—  SPECIALTY CONFERENCE  —

Dermatopathology

Case 7 - Cephalexin-Induced Rash in Infectious Mononucleosis Showing Features of Kikuchi-fujimoto's Disease

J. Andrew Carlson
Albany Medical College
Albany, NY


Click on each slide thumbnail image for an enlarged view
Clinical History
Healthy 22yo male presented with a three day history of flu-like symptoms- fatigue, sore throat, cough, headache, and chest congestion and a low grade fever 99°F. Cefzil (Cephalexin™) was prescribed for presumptive sinusitis. One week later, he complained of an earache and non-pruritic, burning rash. The rash, morbilliform with erythematous and purpuric macules and papules, began on the face then spread to the trunk, arms, legs and feet including palms and soles. His soft and hard palate exhibited petechiae, the tonsils were enlarged and covered by an exudate, and cervical lymphadenopathy was present. Clinical differential diagnosis: Rocky Mountain spotted fever, erythema multiforme, vs. infectious mononucleosis.


Case 7 - Figure 1 - There is a superficial and deep perivascular mononuclear cell infiltrate with exocytosis.
Case 7 - Figure 2 - There is a pronounced lymphocytic interface dermatitis that obscures the dermoepidermal juncttion.
Case 7 - Figure 3 - There is a pronounced lymphocytic interface dermatitis that obscures the dermoepidermal juncttion.


Case 7 - Figure 4 - Nuclear debris is present in the dermis.
Case 7 - Figure 5 - The infiltrate comprises an admixture of CD4- and CD8-expressing lymphocytes and CD68-expressing histiocytes.
Case 7 - Figure 6 - The infiltrate comprises an admixture of CD4- and CD8-expressing lymphocytes and CD68-expressing histiocytes.

Diagnosis
Cephalexin-induced rash in infectious mononucleosis showing features of Kikuchi-Fujimoto's disease

Adverse virus-drug interaction

Clinical History
Healthy 22yo male presented with a three day history of flu-like symptoms- fatigue, sore throat, cough, headache, and chest congestion and a low grade fever 99°F. Cefzil™ (cephalexin) was prescribed for presumptive sinusitis. One week later, he complained of an earache and non-pruritic, burning rash. The rash, morbilliform with erythematous and purpuric macules, began on the face then spread to the trunk, arms, legs and feet including palms and soles. Soft and hard palate exhibited petechiae, the tonsils were enlarged and covered by an exudate, and cervical lymphadenopathy was present. He completely recovered over the course of several weeks.

Laboratory studies
Laboratory tests determined two days prior to outbreak of rash revealed increased large monocytoid atypical lymphocytes, suggestive of an acute viral infection. Heterophile procedure was positive, consistent with mononucleosis. Additional cytological values included a WBC 10.9 *10^3/uL (reference range 4.8-10.8), hemoglobin 15.3 g/dL (reference range 14-18), hematocrit 44.7 % (reference range 42-52), bands 19% (reference range 0-6), seg 21% (reference range 41-71), lymphocytes 52% (reference range 24-44), monocytes 3% (reference range 0-10), eosinophils 5 % (reference range 0-5), atypical lymphocytes 16%. Serology for antinuclear antibodies (ANA) was negative.

Histologic findings
Punch biopsy of a papule revealed an interface dermatitis with perivascular and periadnexal, dense lymphocytic infiltrates. Vacuolar alteration of the basement membrane zone, areas of marked exocytosis, scattered necrotic keratinocytes and nuclear debris in reticular dermis were found, but no evidence of vasculitis (vessel wall destruction, fibrin deposits) or neutrophilic infiltrate was identified.

Immunophenotype
The lymphocytic infiltrate consisted mostly of CD3+, CD8+ and CD4+ lymphocytes with lesser amounts of CD5+> CD7+ lymphocytes. CD68 marked numerous medium-sized macrophages throughout the dermis that appeared to be lymphocytes by light microscopy (so called plasmacytoid monocytes). CD20 labeled rare, scattered solitary small lymphocytes. CD56, CD57 and CD30 antibodies were negative. Antibodies to Epstein-Barr virus (EBV) latent membrane protein and in situ hybridization for EBV RNA (EBER) tests were negative.

Discussion
This singular case can be best classified as an adverse virus-drug reaction. Although not well understood, there exists a spectrum of adverse drug reactions that are caused by the combined action of drugs and viruses [1, 2] :

ampicillin rash in acute infectious mononucleosis (IM)
Reye's syndrome (aspirin and viral infections (e.g. influenza B) leading to encephalopathy and hepatic dysfunction)
hypersensitivity reactions to sulphonamides in patients with HIV infection
drug-induced agranulocytosis
paracetamol (acetaminophen) hepatotoxicity
aspirin (acetylsalicyclic acid)-induced asthma
Epstein-Barr virus-associated lymphoma and methotrexate
AIDS-related Kaposi's sarcoma and nitrite use.

Interaction between drugs and viruses are heterogeneous and include immunologic mechanisms and changes in drug metabolism such as increased toxicity to drug and drug metabolites. In this case report, several poorly understood and likely related clinicopathologic phenomena are present that can be used to classify this patient's presentation: cutaneous manifestations of EBV infection, adverse drug-viral interactions, exanthematous drug reactions, and Kikuchi-Fujimoto's disease. Each phenomenon will be separately discussed.

Infectious mononucleosis (IM)
IM is an acute, self-limited disease caused by Epstein-Barr virus (EBV) that occurs most commonly in children, teenagers and young adults and is characterized by malaise, fever, pharyngitis and lymphadenopathy [3, 4] . These signs and symptoms can be difficult to differentiate from bacterial pharyngitis. Failure to make the correct diagnosis often leads to unnecessary antibiotic treatment [5] . Uncommonly, IM can present with a macular or maculopapular rash occurring on the trunk in 4.2-13% of affected patients. Other cutaneous presentations include morbilliform, scarlatiniform, herpetiform, palmar erythema, erythema-multiforme-like, erythema nodosum-like, acute pityriasis lichenoides-like, petechial/purpuric, granuloma-annulare-like, and urticarial eruptions [4, 6] . The incidence of a skin eruption in IM increases with the concomitant use of oral antibiotics: 14-23% with use of tetracycline and penicillin [7, 8] and from 42% to up to 100% with usage of aminopenicillins ampicillin and amoxicillin [7, 8, 9, 10, 11] . Indeed, the risk of rash for amoxicillin users who have IM is 58 times that for those without IM [12] . This eruption occurs 2-10 days after ingestion of antibiotics. The pathogenesis for this unusually high risk has not been determined, but viral infections are known to enhance the risk of cutaneous drug-allergic reactions [13] .

The histology of EBV's cutaneous eruption are said to be non-specific- a mild perivascular infiltrate of inflammatory cells [14, 15] . Rare photomicrographs of IM's rash [15, 16] show changes best interpreted as an acute vacuolar interface dermatitis (erythema multiforme-like with sparse infiltrates and rare necrotic keratinocytes [17] } similar to that seen in exanthematous (morbilliform} drug eruptions. EBV DNA was detected in keratinocytes from a widespread eruption in a patient with chronic lymphocytic leukemia [16] . In fact, EBV DNA can infect keratinocytes and lead to disease [18, 19] . Other cutaneous manifestations of EBV infection include Gianotti-Crosti syndrome [20, 21, 22] , oral hairy leukoplakia and lymphoproliferative lesions in immunocompromised patients [4, 23] .

Antibiotic-induced skin eruptions Antibiotic (mostly ampicillin related) associated cutaneous eruptions are a well recognized clinical phenomenon in the setting of IM, cytomegalovirus infection, chronic lymphocytic leukemia or in patients who are concurrently taking allopurinol [1, 2, 24, 25] . In the case of IM, mostly penicillin derivatives and several other antibiotics have been implicated in these virus-drug related rashes, which include ampicillin [7, 8, 11, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35] , amoxicillin [5, 36, 37] , methicillin [38] , ampicillin derivatives pivampicillin and talampicillin [39, 40] , cephalexin [41] , minocycline [42] , quinilone [43] , and azithromycin [44] . The pathogenesis of this antibiotic-induced viral eruption has not been elucidated, but it is suspected to be due to either breakdown of tolerance or enhancement of the immune reaction. Two general mechanisms believed to be involved are:

1) Change in the antigenic expression of the drug (or its metabolites) due to altered drug metabolism because of the change in expression of drug-metabolizing enzymes [45, 46, 47, 48]

2} Alteration of immune regulation [13, 49] such as polyclonal activation of lymphocytes [50] , production of antibodies against ampicillin [51] or specific cellular immunity [16, 52] .

A recent study by Renn and coworkers [52] demonstrated the presence of drug specific sensitization in 3 of 4 patients with amoxicillin-induced exanthema and infectious mononucleosis- a finding that argues against a non-allergic etiology [48, 53] . Clinically, rashes due to ampicillin occur in two forms: urticarial eruptions- an IgE mediated, immediate type hypersensitivity reaction [54, 55] ; Or, exanthematous eruptions, in patients with or without IM, seen as erythematous macules and/or papules associated with fever or pruritus [41, 56] . Additional signs include swelling of the lips and eyelids and generalized involvement including palms, soles, and palatal and buccal mucosa [8] . To date, the histologic features of the antibiotic-induced rash of IM have not been reported.

Exanthematous/morbilliform drug eruptions
Clinically, exanthematous drug reactions resemble viral exanthema and are recognized as erythematous, often confluent macules and papules that first appear on the trunk or areas of pressure and spread to involve extremities in a symmetric and often distinctive pattern of T1 dermatome involvement [57, 58] . Histologically, exanthematous drug reactions exhibit focal basal spongiosis and vacuolar change, apoptotic keratinocytes, lymphocyte exocytosis, and superficial perivascular lymphocytic infiltrate [17, 59, 60] . Activation and selection of drug specific T lymphocytes, mostly CD4+ helper cells, are thought to elicit exanthematous reactions [61, 62] .

Kikuchi-Fujimoto disease
Kikuchi-Fujimoto's disease (KFD), a.k.a. histiocytic necrotizing lymphadenitis, is an idiopathic, self-limiting lymphadenopathy associated with high-fever, occurring most often in young women [63] . In the lymph nodes, paracortical necrosis surrounded by foamy histiocytes, immunoblasts, and abundant karyorrhexis are the pathognomonic features [64] . This disease has a strong association with lupus erythematosus and can show skin involvement in 16-40% of affected patients [64] . The cutatnoeus manifestations of KFD are heterogeneous, extremely variable and include urticarial, morbilliform, rubella-like or drug eruption-like rashes, facial erythema, eyelid edema, leukocytoclastic vasculitis, and generalized erythema and papules, plaques and nodules distributed preferentially over the upper parts of the body- face, trunk, and upper extremities [65, 66] . The natural course of the skin eruption matches that of the lymph nodes- resolving spontaneously over a few weeks to months. Affected males with a skin eruption are thought to present with a more severe clinical course [64] .

Many features of KFD point to either an autoimmune or infectious cause. Imamura first suggested that it might a lupus (LE)-like autoimmune condition triggered by viral infection [67] . In fact, KFD lymph node and cutaneous pathology can be difficult to distinguish from lymph node and cutaneous LE [68, 69, 70, 71] . On the other hand, peripheral blood abnormalities (monocytosis, lymphocytosis, atypical lymphocytes and neutropenia), and its benign course with complete recovery are suggestive of a mononucleosis-like viral infection. Many infectious agents have been identified in association with KFD including Yersinia enterocolitica, Toxoplasma, parvovirus B19, HTLV-1, human herpesvirus (HHV) 6, and EBV [63] . The most commonly identified infectious agent is EBV [72, 73, 74, 75, 76, 77, 78] . (Several studies, however, have been negative for EBV [79, 80, 81] ). The number of EBV infected cells inversely correlates with the duration of disease implicating an immune response directed at EBV infected cells [63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74] . Rarely, KFD has rarely been associated with adverse drug reactions [82] .

In this case, the findings of interface dermatitis, perivascular and interstitial infiltrates of mononuclear cells with nuclear dust, and CD68 cells that appear to be lymphocytes by light microscopy point out the overlap with KFD.

Differential diagnosis

  • Lupus erythematosus
  • Other viral infections

Conclusion
Clearly, this patient had IM. Moreover, the onset of the rash a week after ingestion of cephalexin, a reported cause of a rash in IM [41] , implicate an antibiotic-induced exanthema (the antibiotic rash of IM). Singularly, the clinical findings and histology of the skin biopsy matched that reported for KFD, an entity that clinically overlaps with IM, and is suspected by many to represent either a direct reaction to infectious agent, most likely EBV, or self-limited autoimmune-like reaction [63] . Whether these findings represent mere coincidence or are of pathogenic significance cannot be stated with certainty because the pathological findings of antibiotic-induced rashes in IM have not been documented to date, and those of its non-antibiotic associated rash have been infrequently and poorly documented. The absence of EBV RNA and protein in lesional skin argue against a direct infective role for EBV in the etiology of this patient's skin eruption. The T cell predominance of the skin infiltrate [61] and known Th1 cytokine profile of IM [83] point to drug-virus activation of sensitized T cells [52] leading to this patients cutaneous manifestations. Future analysis of the pathologic findings of antibiotic induced rashes in IM will help clarify this phenomenon.

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