Of the 100 cases in the study, 55 were men and 45 were women; the mean age was 35 years (14~79 years). Of the patients with fever and rash, 49% were due to infectious causes, while 41% were due to noninfectious causes and 10 cases were undiagnosed. Distribution of cases is shown in . Based on the data of 100 patients in our study, 66 used any drug because of any underlying diseases, 1 had contact with the tick, and 5 had travel history. Seventy-four patients were hospitalized and 26 were followed as outpatients. Symptoms and signs of these patients were as follows; Symptoms: fatigue 64%, headache 42%, sore throat and cough 40%, myalgia 37%, arthralgia 30%, photophobia 18%, and diarrhea 9%. Signs: lymphadenopathy 37%, tonsillopharyngitis 24%, conjunctivitis 19%, hepatomegaly 16%, cardiac murmur 11%, splenomegaly 9%, abnormal lung oscultation and hypotension 8%, arthritis 7%, and confusion 3%.
Distribution of cases with fever and rash
The types of rash in our series were as follows: macular 14%, maculopapular 34%, papule 7%, diffuse erythema 17%, purpura/ecchymosis 7%, nodule 2%, and polymorphic lesions 18%. Rash was accompanied by itching in 40 patients.
Mortality rate was 5%, despite the appropriate treatment. Diagnoses of these were adult onset Still's disease (ASD), graft-versus-host disease (GVHD), toxic shock syndrome (TSS) and toxic epidermal necrolysis (TEN) (2 cases).
The most common infectious causes were measles (12 cases), chickenpox (11 cases) and rickettsioses (8 cases). Confirmation of clinical diagnosis by serologic tests was available for 11 of 12 measles, 6 of 9 chickenpox and 5 of 6 rickettsial cases. TSS was found as the fourth most frequent etiology among the infectious causes. Three out of 4 patients were women. These patients had erythema and desquamation started from hands and feet after improving of the rash. Erysipelas, infectious mononucleosis and rubella were present in 3 cases each. All 3 cases with erysipelas had an erythema, which was clearly limited, bright, hot, and having a diameter varying from 10 to 20 cm. Two cases had adenopathy in the related lymphatic region. Infectious mononucleosis cases were 2 women and a man, having an age interval of 16~29 years. Two of them had macular and one had urticerial rash. All three experienced itching. Rash of the 2 cases developed after using amoxicilline for tonsillitis (). All of them had cervical lymphadenopathy and atypical lymphocytes in peripheral blood smear. Rubella was present in 3 men; maculopapular lesions were observed mostly in the trunk, and they had cervical and preauricular lymphadenopathies. Other 7 infectious diseases were represented in our series with one case each.
Rash after using amoxicilline in patient with infectious mononucleosis.
Drug reactions were the most common etiology among non-infectious causes. Among the Stevens-Johnson syndrome (SJS) and TEN cases, antibiotics and antiepileptics were the most common drugs (). In 2 cases, the diagnosis of TEN was confirmed with skin biopsy, and both died. Another patient developed purpura fulminans after propylthiouracil use (). Among the noninfectious causes, second largest group was connective tissue diseases. The highest numbers accounted ASD. All 8 cases had a common feature of emergence of rash with fever and disappearing with decreasing of fever. Other than fatigue and myalgia, 4 had sore throat, 3 had arthritis, lymphadenopathy, 2 had hepatomegaly and 1 had splenomegaly. The diagnosis was established by criteria of Cush et al.1
. Acute renal failure developed in 1 patient, who then died of multiple organ failure in the intensive care unit.
Drugs responsible for fever and rash, and rash types
Purpura fulminans after drug use.
Small vessel vasculitis was found in 5 patients in our series after drug reactions and connective tissue diseases. Three of them were diagnosed as Henoch Schönlein purpura (HSP). They had palpable purpuras, especially on gluteal region and extremities. Two patients' skin biopsies were reported as leukocytoclastic vasculitis. Similarly, other 2 cases of small vessel vasculitis were also reported as leukocytoclastic vasculitis. One patient had diffuse palpable purpuras, while another patient had acral cyanosis, accompanying vasculitic bullous lesions. Three women with an age range of 22~41 years were followed as urticeria. Two of them had itching and maculopapular, and one of them had erythematous rash. One of the 3 diseases, which were presented with one patient each in noninfectious causes of our series, was GVHD due to blood transfusion. He had oral mucositis accompanying maculopapular and bullous rashes with positive Nikolsky's sign and desquamation, thereafter. Skin biopsy confirmed the diagnosis; the patient died during follow-up in intensive care unit. A 63-year-old man had nodular, pustular and painful lesions on an erythematous background. He had high erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and leukocytes. Skin biopsy was reported as Sweet's syndrome. No hematologic disease was found. There were 2 patients with erythema nodosum: one was confirmed to have sarcoidosis and the other patient was diagnosed as primary erythema nodosum.
A 27-year-old man was presented with ulcerative colitis, fever, diarrhea and ulcerative, vesiculobullose lesions in various parts of his body. He was diagnosed as attack of ulcerative colitis and pyoderma gangrenosum, and was found to have mild leukocytosis, elevated alanine aminotransferase (ALT), ESR and CRP. Cultures of tissue and blood were negative ().
Pyoderma gangrenosum in a patient with ulcerative colitis.
Undiagnosed cases, with an age range of 16~70 years, consisted of 4 men and 6 women. Clinical, radiologic and microbiological tests were noncontributory. Clinical follow-up established no spesific diagnosis. Rash and fever disappeared without any treatment.
For an easy approach to differential diagnosis, medical history, physical examination and biochemical results of the 3 groups were compared and shown in . Headache (p=0.012) and conjunctivitis (p=0.011) were significant in infectious causes, while drug use (p=0.010) and arthritis (p=0.037) were significant in non-infectious causes. Accompanying sore throat/pharyngitis was determined, especially in measles, IMN and ASD; conjunctivitis in measles and TSS; lymphadenopathy in measles, chickenpox and drug-related rash; arthralgia/arthritis in rickettsial infection, adult Still's disease and drug-related rash. Enanthem was observed in measles and SJS; itching in chickenpox, IMN and urticeria; desquamation in TSS and TEN; hand/foot involvement in rickettsial infection.
Comparison of several features of three groups
Among the laboratory findings, elevation of ESR, lower than 50 mm/hr, was observed in 80% of infectious causes, 55% of noninfectious causes and 83% of undiagnosed group. Nearly 45~60% of all 3 groups had elevation of CRP higher than 10 times, most commonly seen in ASD, HSP, TSS, rickettsial infection and SJS. Leukocytosis was more seen in ASD; IMN and TSS, while leukopenia in measles and TEN. Nine percent of our cases had eosinophilia (≥500/mm3), but there was no significant difference when the three groups were compared (p=0.575). Reasons for fever and rash in eosinophilic patients were usually drug reaction and TSS.