Fungal Plant Pathogen at Heart of Meningitis Outbreak

The outbreak of fungal meningitis caused by contaminated methylprednisolone has topped 200 patients and is likely to include more, according to a review article on the subject published online in the New England Journal of Medicine. The article was written in an attempt to answer some of the "numerous questions have been raised by physicians, patients who received injections from the implicated lots, and the public."

Despite the fact that the first case reported found the mold Aspergillus fumigatus as the cause of the meningitis, this organism was not been detected in any of the subsequent 200-plus cases and is no longer considered as the basis for appropriate treatment. Instead, the fungal plant pathogen, Exserohilum rostratum, has been cultured or identified using polymerase chain reaction assay from cerebrospinal fluid in at least 25 patients and was detected in at least one unopened vial from the implicated lot of methylprednisolone, according to Dr. Carol A. Kaufman of the Veterans Affairs Ann Arbor (Mich.) Healthcare System, and her colleagues from Alabama and Texas.

E. rostratum is a "black mold" containing melanin in its cell wall. It is rarely infectious to humans and is usually restricted to mild diseases, such as allergic sinusitis, keratitis, and localized soft-tissue infection. In tissues, E. rostratum has the same appearance of irregular, beaded hyphae as seen in many other dematiaceous fungi, and unlike the rarely septate, ribbonlike hyphae of Mucorales fungi or the acutely branching, hyaline hyphae of aspergillus species.

Recommendations for treating this rare infection are based on small case series, individual case reports, and personal experience, according to the authors of the review article (N. Engl. J. Med. 2012 [doi:10.10156/NEJMra1212617]). The Centers for Disease Control and Prevention is providing information on the outbreak with daily updates, along with appropriate diagnostic testing and treatment details on its website, according to the authors.

Initially, when the causative agent was not known and the only detected microorganism was A. fumigatus, high doses of both liposomal amphotericin B and voriconazole were recommended. Once the primary pathogen was determined to be the black mold, however, monotherapy with voriconazole was recommended, except for the sickest patients or those who had substantial side-effects to the drug. For these, amphotericin B could still play a role, the said.

Although exserohilum species are susceptible to available antifungals, for some strains, the minimal inhibitor concentration for the usually recommended agents, including voriconazole, is increased. Thus, susceptibility testing is advised, they added.

Because of the potential toxic effects of voriconazole, especially in the large doses recommended, and the host of drug-drug interactions in which it is involved, prophylactic use is not recommended, the authors said. They noted that side effects included visual hallucinations, which have been noted in patients treated during the outbreak. Other side effects can include photopsia, nausea, and hepatic enzyme elevation.

"Without objective evidence of infection in the cerebrospinal fluid, treatment is not recommended. However, patients who have symptoms should be monitored closely, and if there is even subtle progression of symptoms, a repeat lumbar puncture should be performed immediately. If the number of white cells has increased [reaching 5 mm³or more], then empirical antifungal treatment should be initiated immediately," the authors stated.

"It is encouraging to note that clinically apparent disease has developed in only a small percentage of exposed patients. Management recommendations will almost assuredly change as more information becomes available regarding the pathogenesis of these infections," they concluded.

Dr. Kaufman and the other authors reported having no relevant disclosures for their review paper.

The outbreak of fungal meningitis caused by contaminated methylprednisolone has topped 200 patients and is likely to include more, according to a review article on the subject published online in the New England Journal of Medicine. The article was written in an attempt to answer some of the "numerous questions have been raised by physicians, patients who received injections from the implicated lots, and the public."

Despite the fact that the first case reported found the mold Aspergillus fumigatus as the cause of the meningitis, this organism was not been detected in any of the subsequent 200-plus cases and is no longer considered as the basis for appropriate treatment. Instead, the fungal plant pathogen, Exserohilum rostratum, has been cultured or identified using polymerase chain reaction assay from cerebrospinal fluid in at least 25 patients and was detected in at least one unopened vial from the implicated lot of methylprednisolone, according to Dr. Carol A. Kaufman of the Veterans Affairs Ann Arbor (Mich.) Healthcare System, and her colleagues from Alabama and Texas.

E. rostratum is a "black mold" containing melanin in its cell wall. It is rarely infectious to humans and is usually restricted to mild diseases, such as allergic sinusitis, keratitis, and localized soft-tissue infection. In tissues, E. rostratum has the same appearance of irregular, beaded hyphae as seen in many other dematiaceous fungi, and unlike the rarely septate, ribbonlike hyphae of Mucorales fungi or the acutely branching, hyaline hyphae of aspergillus species.

Recommendations for treating this rare infection are based on small case series, individual case reports, and personal experience, according to the authors of the review article (N. Engl. J. Med. 2012 [doi:10.10156/NEJMra1212617]). The Centers for Disease Control and Prevention is providing information on the outbreak with daily updates, along with appropriate diagnostic testing and treatment details on its website, according to the authors.

Initially, when the causative agent was not known and the only detected microorganism was A. fumigatus, high doses of both liposomal amphotericin B and voriconazole were recommended. Once the primary pathogen was determined to be the black mold, however, monotherapy with voriconazole was recommended, except for the sickest patients or those who had substantial side-effects to the drug. For these, amphotericin B could still play a role, the said.

Although exserohilum species are susceptible to available antifungals, for some strains, the minimal inhibitor concentration for the usually recommended agents, including voriconazole, is increased. Thus, susceptibility testing is advised, they added.

Because of the potential toxic effects of voriconazole, especially in the large doses recommended, and the host of drug-drug interactions in which it is involved, prophylactic use is not recommended, the authors said. They noted that side effects included visual hallucinations, which have been noted in patients treated during the outbreak. Other side effects can include photopsia, nausea, and hepatic enzyme elevation.

"Without objective evidence of infection in the cerebrospinal fluid, treatment is not recommended. However, patients who have symptoms should be monitored closely, and if there is even subtle progression of symptoms, a repeat lumbar puncture should be performed immediately. If the number of white cells has increased [reaching 5 mm³or more], then empirical antifungal treatment should be initiated immediately," the authors stated.

"It is encouraging to note that clinically apparent disease has developed in only a small percentage of exposed patients. Management recommendations will almost assuredly change as more information becomes available regarding the pathogenesis of these infections," they concluded.

Dr. Kaufman and the other authors reported having no relevant disclosures for their review paper.

The outbreak of fungal meningitis caused by contaminated methylprednisolone has topped 200 patients and is likely to include more, according to a review article on the subject published online in the New England Journal of Medicine. The article was written in an attempt to answer some of the "numerous questions have been raised by physicians, patients who received injections from the implicated lots, and the public."

Despite the fact that the first case reported found the mold Aspergillus fumigatus as the cause of the meningitis, this organism was not been detected in any of the subsequent 200-plus cases and is no longer considered as the basis for appropriate treatment. Instead, the fungal plant pathogen, Exserohilum rostratum, has been cultured or identified using polymerase chain reaction assay from cerebrospinal fluid in at least 25 patients and was detected in at least one unopened vial from the implicated lot of methylprednisolone, according to Dr. Carol A. Kaufman of the Veterans Affairs Ann Arbor (Mich.) Healthcare System, and her colleagues from Alabama and Texas.

E. rostratum is a "black mold" containing melanin in its cell wall. It is rarely infectious to humans and is usually restricted to mild diseases, such as allergic sinusitis, keratitis, and localized soft-tissue infection. In tissues, E. rostratum has the same appearance of irregular, beaded hyphae as seen in many other dematiaceous fungi, and unlike the rarely septate, ribbonlike hyphae of Mucorales fungi or the acutely branching, hyaline hyphae of aspergillus species.

Recommendations for treating this rare infection are based on small case series, individual case reports, and personal experience, according to the authors of the review article (N. Engl. J. Med. 2012 [doi:10.10156/NEJMra1212617]). The Centers for Disease Control and Prevention is providing information on the outbreak with daily updates, along with appropriate diagnostic testing and treatment details on its website, according to the authors.

Initially, when the causative agent was not known and the only detected microorganism was A. fumigatus, high doses of both liposomal amphotericin B and voriconazole were recommended. Once the primary pathogen was determined to be the black mold, however, monotherapy with voriconazole was recommended, except for the sickest patients or those who had substantial side-effects to the drug. For these, amphotericin B could still play a role, the said.

Although exserohilum species are susceptible to available antifungals, for some strains, the minimal inhibitor concentration for the usually recommended agents, including voriconazole, is increased. Thus, susceptibility testing is advised, they added.

Because of the potential toxic effects of voriconazole, especially in the large doses recommended, and the host of drug-drug interactions in which it is involved, prophylactic use is not recommended, the authors said. They noted that side effects included visual hallucinations, which have been noted in patients treated during the outbreak. Other side effects can include photopsia, nausea, and hepatic enzyme elevation.

"Without objective evidence of infection in the cerebrospinal fluid, treatment is not recommended. However, patients who have symptoms should be monitored closely, and if there is even subtle progression of symptoms, a repeat lumbar puncture should be performed immediately. If the number of white cells has increased [reaching 5 mm³or more], then empirical antifungal treatment should be initiated immediately," the authors stated.

"It is encouraging to note that clinically apparent disease has developed in only a small percentage of exposed patients. Management recommendations will almost assuredly change as more information becomes available regarding the pathogenesis of these infections," they concluded.

Dr. Kaufman and the other authors reported having no relevant disclosures for their review paper.