Eosinophils, Fevers, and Diarrhea With a Surprise Diagnosis in a Patient With AIDS

ContagionOctober 2019
Volume 4
Issue 5

When the CD4 count seems too good to be true.


Drug rash with eosinophilia and systemic symptoms (DRESS) syndrome


A 31-year-old male patient with AIDS (last CD4 count, 77; 3 weeks prior) presented to clinic with a 3-day history of abrupt-onset fatigue, abdominal pain, high-output diarrhea, nausea, weakness, nasal congestion, and dry cough. His stools were watery, nonbloody, and green in color, with a frequency of 5 to 10 episodes daily. He also described progressive, diffuse pruritus over the prior 2 weeks.

Of note, the patient carried a diagnosis of HIV and, in the years leading to presentation, was antiretroviral nonadherent. Six months prior to admission, he was started on antiretroviral therapy and achieved regression of viral load from 269,000 to undetectable within 4 months, with an increase in CD4 count to 77 from 34. Two weeks later, he developed herpes zoster in unilateral trigeminal V2 distribution with overlying impetigo, thought to be a manifestation of immune reconsti­tution inflammatory syndrome (IRIS). He subsequently devel­oped debilitating postherpetic trigeminal neuralgia and was treated with carbamazepine and gabapentin. The patient was adherent with antiretroviral therapy and appropriate oppor­tunistic infection prophylaxis throughout this time.

The patient was sent to the emergency department for inpatient work-up of diarrhea. Initial differential was broad given the patient’s AIDS status, with high suspicion for viral, bacterial, or parasitic gastroenteritis.


AIDS and postherpetic trigeminal neuralgia as described above


Bictegravir (tenofovir alafenamide/emtricitabine/bictegravir), dapsone for prophylaxis, carbamazepine, and gabapentin


The patient is a US immigrant born on the Ivory Coast. He had traveled between Philadelphia, Pennsylvania, and Virginia over the prior year and to France in the prior 5 years but had not returned to the Ivory Coast in the prior 10 years. He was sexually active with 3 female partners, with condom use. He denied tobacco, alcohol, or other drug use. He works as a computer programmer, lives alone, and has no pets.


Physical examination at presentation was unremarkable aside from mild tachycardia of 105 beats per minute and diffuse abdominal tenderness without guarding. He was afebrile with nonlabored respirations. Oropharynx was clear, lungs were clear to auscultation, extremities were nonedematous, and no lymphadenopathy was appreciated. Despite the patient’s pruritus, skin examination revealed only mild excoriations on the arms and trunk, with no rashes.


On admission, the patient’s labs showed a nonanion gap metabolic acidosis with respiratory compensation, consis­tent with lower gastrointestinal fluid loss in the setting of diarrhea. Metabolic panel also revealed creatinine level elevation to 3 times the baseline, with a ratio of blood urea nitrogen to creatinine of 9. Urinalysis revealed proteinuria and granular casts; urine cultures were negative. Complete blood count demonstrated a neutrophilic predominant leukocytosis with left shift. Absolute eosinophil count was elevated, at 6000 cells/μL. CD4 T-cell count was 748, up from 77 three weeks prior.

The normal CD4 count was regarded with suspicion given the recent AIDS status, and initial diarrhea work-up included opportunistic infections with high suspicion for parasites. Stool specimen showed many white blood cells. Work-up was negative for stool ova/parasites, Microsporidium, Cryptosporidium, Isospora, Clostridioides difficile, acid-fast bacilli (AFB) smear, giardia, and shiga toxin. Strongyloides serology; hepatitis A, B, and C serology; histoplasma urine antigen; Aspergillus antigen; and (1,3)-β-D-glucan were negative as well. No AFB grew in blood cultures. Abdominal computed tomography (CT) was significant for only diffuse lymphadenopathy.

Pertinent positive results included remarkably elevated serum immunoglobulin (Ig) E at 48,647 units/mL, bronchial wash positive for adenovirus serogroup C, positive human herpesvirus 6 (HHV6), and Epstein-Barr virus (EBV) in blood.


Upper and lower enteroscopy showed normal stomach and duodenum, diffuse colitis, and nodularity of the terminal ileum. Biopsy showed moderate duodenitis, moderate ileitis, and severe crypt destructive colitis, with pathologic find­ings suggestive of chronic enteric infection. Granulomas, Cryptosporidium, AFB, and cyto­megalovirus (CMV) were absent.


After receiving 2 days of fluids and broad-spectrum antibiotics, the patient left against medical advice, only to return the next day with persisting symptoms. Shortly after read­mission, the patient developed tachycardia and tachypnea, which progressed over 3 days to respi­ratory failure requiring transfer to the intensive care unit (ICU) and intubation on hospital day 8. Immediately before initial intubation, the patient’s exam was significant for a respiratory rate greater than 40 breaths per minute, diffuse retractions, and absent breath sounds. Along with respira­tory failure, the patient also developed worsening fevers, leukocytosis, thrombocytopenia, transami­nitis, and hypereosinophilia, along with facial and extremity edema on exam (see FIGURE). HHV6 was positive in blood, and respiratory virus panel was positive for adenovirus.

After intubation, the patient was started on a 9-day methylprednisolone taper for suspected DRESS and experienced gradual symptomatic improvement and resolution of hypereosinophilia (see Figure online). Treatment of adenovirus was considered but decided against because of acute liver injury. On hospital day 17, the patient was extubated successfully and transferred to the progressive care unit. In total, the patient was hospitalized for 2 months, with 1 month spent in the ICU. He was ultimately discharged to a rehabil­itation facility with tracheostomy and gastrostomy tube in place to begin recovery after a lengthy hospital course.


DRESS is a moderate-to-severe reaction with onset generally occurring 2 to 6 weeks after drug initi­ation. DRESS encompasses a diverse yet distinct set of reactions characterized by fevers, rash, leukocyte abnormalities, and multiorgan symp­toms.1 The RegiSCAR and JSCAR criteria have been proposed for diagnosis of DRESS. RegiSCAR criteria describe potential DRESS if the reaction was suspected to be drug related and the patient required hospitalization with 3 or more of the following findings: acute skin rash, fever, lymph­adenopathy, visceral organ involvement, leukocy­tosis, eosinophilia, thrombocytopenia.2 The JSCAR criteria are similar but notably include prolonged symptoms longer than 2 weeks following drug discontinuation and HHV6 reactivation.3 Mortality is estimated at 10% and is usually due to hepatic necrosis.4 Carbamazepine is the agent most commonly implicated in DRESS.5

Risk for developing DRESS is multifactorial, but the reaction appears to emerge within a milieu of drug toxicity and maladaptive immune response. Mutations in drug detoxification and metabolism enzymes, which result in accumula­tion of toxic metabolites, have been implicated in anticonvulsant- and sulfonamide-associated DRESS.1 Certain HLA haplotypes are associated with increased risk, with reactions to carbamaz­epine being associated with HLA-A*31:01, A*11, and B*51.6 These associations, along with a 2- to 6-week delay in symptom onset after drug initi­ation, suggest a delayed-type, hypersensitivitylike reaction to the drug, immunogenic metabolites, or haptens. Indeed, T cells reacting to carbamaz­epine have been identified in patients.7 However, other immunologic and infectious phenomena observed in DRESS suggest a more complex patho­genesis. In initial stages of disease, patients enter an immunosuppressive state characterized by increased regulatory T cells and decreased IgG and IgA. Within this environment, latent herpesviruses sequentially reactivate, either by direct stimulation from the drug or by virtue of opportunity.8 HHV6 reactivation, generally measured as a rise in HHV6 IgG, is especially characteristic.3 Generally HHV6 and EBV are seen early in disease, and CMV is seen as the patient experiences sequential flares.6 As disease progresses, an expansion of cytotoxic T lymphocytes occurs, heralding systemic inflamma­tion.8 Activity of cytotoxic T cells against tissues harboring reactivated virus is thought to be a significant cause of organ damage.9

Visceral organ involvement is the major cause of morbidity in DRESS syndrome.10 The most frequently involved organs, in order, are the liver, the kidney, and the lung.6 Gastrointestinal involve­ment is rare but can be serious and often leads to dehydration.1 Cases of DRESS involving nonin­fectious, inflammatory colitis have been described in reactions to carbamazepine11 and vancomycin.12 Skin involvement is reported in up to 100% of DRESS reactions.13 Maculopapular rash is most common, but cutaneous manifestations are highly variable and range from erythema to toxic epidermal necrolysis.4 Facial edema is common, as well, present in up to 76% of cases.13 Cases of DRESS without rash have been reported, but they are rare.5

This patient is somewhat of an atypical case, presenting with diarrhea. No rash was observed throughout the hospital course, with the only cuta­neous findings being pruritus and facial edema. The patient did, however, qualify for RegiSCAR criteria,2 with development of fevers, hypereo­sinophilia, lymphadenopathy, and organ involve­ment—namely liver, lung, and potentially kidney. With persistence of symptoms and a finding of HHV6, the patient also qualified as an atypical case of DRESS per JSCAR criteria.3

Treatment of DRESS begins with immediate withdrawal of the offending drug. Improvement of symptoms and lab abnormalities is best achieved with corticosteroids and supportive care.14 Intravenous IG treatment has been proposed but carries a high risk of severe adverse effects and is thus advised against.15 As viral reactivation plays an integral role in disease pathogenesis, antivirals such as ganciclovir and cidofovir have been used, as well, but toxicity is a major concern in the setting of multiorgan disease.16 Cidofovir is the only agent with consistent demonstratable effi­cacy against adenovirus.17 Cidofovir treatment was considered in the patient after evidence of adeno­virus in bronchoalveolar lavage was found, but the risk of nephrotoxicity was considered too great.

Corticosteroids, though efficacious, may increase the risk of developing infection and even sepsis by exacerbating the patient’s already immunosuppressed state.6

Patients with AIDS present a unique chal­lenge in both diagnosis and treatment of DRESS. The multiorgan manifestations of DRESS, when presenting in patients with AIDS, require extensive work-up to rule out a readily treatable infectious cause. As mentioned, corticosteroids are the only known effective treatment for DRESS but may increase risk of secondary infection or exacer­bate existing infection. Furthermore, DRESS in itself is associated with an immunosuppres­sive state in which reactivation of latent viruses leads to morbidity and organ damage through intense inflammatory response. Descamps et al have noted that DRESS-like syndromes occur in immunosuppressed patients in the absence of an offending drug, which they have proposed may represent a “viral reactivation with eosinophilia and systemic symptoms.”16 One such example is IRIS, which in this patient manifested with an immune response to the zoster herpesvirus. This overlap in disease mechanism can complicate the distinction between DRESS and IRIS,18 especially as many drugs frequently used in patients with AIDS have been implicated in DRESS, including antibiotics such as trimethoprim/sulfamethox­azole, mycobacterial therapies,6 and antiretrovi­rals such as raltegravir19 and dolutegravir.20 Cases of DRESS in patients with AIDS are rarely shared in the literature, perhaps because of low inci­dence. Practitioners who observe this syndrome in immunocompromised individuals and patients with AIDS should share their experience to better elucidate how clinicians can optimize DRESS therapy for this vulnerable population.

Whitehill is a fourth-year medical student at Drexel University College of Medicine currently applying for residency in internal medicine. He has a long-standing interest in hematology/oncology and has recently developed a waxing fascination with infectious disease. Adegoke is a fourth-year medical student from Long Island, New York, pursuing a career in internal medicine. She is passionate about patient advocacy and delivering high-quality care to underserved communities. Onyekaba is a second-year infectious disease fellow at Cooper University Hospital in Camden, New Jersey.


1.) Husain Z, Reddy YB, Schwartz RA. DRESS syndrome Part I. Clinical Perspectives. J Am Acad Dermatol. 2013 May;68(5):693.e1-14; quiz 706-8. doi: 10.1016/j.jaad.2013.01.033..

2.) Kardaun SH, Sidoroff A, Valeyrie-Allanore L, et al. Variability in the clinical pattern of cutaneous side-effects of drugs with systemic symptoms: does a DRESS syndrome really exist? Br J Dermatol. 2007 Mar;156(3):609-11. doi: 10.1111/j.1365-2133.2006.07704.x.

3.) Shiohara T, Iijima M, Ikezawa Z, et al. The diagnosis of a DRESS syndrome has been sufficiently established on the basis of typical clinical features and viral reactivations. Br J Dermatol. 2007 May;156(5):1083-4. Epub 2007 Mar 23. doi: 10.1111/j.1365-2133.2007.07807.x.

4.) Peyriere H, Dereure O, Breton H, et al. Variability in the clinical pattern of cutaneous side‐effects of drugs with systemic symptoms: does a DRESS syndrome really exist? British J Dermatol. 2006 Aug;155(2):422-8. doi: 10.1111/j.1365-2133.2006.07284.x.

5.) Cacoub P, Musette P, Descamps V, et al. The DRESS Syndrome: A Literature Review. Am J Med. 2011 Jul;124(7):588-97. doi: 10.1016/j.amjmed.2011.01.017. Epub 2011 May 17.

6.) Cho Y, Yang CW, Chu CY. Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): An Interplay among Drugs, Viruses, and Immune System. Int J Mol Sci. 2017 Jun 9;18(6). pii: E1243. doi: 10.3390/ijms18061243.

7.) Naisbitt DJ, Britschgi M, Wong G, et al. Hypersensitivity reactions to carbamazepine: characterization of the specificity, phenotype, and cytokine profile of drug-specific T cell clones. Mol Pharmacol. 2003 Mar;63(3):732-41. doi: 10.1124/mol.63.3.732.

8.) Criado PR, Criado RFJ, Avancini JM, et al. Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/ Drug-Induced Hypersensitivity Syndrome (DIHS): a review of current concepts. An Bras Dermatol. 2012 May-Jun;87(3):435-49. doi: 10.1590/s0365-05962012000300013.

9.) Picard D, Janela B, Descamps V, et al. Drug reaction with eosinophilia and systemic symptoms (DRESS): a multiorgan antiviral T cell response. Sci Transl Med. 2010 Aug 25;2(46):46ra62. doi: 10.1126/scitranslmed.3001116.

10.) Choudhary S, McLeod M, Torchia D, et al. Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Syndrome. J Clin Aesthet Dermatol. 2013 Jun;6(6):31-7.

11.) Eland IA, Dofferhoff AS, Vink R, Zondervan PE, Stricker BH. Colitis may be part of the antiepileptic drug hypersensitivity syndrome. Epilepsia. 1999 Dec;40(12):1780-3. doi: 10.1111/j.1528-1157.1999.tb01598.x.

12.) Adike A, Boppana V, Lam-Himlin D, Stanton M, Nelson S, Ruff KC. A Mysterious DRESS Case: Autoimmune Enteropathy Associated with DRESS Syndrome. Case Rep Gastrointest Med. 2017;2017:7861857. doi: 10.1155/2017/7861857. Epub 2017 Nov 26.

13.) Kardaun SH, Sekula P, Valeyrie-Allanore L, et al. Drug reaction with eosinophilia and systemic symptoms (DRESS): an original multisystem adverse drug reaction. Results from the prospective RegiSCAR study. Br J Dermatol. 2013 Nov;169(5):1071-80. doi: 10.1111/bjd.12501.

14.) Husain Z, Reddy YB, Schwartz RA. DRESS syndrome Part II. Management and Therapeutics. J Am Acad Dermatol. 2013 May;68(5):709.e1-9; quiz 718-20. doi: 10.1016/j.jaad.2013.01.032.

15.) Joly P, Janela B, Tetart F, et al. Poor benefit/risk balance of intravenous immunoglobulins in DRESS. Arch Dermatol. 2012 Apr;148(4):543-4. doi: 10.1001/archderm.148.4.dlt120002-c.

16.) Descamps V, Ranger-Rogez S. DRESS Syndrome. Joint Bone Spine. 2014 Jan;81(1):15-21. doi: 10.1016/j.jbspin.2013.05.002. Epub 2013 Jun 29.

17.) Lion T. Adenovirus infections in immunocompetent and immunocompromised patients. Clin Microbiol Rev. 2014 Jul;27(3):441-62. doi: 10.1128/CMR.00116-13.

18.) Almudimeegh A, Rioux C, Ferrand H, Crickx B, Yazdanpanah Y, Descamps V. Drug reaction with eosinophilia and systemic symptoms, or virus reactivation with eosinophilia and systemic symptoms as a manifestation of immune reconstitution inflammatory syndrome in a patient with HIV. Br J Dermatol. 2014 Oct;171(4):895-8. doi: 10.1111/bjd.13079. Epub 2014 Sep 4.

19.) Thomas M, Hopkins C, Duffy E, et al. Association of the HLA-B*53:01 allele with drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome during treatment of HIV infection with raltegravir. Clin Infect Dis. 2017 May 1;64(9):1198-1203. doi: 10.1093/cid/cix096.

20.) Martin C, Payen MC, De Wit S. Dolutegravir as a trigger for DRESS syndrome? Int J STD AIDS. 2018 Sep;29(10):1036-1038. doi: 10.1177/0956462418764973. Epub 2018 Apr 5.

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