references. On closer examination, some 1,200 references appeared to provide the requisite types and quality of scientific evidence for this study.

Assessing the Strength of the Evidence

By evaluating the evidence in the published scientific literature, the committee determined the relationships between each of the nine diseases of interest and specific adverse health outcomes that might appear weeks to years after the primary infection. Those relationships are conceived in terms of the strength of association between the primary infection and a specific long-term adverse health outcome.

The committee framed its conclusions in categories, described below, that qualitatively rank the strength of the evidence of an association. Used by many previous IOM committees, including those in the Gulf War and Health series, this five-tier framework was adapted from the system used by the International Agency for Research on Cancer to evaluate evidence of the carcinogenicity of various agents.


Sufficient Evidence of a Causal Relationship

The evidence is sufficient to conclude that there is a causal relationship between exposure to a specific agent and a specific health outcome in humans. The evidence is supported by experimental data and fulfills the guidelines for sufficient evidence of an association (defined below). The evidence must be biologically plausible and must satisfy several of the guidelines used to assess causality, such as strength of association, a dose– response relationship, consistency of association, and a temporal relationship.

The committee concludes that there is sufficient evidence of a causal relationship between

  • Coxiella burnettii infection (Q fever) and osteomyelitis.

  • Malarial infection and

    • Ophthalmologic manifestations, particularly retinal hemorrhage and scarring, recognized for the first time months or years after the infection.

    • Hematologic manifestations weeks or months later, particularly anemia after falciparum malaria and splenic rupture after vivax malaria.

    • Renal disease, especially the nephrotic syndrome that may occur weeks to months after acute infection.

    • Late presentation of disease (Plasmodium malariae) or relapse of disease (Plasmodium ovale or Plasmodium vivax) months to years after acute infection.

  • Mycobacterium tuberculosis infection and occurrence of active TB months to decades after infection.

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