Lymphadenopathy is prevalent in DIDMOHS, affecting 75 % of patients. Patients may experience limited lymph node involvement or generalized lymphadenopathy with enlargement (1–2 cm) and tenderness involving the cervical, axillary, and inguinal lymph nodal regions. Two distinct variants are present on histopathology: benign lymphoid hyperplasia and pseudolymphoma.

Hematologic abnormalities are common in DIDMOHS. Eosinophilia is prominent, with eosinophil counts above >700/μL in 50–90 % of cases. Patients often demonstrate leukocytosis, up to 50 × 10⁹ leukocytes/L. During the period between drug initiation and the onset of DIDMOHS symptoms, a period of leukopenia or lymphopenia frequently precedes leukocytosis. Atypical lymphocytosis with large activated lymphocytes, lymphoblasts, or mononucleosis-like cells may be observed. Atypical lymphocytes, often regarded as characteristic for DIDMOHS, are present in roughly two-thirds of patients.

Hematology may also reveal a decrease in hemoglobin and hematocrit, as well as thrombocytopenia. In rare, severe cases, hemophagocytic syndrome has been linked with DIDMOHS approximately 2 weeks following reaction onset.

The liver is the most frequent site of internal organ involvement in DIDMOHS. Hepatic features are associated with phenytoin, minocycline, and dapsone-induced DIDMOHS. Hepatomegaly and jaundice may be seen, often with concurrent hepatitis of varying severity. Hepatitis associated with DIDMOHS is generally anicteric. In most cases, hepatitis is asymptomatic and detected only after laboratory studies are obtained. Approximately 70 % of patients exhibit serum alanine aminotransferase (ALT) elevation. DIDMOHS with erythema multiforme (EM)-like cutaneous findings (purpura and atypical targets) correlates with significantly greater increase of liver enzymes. Liver enzyme levels frequently remain elevated for several days following culprit drug withdrawal. In some cases, ALT elevation may persist for months.

Severe acute hepatitis, defined by ALT elevation of >10 times the upper limit of normal and/or acute hepatic failure with coagulopathy and encephalopathy, may occur in conjunction with DIDMOHS. Sulfasalazine is the most frequently implicated drug in this instance. In severe cases, generalized hepatic necrosis may be observed. Liver failure with coagulopathy and sepsis may complicate hepatic necrosis. In fact, hepatic necrosis is the leading cause of mortality in DIDMOHS. Jaundice as well as profound elevation of aspartate aminotransferase (AST) and bilirubin are prognostic markers for incipient liver transplantation or death, as cases of life-saving emergency liver transplantation have been reported.

Renal manifestations occur in 10–30 % of DIDMOHS patients; most commonly acute interstitial nephritis. Those with comorbid kidney disease and the elderly are particularly susceptible. Allopurinol is most closely linked with renal involvement, though carbamazepine and dapsone are also associated. In most cases, patients are asymptomatic, though patients may rarely report hematuria. Laboratory studies reveal serum creatinine and blood urea nitrogen (BUN) elevation consistent with impaired clearance. Proteinuria and eosinophiluria may also be observed. Typically, renal dysfunction is mild and recovery occurs following withdrawal of the culprit drug.

Pulmonary manifestations of DIDMOHS may also occur. Patients may experience dyspnea as well as nonproductive cough. Interstitial pneumonia may be observed, particularly in minocycline-induced DIDMOHS. In addition, pleuritis and impaired pulmonary function in association with DIDMOHS have been reported. DIDMOHS patients are also at risk for acute respiratory distress syndrome (ARDS) requiring emergent intubation and mechanical ventilation.

DIDMOHS may also involve the heart in the form of myocarditis. Minocycline and ampicillin are the most frequently implicated drugs. The onset of myocarditis is unpredictable, as it may occur early in the evolution of DIDMOHS or months following drug withdrawal.

Endocrine dysfunction may also be observed in association with DIDMOHS, more commonly as a long-term complication than during the acute phase of hypersensitivity. Thyroid abnormalities, most commonly thyroiditis and sick euthyroid syndrome, may be found, both of which may generate clinical hyperthyroidism, hypothyroidism, or both during their course. In addition, isolated elevation of free T4 or low thyrotropin (TSH) may be observed. Three to twelve months after DIDMOHS resolution, antithyroid antibodies may be detected. Correspondingly, symptoms of classical Graves’ Disease ensue. In rare cases, overt thyrotoxicosis may develop. Hashimoto’s Thyroiditis with antibodies directed to thyroid peroxidase (TPO) and thyroglobulin may also complicate DIDMOHS. Thus, routine assessment of thyroid function is recommended for at least 2 years in patients recovering from DIDMOHS.

Fulminant Type 1 diabetes mellitus (DMT1) may also present as a rare complication of DIDMOHS. Autoantibodies associated with classical DMT1 (i.e., islet cell and glutamic acid decarboxylase autoantibodies, etc.) are characteristically absent. Instead, DMT1 associated with DIDMOHS is thought to be related to HHV-6 reactivation.

DIDMOHS may also affect the gastrointestinal system. Gastroenteritis and associated dehydration are the most frequent findings. Acute gastrointestinal bleeding may also occur as a complication of ulcers, particularly in the setting of disseminated CMV infection. Arterial bleeding demonstrated via endoscopy may require emergent clipping and blood transfusion. In addition, colitis, pancreatitis, and even chronic enteropathy have also been reported.

Musculoskeletal involvement in the form of arthralgia and/or arthritis, in addition to myositis, may also occur in the context of DIDMOHS.

In rare cases, neurological manifestations evolve from DIDMOHS, namely meningitis and encephalitis. These complications develop roughly 2–4 weeks following reaction onset. Associated clinical findings include speech abnormalities, headache, seizure, muscle weakness, cranial nerve palsies, and coma.