By Dean L. Winslow, MD, FACP, FIDSA

Professor of Medicine, Division of General Medical Disciplines, Division of Infectious Diseases and Geographic Medicine, Stanford University School of Medicine

Dr. Winslow reports no financial relationships relevant to this field of study.

SYNOPSIS: Two patients with Crimean-Congo hemorrhagic fever acquired in Spain are reported. The index patient acquired infection from a tick bite, and the second patient was a nurse who cared for the index patient. The first patient died in the hospital with multi-system organ failure and was diagnosed at autopsy. The second patient recovered with supportive care and was treated with ribavirin, but it was unclear whether the use of ribavirin was helpful.

SOURCE: Negredo A, de la Calle-Prieto F, Palencia-Herrejon E, et al. Autochthonous Crimean-Congo hemorrhagic fever in Spain. N Engl J Med 2017;377:154-161.

The index patient was a 62-year-old man from Madrid who presented with a two-day history of fever, abdominal pain, nausea, and diarrhea. After admission to the hospital, he rapidly developed purpuric skin lesions and hematomas at venipuncture sites, had evidence of severe coagulopathy and thrombocytopenia, and required transfer to the ICU. Four days before admission, his family reported that he had walked through fields in the province of Avila in central-western Spain and had removed a tick from his knee. By the seventh day of illness, his condition had deteriorated dramatically, with macroscopic hematuria, worsening purpura, hematomas, fulminant hepatic failure, acute respiratory distress syndrome (ARDS), encephalopathy, hypoglycemia, and severe metabolic acidosis. After transfer to a tertiary care hospital, he developed shock, acute renal failure, worsening acidosis, and died. Autopsy findings included generalized visceral edema, bloody ascites, extensive cutaneous and visceral hemorrhages, and hepatic necrosis. Retrospective analysis of serum samples obtained on the sixth and eighth day of illness revealed 1.0 × 108 and 1.2 × 109 viral copies of Crimean-Congo hemorrhagic fever (CCHF), respectively.

The second patient was a 50-year-old female nurse who had assisted during the endotracheal intubation of the index patient and during insertion of central venous and arterial lines. Although she did not sustain a puncture, she reported direct contact of index patient blood with her intact skin. Four days after the reported exposure, she developed fever, arthralgia, and myalgia. The following day, she presented to the hospital with petechiae, thrombocytopenia, and moderately elevated transaminases. On the third day of illness, vaginal bleeding developed. The next day, after her clinicians suspected CCHF, she was started on ribavirin 1,000 mg IV every six hours. On the sixth day of illness, the ribavirin dose was reduced to 500 mg IV every eight hours, and she was transferred to a tertiary care hospital in Madrid. She had mild acute kidney injury, some degree of hypoxic respiratory failure, in part related to a moderate-sized pleural effusion, but did not require mechanical ventilation. Her liver enzymes began decreasing by the ninth day of illness and her platelet count started to increase by day 11. Severe hemolysis necessitated discontinuation of ribavirin on day 9. Analysis of stored samples showed that her CCHF viral load was highest on the second day of illness, at 3.6 × 107 copies/mL. The first negative RT-PCR in serum was observed at day 20. Anti-CCHF antibodies were not detectable initially, but IgM antibodies increased to 1:640 on day 6 and started to decrease at day 15. IgG antibodies rose later and remained constant at 1:640. Vaginal, saliva, conjunctival, and rectal swabs were intermittently positive for CCHF virus by RT-PCR, but all of these body fluids were negative by day 14.

A total of 437 hospital personnel at the various hospitals that cared for these two patients were identified and of these, 386 were deemed to be at high risk of acquiring infection. None were observed to have acquired infection.

COMMENTARY

CCHF is a widely distributed viral infection seen in more than 30 countries in Africa, Asia, and the Middle East, but prior to these cases was seen only in the far Southeastern part of Europe (Russia, Ukraine, Bulgaria, Albania, Kosovo, Greece, and Turkey).

Humans acquire CCHF through tick bites or contact with viremic animals or humans.

As with other viral hemorrhagic fevers, heroic supportive care often is necessary for survival. It is interesting that the second patient was treated with ribavirin despite numerous studies and a meta-analysis showing that ribavirin is ineffective in CCHF.1 As my colleagues and trainees know, ribavirin treatment of viral diseases is one of my pet peeves. Ribavirin displays nonspecific antiviral activity against many DNA and RNA viruses in vitro. However, if one determines the TC50 (cytotoxicity) using a sensitive indicator of cytotoxicity, such as a tetrazolium assay (rather than the insensitive trypan blue dye exclusion), one usually finds that the TC50 and IC50 are very close. This is probably because ribavirin is not even acting as a viral polymerase inhibitor, but rather just making the cells sick by nonspecifically altering intracellular nucleotide pools. There is a certain philosophy among many clinicians that it is justifiable to “throw the kitchen sink” at very ill patients. However, I believe that with toxic drugs like ribavirin, this approach has significant potential for harm.

REFERENCE

  1. Soares-Weiser K, Thomas S, Thomson G, Garner P. Ribavirin for Crimean-Congo hemorrhagic fever: Systematic review and meta-analysis. BMC Infec Dis 2010;10:207.