Isoniazid-associated pellagra during mass scale-up of tuberculosis preventive therapy: a case-control study.

BACKGROUND: Pellagra is caused by niacin (vitamin B3) deficiency and patients with pellagra present with a characteristic rash. Isoniazid disrupts intracellular niacin synthesis and might induce niacin deficiency. In 2017, Malawi scaled up continuous isoniazid preventive treatment (IPT) for tuberculosis prevention among people living with HIV. In addition, an under-diversified diet based on subsistence maize, as is commonly the case in Malawi, is a risk factor for pellagra. We aimed to investigate whether large-scale isoniazid exposure in Malawi contributed to the cumulative risk for pellagra in a nutritionally vulnerable population. METHODS: We did a matched case-control study to evaluate the association between daily, continuous isoniazid exposure and pellagra. We matched sequentially enrolled patients with pellagra each with four control participants by sex and age from referral dermatology centres in three IPT scale-up districts in Malawi (Lilongwe, Blantyre, and Zomba) to evaluate isoniazid as a risk for pellagra using multivariable conditional logistic regression. We established a community clinic referral system surrounding the dermatology clinic in each district to enhance case-finding and included all patients with pellagra, regardless of referral status. The primary outcome was dermatologist-diagnosed pellagra. We calculated the interval between isoniazid initiation and rash onset and assessed 30-day clinical outcomes after multi-B vitamin treatment containing 300 mg nicotinamide daily. FINDINGS: Between Feb 5 and Aug 9, 2019, we enrolled 197 patients with pellagra and 781 matched controls. Isoniazid exposure was associated with an increased risk of pellagra (adjusted odds ratio 42·6 [95% CI 13·3-136·6]). Significant covariates included HIV infection, referral status, food insecurity, underweight, excess alcohol consumption, and, among women, lactation. The median time from isoniazid initiation to rash onset was shorter during the season of food scarcity (5 months [IQR 3-7]) compared with the harvest season (9 months [8-11]; hazard ratio 7·2 [95% CI 3·2-16·2], log-rank p<0·0001). Those with isoniazid-associated pellagra who discontinued isoniazid and adhered to multi-B vitamin treatment showed 30-day clinical improvement. INTERPRETATION: Continuous IPT scale-up and the annual period of food scarcity both increased the risk of pellagra in Malawi. Use of shorter rifamycin-based regimens for tuberculosis prevention and food fortification in populations with undernutrition might reduce this risk. Niacin-containing multi-B vitamin co-administration with isoniazid as pellagra prevention is worth exploring further. FUNDING: This study was supported by the President's Emergency Plan for AIDS Relief through the US Centers for Disease Control and Prevention under project 7173.

Effect of niacin supplementation on nausea-like behaviour in an isoniazid-induced mouse model of pellagra.

Niacin deficiency causes pellagra, the symptoms of which include dermatitis, diarrhoea and dementia. Investigating the mechanism underlying these phenotypes has been challenging due to the lack of an appropriate animal model. Here, we report a mouse model of pellagra-related nausea induced by feeding mice a low-niacin diet and administering isoniazid (INH), which is thought to induce pellagra. Mice fed a normal or low-niacin diet received INH (0·3 or 1·0 mg/mg per animal, twice daily, 5 d), and nausea was evaluated based on pica behaviour, which considered the rodent equivalent of the emetic reflex. Furthermore, the effect of therapeutic niacin administration on nausea was evaluated in this model. Urinary and hepatic metabolite levels were analysed by LC coupled with MS. INH-induced pica was observed in mice fed a low-niacin diet but not in those fed a normal diet. Levels of urinary metabolites, such as 1-methyl-2-pyridone-5-carboxamide, kynurenic acid and xanthurenic acid, were significantly reduced in the mice treated with INH compared with those that did not receive INH. Furthermore, niacin supplementation prevented pica and restored the levels of some metabolites in this mouse model. Our findings suggest that INH-related nausea is pellagra-like. We also believe that our newly established method for quantifying pica is a useful tool for investigating the mechanisms of pellagra-related nausea.

A peculiarly characterised case of isoniazid-induced pellagra- 2 Ds and a C: a case report.

Niacin or tryptophan deficiency causes pellagra. Isoniazid interferes with the absorption of niacin and individuals on Isoniazid (INH) are at risk of pellagra. Isoniazid preventive therapy (IPT) is the administration of isoniazid to immunosuppressed individuals to prevent active tuberculosis (TB). IPT, in sub-Saharan Africa, the region worst hit by HIV and with a high TB prevalence, is recommended. A 40-year-old, HIV+ Zambian woman on Antiretroviral therapy for five years and IPT for three months presented with a four-day history of constipation, generalised body weakness and irrelevant talk. She complained of a generalised rash, sloughing off, and darkening of the skin on the face, neck, forearms, and dorsum of both feet. A physical examination revealed features of pellagra, and rapid response to oral niacin reaffirmed the diagnosis of pellagra. Unlike typical cases of pellagra presenting with the classic 3 Ds of Diarrhoea, Dementia and Dermatitis, our patient presented with constipation instead of diarrhoea. A consideration of Pellagra in HIV+ patients on IPT whose diet is mostly maize-based will be beneficial, even if the classic 3 Ds of diarrhoea, dementia, and dermatitis are not wholly present. A timely diagnosis and prompt treatment of pellagra can be lifesaving.

Pellagra a review exploring causes and mechanisms, including isoniazid-induced pellagra.

Pellagra is a clinical syndrome caused by a deficiency of niacin (nicotinic acid) and/or its precursor tryptophan. The cardinal manifestations are 4 D's: dermatitis, diarrhoea, dementia and in worst case death. Increased use of isoniazid prophylaxis along with antiretroviral therapy in countries where latent tuberculosis is common has been associated with increased presentations with pellagra.

Azathioprine-induced pellagra in neuromyelitis optica: A case report and review of literature.

Neuromyelitis optica (NMO), also known as Devic's disease, is a classical autoimmune disorder of the central nervous system (CNS). The relapsing-remitting disease course contributes to application of a variety of immunosuppressants to prevent further relapses after high-dose methylprednisolone pulse therapy for acute attacks. Azathioprine is one of the most widely used immunosuppressive drugs during the remission stage of NMO due to its good efficacy and favorable side-effect profile. Even if, enough attention should be paid to some rare but devastating adverse events, such as pellagra. Herein, we reported that a well-nourished patient experienced serious pellagra while receiving oral azathioprine for treating her NMO. Moreover, literature on azathioprine-induced pellagra was reviewed to raise concerns regarding patient safety.

Drug-induced photosensitivity: new insights into pathomechanisms and clinical variation through basic and applied science.

Drug-induced photosensitivity occurs when a drug is capable of absorbing radiation from the sun (usually ultraviolet A) leading to chemical reactions that cause cellular damage (phototoxicity) or, more rarely, form photoallergens (photoallergy). The manifestation varies considerably in presentation and severity from mild pain to severe blistering. Despite screening strategies and guidelines in place to predict photoreactive drugs during development there are still new drugs coming onto the market that cause photosensitivity. Thus, there is a continuing need for dermatologists to be aware of the different forms of presentation and the culprit drugs. Management usually involves photoprotection and cessation of drug treatment. However, there are always cases where the culprit drug is indispensable. The reason why some patients are susceptible while others remain asymptomatic is not known. A potential mechanism for the phototoxic reactions is the generation of reactive oxygen species (ROS), and there are a number of reasons why some patients might be less able to cope with enhanced levels of ROS.

Ethionamide-induced Pellagra.

Pellagra is a disorder characterized by dermatitis, diarrhea, dementia and eventually death, resulting from a deficiency of niacin or its precursor tryptophan. Ethionamide (a second-line antituberculosis agent)-induced pellagra is rarely encountered in clinical practice. Prompt diagnosis and treatment with nicotinamide can prevent life-threatening complications. To date, only three cases have been reported. We report a 13-year-old girl presenting with ethionamide-induced pellagra that resolved after the administration of niacin.

Phenobarbital-induced pellagra resulted in death.

Pellagra is caused by deficiency of niacin or its precursor tryptophan. While cutaneous lesions are the most prominent feature of the disease, gastrointestinal, neurological and psychiatric signs and symptoms are the other characteristics of the disease. In this case report, we present a 29-year-old female patient with discoloration of hands and feet diagnosed with pellagra.

Ethionamide-induced pellagroid dermatitis resembling lichen simplex chronicus: a report of two cases.

Pellagra is a niacin deficiency disorder characterized clinically by diarrhea, dermatitis, and dementia. However, few drugs also cause pellagroid dermatitis. Recently, we encountered two cases of pellagroid dermatitis; both were on second line of antituberculosis drugs. Case 1 was of multidrug-resistant pulmonary tuberculosis. Patient was on ethionamide since one year before developing pellagroid dermatitis. Case 2 was of central nervous system tuberculoma and was on second line of antitubercular drugs. This patient was on ethionamide and isoniazid (INH) since six months before developing pellagroid dermatitis. This patient had previously taken first line of antituberculous therapy, inclusive of INH, for 1 year without any dermatitis. The skin lesions in both patients were symmetric hyperpigmented thickened plaques with prominent skin markings resembling lichen simplex chronicus. Nicotinamide 300 mg in three divided doses healed the lesions completely within 4 weeks and 3 weeks in first and second patient, respectively.

Isoniazid-induced pellagra.

Pellagra is characterized by dermatitis, diarrhea, dementia and eventually death occurring as a result of niacin or its precursor tryptophan deficiency. Although pellagra is a well-known complication of isoniazid (INH) therapy, the clinical diagnosis may be missed or delayed that may cause life-threatening consequences. Due to the diversity of pellagra-related signs and symptoms, the diagnosis can be made with an appropriate index of suspicion. We report a 7-year-old boy presenting with INH-induced pellagra that resolved after the administration of the niacin therapy.

[Two cases of pellagra associated with chemotherapy of docetaxel, estramustine, dexamethasone].

An 81-year-old male with hormone refractory prostate cancer, received chemotherapy of Docetaxel, Estramustine and dexamethasone as an outpatient. After 4 courses of chemotherapy, he was admitted to our hospital in December 2007 because of general fatigue, appetite loss and erythema of the back of hands and face. He was diagnosed with pellagra. Nicotinic acid was administered and the symptoms disappeared. An 80-year-old male with hormone refractory prostate cancer, received chemotherapy of Docetaxel, Estramustine and dexamethasone without admission. After 8 courses of the chemotherapy, appetite loss appeared. In January 2008, medical examinations revealed nails peeling off, facial erythema and erosion of the back of his hands. He was diagnosed with pellagra. Nicotinic acid was administered and the symptoms disappeared. Pellagra, a nicotinic acid deficiency disease, is rarely observed clinically nowadays. However, it may occur in the patients, undergoing chemotherapy without admission.

EMLA cream-induced irritant contact dermatitis.

BACKGROUND: The Eutectic Mixture of Local Anesthetics (EMLA cream) is a topical anesthetic used for providing pain relief in patients undergoing superficial surgical procedures. Cutaneous side-effects have been reported rarely. CASE REPORT: We present a case of irritant contact dermatitis induced by EMLA cream in a 6-year-old boy with Wiskott-Aldrich syndrome. Our patient showed clinically a well circumscribed patch corresponding to the site of application of the topical anesthetic. Histopathology showed confluent necrosis of keratinocytes in the upper epidermis, a mixed inflammatory infiltrate with priminent neutrophils in the upper dermis, and focal signs of interface changes including basal cell vacuolization and subepidermal cleft formation. CONCLUSIONS: Graft-vs.-host-disease (GVHD), necrolytic migratory erythema, dermatitis enteropathica and pellagra should be considered in the histopathologic differential diagnosis of acute contact dermatitis caused by EMLA.