Diagnosis is made by a positive direct Coombs test, other lab tests, and clinical examination and history. The direct Coombs test looks for antibodies attached to the surface of red blood cells.

Laboratory findings include severe anemia, increased mean corpuscular volume (MCV, due to the presence of a large number of reticulocytes), and hyperbilirubinemia (from increased red cell destruction) that can be of the conjugated or unconjugated type.

The following findings may be present:

- Increased red cell breakdown

- Elevated serum bilirubin (unconjugated)

- Excess urinary urobilinogen

- Reduced plasma haptoglobin

- Raised serum lactic dehydrogenase (LDH)

- Hemosiderinuria

- Methemalbuminemia

- Spherocytosis

- Increased red cell production:

- Reticulocytosis

- Erythroid hyperplasia of the bone marrow

- Specific investigations

- Positive direct Coombs test

Diagnosis is made by first ruling out other causes of hemolytic anemia, such as G6PD, thalassemia, sickle-cell disease, etc. Clinical history is also important to elucidate any underlying illness or medications that may have led to the disease.

Following this, laboratory investigations are carried out to determine the etiology of the disease. A positive DAT test has poor specificity for AIHA (having many differential diagnoses); so supplemental serological testing is required to ascertain the cause of the positive reaction. Hemolysis must also be demonstrated in the lab. The typical tests used for this are a complete blood count (CBC) with peripheral smear, bilirubin, lactate dehydrogenase (LDH) (in particular with isoenzyme 1), haptoglobin and urine hemoglobin.

Drug-induced autoimmune hemolytic anemia is a form of hemolytic anemia.

In some cases, a drug can cause the immune system to mistakenly think the body's own red blood cells are dangerous, foreign substances. Antibodies then develop against the red blood cells. The antibodies attach to red blood cells and cause them to break down too early. Drugs that can cause this type of hemolytic anemia include:

- Cephalosporins (a class of antibiotics) – most common cause

- Dapsone

- Levodopa

- Levofloxacin

- Methyldopa

- Nitrofurantoin

- Nonsteroidal anti-inflammatory drugs (NSAIDs)

- Phenazopyridine (pyridium)

- Quinidine

Penicillin in high doses can induce immune mediated hemolysis via the hapten mechanism in which antibodies are targeted against the combination of penicillin in association with red blood cells. Complement is activated by the attached antibody leading to the removal of red blood cells by the spleen.

The drug itself can be targeted by the immune system, e.g. by IgE in a Type I hypersensitivity reaction to penicillin, rarely leading to anaphylaxis.

Drug induced hemolysis has large clinical relevance. It occurs when drugs actively provoke red blood cell destruction. It can be divided in the following manner:

- Drug-induced autoimmune hemolytic anemia

- Drug-induced nonautoimmune hemolytic anemia

A total of four mechanisms are usually described, but there is some evidence that these mechanisms may overlap.

Acquired hemolytic anemia can be divided into immune and non-immune mediated forms of hemolytic anemia.

Drug-induced nonautoimmune hemolytic anemia is a form of hemolytic anemia.

Non-immune drug induced hemolysis can occur via oxidative mechanisms. This is particularly likely to occur when there is an enzyme deficiency in the antioxidant defense system of the red blood cells. An example is where antimalarial oxidant drugs like primaquine damage red blood cells in Glucose-6-phosphate dehydrogenase deficiency in which the red blood cells are more susceptible to oxidative stress due to reduced NADPH production consequent to the enzyme

deficiency.

Some drugs cause RBC (red blood cell) lysis even in normal individuals. These include dapsone and sulfasalazine.

Non-immune drug-induced hemolysis can also arise from drug-induced damage to cell volume control mechanisms; for example drugs can directly or indirectly impair regulatory volume decrease mechanisms, which become activated during hypotonic RBC swelling to return the cell to a normal volume. The consequence of the drugs actions are irreversible cell swelling and lysis (e.g. ouabain at very high doses).

Drug-induced thrombocytopenic purpura is a skin condition result from a low platelet count due to drug-induced anti-platelet antibodies caused by drugs such as heparin, sulfonamines, digoxin, quinine, and quinidine.

Patients show markedly low immunoglobulin levels of IgG, IgA, and IgM.

In all cases of suspected NEH, a skin biopsy should be performed, because the clinical symptoms are non specific, but the histopathological findings on the biopsy are specific. The biopsy shows characteristic changes of the eccrine glands, the major sweat glands of the body.

In NEH, eccrine gland necrosis, and neutrophils surroundings the eccrine glands, are typical findings on biopsy. If the chemotherapy has recently been administered, chemotherapy induced neutropenia may be present, and, as a result, the neutrophils may be absent. But the other characteristic finding, i.e. eccrine gland necrosis, can still be seen. A vacuolar interface dermatitis also is visible in glands and ducts, along with necrosis of the lining cells.

In addition, in patients receiving chemotherapy, keratinocyte atypia can be seen.

The diagnosis is based on involvement of less than 10% of the skin. It is known as TEN when more than 30% of the skin is involved and an intermediate form with 10 to 30% involvement. A positive Nikolsky's sign is helpful in the diagnosis of SJS and TEN. A skin biopsy is helpful, but not required, to establish a diagnosis of SJS and TEN.

Drug eruptions are diagnosed mainly from the medical history and clinical examination. However, they can mimic a wide range of other conditions, thus delaying diagnosis (for example, in drug-induced lupus erythematosus, or the acne-like rash caused by erlotinib). A skin biopsy, blood tests or immunological tests can also be useful.

Drug reactions have characteristic timing. The typical amount of time it takes for a rash to appear after exposure to a drug can help categorize the type of reaction. For example, Acute generalized exanthematous pustulosis usually occurs within 4 days of starting the culprit drug. Drug Reaction with Eosinophilia and Systemic Symptoms usually occurs between 15 and 40 days after exposure. Toxic epidermal necrolysis and Stevens-Johnson syndrome typically occur 7–21 days after exposure. Anaphylaxis occurs within minutes. Simple exanthematous eruptions occur between 4 and 14 days after exposure.

TEN and SJS are severe cutaneous drug reactions that involve the skin and mucous membranes. To accurately diagnose this condition, a detailed drug history is crucial. Often, several drugs may be causative and allergy testing may be helpful. Sulfa drugs are well-known to induce TEN or SJS in certain people. For example, HIV patients have an increased incidence of SJS or TEN compared to the general population and have been found to express low levels of the drug metabolizing enzyme responsible for detoxifying sulfa drugs. Genetics plays an important role in predisposing certain populations to TEN and SJS. As such, there are some FDA recommended genetic screening tests available for certain drugs and ethnic populations to prevent the occurrence of a drug eruption. The most well known example is carbamezepine (an anti-convulsant used to treat seizures) hypersensitivity associated with the presence of HLA-B*5801 genetic allele in Asian populations.

DIHS is a delayed onset drug eruption, often occurring a few weeks to 3 months after initiation of a drug. Interestingly, worsening of systemic symptoms occurs 3-4 days after cessation of the offending drug. There are genetic risk alleles that are predictive of the development of DIHS for particular drugs and ethnic populations. The most important of which is abacavir (an anti-viral used in the treatment of HIV) hypersensitivity associated with the presence of the HLA-B*5701 allele in European and African population in the United States and Australians.

AGEP is often caused by antimicrobial, anti-fungal or antimalarial drugs. Diagnosis is often carried out by patch testing. This testing should be performed within one month after resolution of the rash and patch test results are interpreted at different time points: 48 hours, 72hours and even later at 96 hours and 120 hours in order to improve the sensitivity.

It is estimated that 2—3 percent of hospitalised patients are affected by a drug eruption, and that serious drug eruptions occur in around 1 in 1000 patients.

Stevens–Johnson syndrome (SJS) is a milder form of toxic epidermal necrolysis (TEN). These conditions were first recognised in 1922. A classification first published in 1993, that has been adopted as a consensus definition, identifies Stevens–Johnson syndrome, toxic epidermal necrolysis, and SJS/TEN overlap. All three are part of a spectrum of severe cutaneous reactions (SCAR) which affect skin and mucous membranes. The distinction between SJS, SJS/TEN overlap, and TEN is based on the type of lesions and the amount of the body surface area with blisters and erosions. It is agreed that the most reliable method to classify EM, SJS, and TEN is based on lesion morphology and extent of epidermal detachment. Blisters and erosions cover between 3% and 10% of the body in SJS, 11–30% in SJS/TEN overlap, and over 30% in TEN. The skin pattern most commonly associated with SJS is widespread, often joined or touching (confluent), papuric spots (macules) or flat small blisters or large blisters which may also join together. These occur primarily on the torso.

SJS, TEN, and SJS/TEN overlap can be mistaken for erythema multiforme. Erythema multiforme, which is also within the SCAR spectrum, differs in clinical pattern and etiology. Although both SJS and TEN can also be caused by infections, they are most often adverse effects of medications.

A new investigation has identified a seemingly successful treatment for LRBA deficiency by targeting CTLA4. Abatacept, an approved drug for rheumatoid arthritis, mimics the function of CTLA4 and has found to reverse life-threatening symptoms. The study included nine patients that exhibited improved clinical status and halted inflammatory conditions with minimal infectious or autoimmune complications. The study also suggests that therapies like chloroquine or hydroxychloroquine, which inhibit lysosomal degradation, may prove to be effective, as well. Larger cohorts are required to further validate these therapeutic approaches as effective long-term treatments for this disorder.

NEH is self-limited and usually resolves without treatment. In the overwhelming majority of the cases, spontaneous resolution occurs within 1–2 weeks.

However, if the patient developed NEH after chemotherapy, the offending cytotoxic drug has to be discontinued, and the patient must avoid this particular cytotoxic drug in the future, because NEH usually re occurs upon re exposure to the same cytotoxic drug.

Despite the fact that NEH is self limited and usually resolves without treatment, some researchers use treatment, mainly systemic corticosteroids, although the efficacy of such a therapy has not been demonstrated in a large randomised controlled clinical trial until now.

A careful history is of utmost importance when the diagnosis of pseudoporphyria is being considered. A personal and family history of hepatitis, porphyria, or photosensitivity disorder must be sought.

Although a genetic factor has not been considered in pseudoporphyria, one case of monozygotic twins developing pseudoporphyria after excessive UV-A exposure from long-term tanning bed use has been documented.

The patient should be thoroughly questioned regarding any symptoms of connective tissue disorder, which may be the underlying pathology of the photosensitivity. Recent reports suggest that a connective tissue disorder may be a predisposing factor in patients using nonsteroidal anti-inflammatory drugs (NSAIDs) who develop pseudoporphyria.

This remains a challenge in clinical practice due to a lack of reliable markers. Many other conditions lead to similar clinical as well as pathological pictures. To diagnose hepatotoxicity, a causal relationship between the use of the toxin or drug and subsequent liver damage has to be established, but might be difficult, especially when idiosyncratic reaction is suspected. Simultaneous use of multiple drugs may add to the complexity. As in acetaminophen toxicity, well established, dose-dependent, pharmacological hepatotoxicity is easier to spot. Several clinical scales such as CIOMS/RUCAM scale and Maria and Victorino criteria have been proposed to establish causal relationship between offending drug and liver damage. CIOMS/RUCAM scale involves a scoring system that categorizes the suspicion into "definite or highly probable" (score > 8), “probable” (score 6-8), “possible” (score 3-5), “unlikely” (score 1-2) and “excluded” (score ≤ 0). In clinical practice, physicians put more emphasis on the presence or absence of similarity between the biochemical profile of the patient and known biochemical profile of the suspected toxicity (e.g., cholestatic damage in amoxycillin-clauvonic acid ).

Drugs that commonly induce DRESS syndrome include phenobarbital, carbamazepine, phenytoin, lamotrigine, minocycline, sulfonamides, allopurinol, modafinil, dapsone, ziprasidone, vancomycin, and most recently olanzapine.

It has been associated with HHV-6 reactivation.

Drug-induced purpura is a skin condition that may be related to platelet destruction, vessel fragility, interference with platelet function, or vasculitis.

Several health authorities have issued related guidance documents, which need to be considered for drug development:

- ICH (International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use)

- M3(R2) "Guidance on Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals"

- S9 "Nonclinical Evaluation for Anticancer Pharmaceuticals"

- S10 "Photosafety Evaluation"

- EMA (European Medicines Agency)

- "Note for Guidance on Photosafety Testing" (revision on-hold)

- "Question & Answers on the Note for Guidance on Photosafety Testing"

- FDA (U.S. Food and Drug Administration)

- MHLW/PMDA (Japanese Ministry of Health, Labour and Welfare / Pharmaceuticals and Medical Devices Agency)

The symptoms of DRESS syndrome usually begin several weeks after exposure to the offending drug. No gold standard exists for diagnosis, and at least two diagnostic criteria have been proposed. The RegiSCAR criteria and the Japanese consensus group criteria are detailed in the table below.

Symptoms may be severe and involve many different organs. In a retrospective Taiwanese cohort study of 60 patients, these incidences were observed.

In most cases, liver function will return to normal if the offending drug is stopped early. Additionally, the patient may require supportive treatment. In acetaminophen toxicity, however, the initial insult can be fatal. Fulminant hepatic failure from drug-induced hepatotoxicity may require liver transplantation. In the past, glucocorticoids in allergic features and ursodeoxycholic acid in cholestatic cases had been used, but there is no good evidence to support their effectiveness.

An elevation in serum bilirubin level of more than 2 times ULN with associated transaminase rise is an ominous sign. This indicates severe hepatotoxicity and is likely to lead to mortality in 10% to 15% of patients, especially if the offending drug is not stopped (Hy's Law). This is because it requires significant damage to the liver to impair bilirubin excretion, hence minor impairment (in the absence of biliary obstruction or Gilbert syndrome) would not lead to jaundice. Other poor predictors of outcome are old age, female sex, high AST.

The primary treatment strategy is to eliminate or discontinue the offensive agent. Supportive therapy, such as ice packs, may be provided to get the body temperature within physiologic range. In severe cases, when the fever is high enough (generally at or above ~104° F or 40° C), aggressive cooling such as an ice bath and pharmacologic therapy such as benzodiazepines may be deemed appropriate.