal medicine), diaminodiphenyl sulfone, cyclosporin and topical tacrolimus were effective for indomethacin‐resistant cases. Although the preclusion of direct comparison among cases was one limitation, this study provides a dataset that is applicable to the construction of therapeutic algorithms for EPF.     

Fas‐ligand staining in non‐drug‐ and drug‐induced maculopapular rashes

Background: Morphologically and histopathologically, drug‐ and non‐drug‐induced maculopapular rashes can be almost indistinguishable. It has been postulated that Fas‐ligand (Fas‐L) is involved in the pathogenesis of drug rashes but not in the genesis of rashes, such as viral exanthems, that are not induced by medications. Aim: This study sought to determine if epidermal Fas‐L is a distinguishing feature in the pathology of drug and non‐drug maculopapular rashes. Methods: Archived skin biopsies of patients with a confirmed diagnosis of drug or non‐drug maculopapular rashes (n = 10 each) and positive and negative controls were retrieved for immunohistochemical staining for Fas‐L. The proportion of Fas‐L‐positive skin biopsies were compared. The presence of tissue eosinophilia was also evaluated. Results: Ten percent of non‐drug‐induced rashes were Fas‐L positive compared to 50% of drug rashes (p = 0.05). Twenty percent of non‐drug exanthems had moderate tissue eosinophilia, while 60% from drug rashes had moderate to dense tissue eosinophilia (p = 0.17). Conclusion: There is a trend toward Fas‐L being more prevalent in the epidermis of drug maculopapular rashes, although this did not reach statistical significance. This is possibly because of the small sample size. Wang ECE, Lee JSS, Tan AWH, Tang MBY. Fas‐ligand staining in non‐drug‐ and drug‐induced maculopapular rashes.     

Eosinophilic pustular folliculitis: The transition in sex differences and interracial characteristics between 1965 and 2013

Eosinophilic pustular folliculitis (EPF) is characterized by a non‐infectious infiltration of eosinophils in the hair follicles. It has three variants: (i) classic EPF; (ii) immunosuppression‐associated EPF, which herein is subdivided into HIV‐associated (IS/HIV) and non‐HIV‐associated (IS/non‐HIV); and (iii) infancy‐associated EPF (I‐EPF). The rarity of EPF has hindered our understanding of this entity. To examine the characteristics of EPF, with respect to age, sex, race, and chronology, published in case reports to date, we queried PubMed using the following terms: (“eosinophilic pustular folliculitis” [All Fields] OR “eosinophilic folliculitis” [All Fields]) AND (“1965/1/1” [PDAT]: “2013/12/31” [PDAT]). Additional Japanese cases were collected from Igaku Chuo Zasshi through Ichushi‐Web, JDream III, and secondhand quotations from domestic periodicals published in Japan. Proceedings were excluded. The PubMed search produced 275 citations containing 358 cases of EPF (224 men, 132 women, and two of unspecified sex); these cases involved classic EPF (101 Japanese and 81 non‐Japanese), IS/HIV (4 Japanese and 85 non‐Japanese), IS/non‐HIV (4 Japanese and 20 non‐Japanese), and I‐EPF (4 Japanese and 59 non‐Japanese). Ichushi generated an additional 148 citations containing 207 cases of Japanese (148 men and 59 women), which included cases of classic EPF (181 cases), IS/HIV (14 cases), IS/non‐HIV (9 cases), and I‐EPF (3 cases). There was no sex difference in the classic EPF cases reported between 2003 and 2013, whereas IS/HIV, IS/non‐HIV, and I‐EPF were predominated by men. There is room for reconsideration of sex differences, particularly with regard to classic EPF. The rarity and specificity of I‐EPF in Japan may reflect a state of uncertainty about this entity.     

Procalcitonin as a diagnostic indicator for systemic bacterial infections in patients with Stevens–Johnson syndrome/toxic epidermal necrolysis

Elevated serum procalcitonin (PCT) level has been reported to be a diagnostic index in systemic bacterial infections, but it can also increase in some non‐infectious inflammatory diseases. Stevens–Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) is a rare immune‐mediated cutaneous mucosal reaction which is susceptible to bacterial infections and may have elevated PCT levels. The value of serum PCT has not been assessed in series of SJS/TEN patients. We aimed to investigate the PCT levels in SJS/TEN patients with systemic bacterial infections (systemic infected group), with skin surface bacterial infections (skin surface infected group) and without infections (non‐infected group), to assess whether PCT was a valuable indicator for systemic bacterial infections in SJS/TEN patients. The PCT and C‐reactive protein (CRP) levels of 42 inpatients with SJS/TEN were retrospectively analysis. The receiver–operator curve (ROC) was used to determine the diagnostic efficacy of PCT for systemic bacterial infections in SJS/TEN patients. The results demonstrated that PCT levels in the systemic infected group were significantly higher than those in the other two groups (P < 0.05). There was no significant difference in CRP between the three groups. The cut‐off PCT level of 0.65 ng/mL calculated by ROC had optimal diagnostic efficacy, with sensitivity and specificity of 84.6% and 89.7%, respectively. PCT and severity‐of‐illness score for toxic epidermal necrolysis were positively correlated (P < 0.05). In conclusion, PCT is a valuable index and superior to CRP in detecting systemic bacterial infections in SJS/TEN patients. The level of PCT can partially reflect the severity of the disease.     

Infection and panniculitis

Infection‐induced panniculitis may result from a number of microbes including bacteria, fungi, and parasites. Viruses have also been implicated as a cause. This type of panniculitis can occur as a primary infection by direct inoculation of infectious microorganisms into the subcutaneous tissue, or secondarily via microbial hematogenous dissemination with subsequent infection of the subcutaneous tissue. Panniculitis is rarely viewed solely in terms of infectious causes. Also, subcutaneous infections are infrequently viewed in terms of infection‐induced panniculitis but rather as cutaneous infections with subcutaneous involvement. Little information exists specifically on the subject of infection‐induced panniculitis outside of the realm of case reports and case series. In this review, the present authors address panniculitis from the vantage point of infectious causes, focusing on those microorganisms with infection‐induced panniculitis reports in the literature. Diagnosis and treatment are also discussed.     

Characteristics of fever,etiologic factors,antibiotic use and prognosis in febrile dermatology inpatients

Background Generally, fever is observed in >30% of hospitalized patients. However, little is known about fever in dermatology inpatients. Objectives The aim of this study was to investigate and document the incidence, characteristics, and etiologic factors of fever in febrile dermatology inpatients and to describe the practice of antibiotic use and prognosis in the same group. Methods The medical records for 928 inpatients were retrospectively analyzed. Results The incidence of fever was found to be 16.2%. Mean length of hospital stay was found to be longer in febrile patients. Of the 176 febrile episodes, 79 (44.9%) occurred in patients without infections, 43 (24.4%) in patients with community‐acquired infections, 25 (14.2%) in patients with healthcare‐associated infections, 18 (10.2%) in patients classified with fever of non‐infectious/infectious causes, and 11 (6.3%) in a group for whom the etiologic factors of fever were undetermined. Antibiotic treatment was started in 36.2% of febrile inpatients. The overall mortality rate was 0.6%. Conclusions This is the first study to investigate febrile episodes in dermatology inpatients. Fever is a frequently encountered symptom in dermatology inpatients. Febrile episodes resulted from mostly non‐infectious entities, mainly consisting of inflammatory dermatologic disorders. Antibiotics were ordered in a higher percentage of patients in the febrile group. Dermatologists started prophylactic or empiric antibiotic therapy in febrile patients with non‐infectious or inflammatory diagnoses on the assumption that these patients had an increased risk for infection as a result of impaired skin integrity and use of immunosuppressive drug therapy. The overall mortality rate was very low in the study group of dermatology inpatients.     

Portable negative‐pressure wound therapy for pyoderma gangrenosum: Report of two cases

Pyoderma gangrenosum is a chronic non‐infectious neutrophilic dermatosis that causes undermining ulcers. Topical therapies for the deep ulcers of pyoderma gangrenosum have not been established. To investigate whether negative‐pressure wound therapy is effective for a pyoderma gangrenosum ulcer, we used the PICO single use negative‐pressure wound therapy system (Smith & Nephew, London, UK) for two pyoderma gangrenosum patients. In these cases, the ulcers decreased in size and necrolytic tissue was removed notably. Moreover, there were no secondary infections nor was there Koebner phenomena. Our cases suggest that portable negative‐pressure wound therapy can be a treatment option for deep, intractable ulcers caused by pyoderma gangrenosum. Because portable negative‐pressure wound therapy devices afford increased mobility to patients, they can give the patient a better quality of life than standard negative‐pressure wound therapy systems do.     

Cutaneous side effects of TNF‐alpha inhibitors

Since the early 1990s, tumor necrosis factor alpha (TNF‐alpha) inhibitors have been successfully used in the treatment of various immune‐mediated inflammatory diseases. By now, comprehensive safety data has been compiled. While adverse reactions do occur, they are – in relation to the frequent use of these agents – rare and usually not serious. Cutaneous side effects include local injection site reactions, infections, immune‐mediated reactions, and neoplasms. The most common serious adverse events are of an infectious nature. Mycobacteria but also non‐mycobacterial pathogens, such as viruses and fungi, may cause serious, even lethal, systemic infections. The present article is meant to review current knowledge with respect to cutaneous side effects of TNF‐alpha inhibitors.     

Pigmented vulvar lesions

Pigmented lesions represent an enormous range of conditions, from benign to malignant tumors, and from infectious to post‐inflammatory. Pigmented lesions are much less easily diagnosed on anogenital skin, and clinicians should have a low threshold for biopsy confirmation of diseases not classic in appearance.     

Cationic membrane‐active peptides – anticancer and antifungal activity as well as penetration into human skin

Cationic antimicrobial peptides are ancient natural broad‐spectrum antibiotics, and several compounds also exhibit anticancer activity. However, most applications pertain to bacterial infections, and treatment for skin cancer is less frequently considered. The cytotoxicity of melittin, cecropin A, protegrin‐1 and histatin 5 against squamous skin cancer cell lines and normal human keratinocytes was evaluated and compared to established drugs. The results show that melittin clearly outperforms 5‐fluorouracil regarding antitumor activity. Importantly, combined melittin and 5‐fluorouracil enhanced cytotoxic effects on cancer cells and reduced toxicity on normal keratinocytes. Additionally, minimum inhibitory concentrations indicate that melittin also shows superior activity against clinical and laboratory strains of Candida albicans compared to amphotericin B. To evaluate its potential for topical applications, human skin penetration of melittin was investigated ex vivo and compared to two non‐toxic cell‐penetrating peptides (CPPs), low molecular weight protamine (LMWP) and penetratin. The stratum corneum prevents penetration into viable epidermis over 6 h; however, the peptides gain access to the viable skin after 24 h. Inhibition of digestive enzymes during skin penetration significantly enhances the availability of intact peptide. In conclusion, melittin may represent an innovative agent for non‐melanoma skin cancer and infectious skin diseases. In order to develop a drug candidate, skin absorption and proteolytic digestion by skin enzymes need to be addressed.     

Non‐antibiotic properties of tetracyclines and their clinical application in dermatology

Dermatologists have used tetracyclines since the 1950s to treat disorders that do not necessarily have an infectious aetiology. Their anti‐inflammatory and anti‐collagenase properties contribute significantly to their success in treating diseases such as rosacea and acne. This article reviews the non‐antibiotic properties of tetracyclines and their clinical application in dermatology.     

Cutaneous side effects of inhibition of VEGF signal transduction

The VEGF signaling pathway (including ligands, surface‐bound receptors and intracellular downstream signaling cascades) is critically involved in angiogenesis under normal and pathological conditions, in particular in malignant tumors. As a consequence, several therapies that target specific components of this pathway have been approved for clinical use or are in various stages of clinical development. Currently, the monoclonal antibodies bevacizumab and ranibizumab, as well as the small‐molecule kinase inhibitors sorafenib and sunitinib, have been approved for cancer therapy. The spectrum of cutaneous side effects elicited by bevacizumab is considerably less pronounced than that seen with EGF inhibitors and includes peripheral sensory neuropathy, stomatitis, skin dryness, skin discoloration and exfoliative dermatitis. In contrast, unwanted cutaneous side effects seen with the less specific small molecule compounds include pruritic exanthems, nail changes, cheilitis and the painful hand‐foot‐syndrome.